Hiv 1nnrtis

HIV-1 NNRTIs: Structural Diversity,
Pharmacophore Similarity, and

Implications for Drug Design
Peng Zhan,1 Xuwang Chen,1 Dongyue Li,1 Zengjun Fang,1 Erik De Clercq,2
and Xinyong Liu1
1
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan,
Shandong, P.R. China
2
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium
Published online 26 April 2011 in Wiley Online Library (wileyonlinelibrary.com).

DOI 10.1002/med.20241
.
Abstract: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent very potent and
most promising anti-AIDS agents that specically target the HIV-1 reverse transcriptase (RT). However,
the effectiveness of NNRTI drugs can be hampered by rapid emergence of drug-resistant viruses and severe
side effects upon long-term use. Therefore, there is an urgent need to develop novel, highly potent NNRTIs
with broad spectrum antiviral activity and improved pharmacokinetic properties, and more efcient
strategies that facilitate and shorten the drug discovery process would be extremely benecial. Fortunately,
the structural diversity of NNRTIs provided a wide space for novel lead discovery, and the pharmacophore
similarity of NNRTIs gave valuable hints for lead discovery and optimization. More importantly, with the
continued efforts in the development of computational tools and increased crystallographic information on
RT/NNRTI complexes, structure-based approaches using a combination of traditional medicinal chem-
istry, structural biology, and computational chemistry are being used increasingly in the design of NNRTIs.
First, this review covers two decades of research and development for various NNRTI families based on
their chemical scaffolds, and then describes the structural similarity of NNRTIs. We have attempted to
assemble a comprehensive overview of the general approaches in NNRTI lead discovery and optimization
reported in the literature during the last decade. The successful applications of medicinal chemistry stra-
tegies, crystallography, and computational tools for designing novel NNRTIs are highlighted. Future
directions for research are also outlined. & 2011 Wiley Periodicals, Inc. Med. Res. Rev., 33, No. S1, E1E72, 2013
Key words: HIV-1; RT; NNRTIs; drug resistance; drug design; medicinal chemistry; crystallography;
computational chemistry
Contract grant sponsor: National Natural Science Foundation of China (NSFC); Contract grant numbers: 30873133; 30772629;
30371686; Contract grant sponsor: Key Project of NSFC for International Cooperation; Contract grant number: 30910103908; Con-
tract grant sponsor: Research Fund for the Doctoral Program of Higher Education of China; Contract grant number: 070422083;
Contract grant sponsor: Independent Innovation Foundation of Shandong University (IIFSDU); Contract grant number:
2010GN044; Contract grant sponsor: Shangdong Postdoctoral Innovation Science Research Special Program; Contract grant number:
201002023; Contract grant sponsor: China Postdoctoral Science Foundation; Contract grant number: 20100481282.
Correspondence to: Xinyong Liu, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University,
44,West Culture Road, 250012, Jinan, Shandong, P.R. China, E-mail: xinyongl@sdu.edu.cn
Medicinal Research Reviews, 33, No. S1, E1E72, 2013

& 2011 Wiley Periodicals, Inc.
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1. INTRODUCTION
Human immunodeciency virus type 1 (HIV-1) reverse transcriptase (RT) is a primary target
for antiretroviral chemotherapy. HIV-1 nonnucleoside reverse transcriptase inhibitors
(NNRTIs) are important in the drug combination therapies (namely, highly active anti-
retroviral therapy) currently used to treat HIV infection and AIDS due to their unique
antiviral activity, high specicity, and low toxicity.13 Nevertheless, drug resistance is still the
main reason of failure for their anti-HIV infection efcacy. Three NNRTIs clinically used
(efavirenz, nevirapine, and delavirdine) could effectively inhibit proliferation of the wild-type
(WT) HIV, but they are less effective against clinically important RT mutant viruses, such as
Y188C, Y181C, K103N, and L100I, which are involved in high-level resistance to most
current NNRTIs.2 Although the newly approved etravirine (Fig. 1) shows improved potency
against many drug resistance mutations, it lacks the convenience of once-daily dosing and is
also involved in cutaneous and hypersensitivity.4 In addition, efavirenz, as the most pre-
scribed NNRTI, is associated with side effects including dysfunction of central nervous
system and teratogenicity.5 Therefore, there is compelling need for the discovery of next
generation NNRTIs that possess an improved safety property with the convenience of once-
daily administration and high activity against drug-resistant mutant viruses.6
NNRTIs are targeted at a specic and allosteric binding site (an especially exible pocket
formed upon binding the inhibitor) situated about 10 A from the polymerase catalytic site
within the HIV-1 RT. One of the main issues in computational NNRTIs drug design is
incorporation of the inherent exibility of the NNRTIs binding pocket (NNIBP). This is
especially crucial in ligand binding process, when induced t can lead to structural re-
arrangement of RT. Although current computational methods (such as docking) deal with
exible ligands, it is very challenging to manage receptor exibility.79 To date, the advances
in the medicinal chemistry of HIV-1 NNRTIs have relied mostly on ligand-based design.
The exibility of the binding pocket in RT resulted in the structural and chemical diversity
of NNRTIs, providing a wide opportunity for novel scaffold discovery. Although they are
structurally quite diverse, all NNRTIs bind in the NNIBP in a similar conformation and in
identical fashion, providing valuable information on NNRTI lead discovery and optimization.
Furthermore, with the continued efforts in the development of computational tools and in-
creased structural information on RT, coordinated multidisciplinary effort involving tradi-
tional medicinal chemistry (SAR analysis, bioisosteric replacement, molecular hybridization,
scaffold hopping, multi-target/multivalent drug design, etc.), structural biology (crystal-
lography), and computational chemistry (molecular modeling) have proven to be powerful
strategies to handle exibility of the NNIBP and to identify novel NNRTIs with high antiviral
activity against WT and mutant viruses, and improved pharmacokinetic proles (Fig. 2).
Me
CN CN
Me
HN
N
N Me Me
N
N O F3C O N NH
N H Cl
Me S N N O
N
O Br
N N O
H O N O
Me CH3SO3H H NH2
H
1, Nevirapine 2, Delavirdine 3, Efavirenz 4, Etravirine/TMC-125
Figure 1. Chemical structures of NNRTIs approved by the FDA for HIV-1 treatment.
Medicinal Research Reviews DOI 10.1002/med

HIV-1 NNRTIs K E3
RT
Mutations in NNIBP Flexibility of NNIBP
NNRTIs
Pharmacophore
Drug Resisitance Structural Diversity Similarity
Necessity Feasibility Inspiration
NNRTIs Leads Discovery and Optimization
Medicinal Chemistry Crystallography Computational Chemistry
Bioisosterism Principle The Explanation of QSAR Molecular Docking

RT/NNRTI Interaction
Database Searching
Molecular Hybridization Concept
The Identification of Pharmacophore Modeling
Scaffold Hopping Tolerate Region in NNRTI
De Novo Methodologies
Prodrug Approach
Structural Basis Free Energy Perturbation
Multiple Ligands Design
QM/MM calculations
Multivalency Theory Strategies Tools
Multidisciplinary Coordination
Figure 2. The paradigm for NNRTI lead discovery and optimization. [Color figures can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
In this review article, we will rst describe the structural diversity and the pharmaco-
phore similarity of NNRTIs, as well as the implications for drug design. Then, the following
sections will emphasize recent research approaches in NNRTIs lead discovery and mod-
ications. Especially, the application of the medicinal chemistry strategies in the structural
modications will be discussed with the aid of illustrative examples.
2. STRUCTURAL DIVERSITY OF NNRTIS
Currently, more than 50 structurally diverse classes of compounds have been identied as
genuine NNRTIs (Table I), which specically suppress HIV-1 replication and are targeted at
the NNIBP.1017 These compounds can be divided into two classes: the rst generation
NNRTIs (exemplied by HEPT and TIBO), originally obtained by fortuitous discovery
(HEPT) or targeted screening, and showed a dramatic decrease of activity against single
point mutations in the NNIBP, and the second generation NNRTIs, discovered as a result of
comprehensive strategies involving computational chemistry (molecular modeling), struc-
ture-based rational drug design and synthesis, and biological and pharmacokinetic assays.
Generally, second generation NNRTIs tend to be more active against WT and broad-
spectrum HIV-1 drug-resistant strains than the rst generation compounds.
Based on the types of the chemical scaffolds, the structural classes of NNRTIs can
be devided into: multicyclic scaffolds, benzo-fused heterocyclic scaffolds, six-membered
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Table I. Overview of the Structural Classes of NNRTIs
Chemical General Representative

scaffolds NNRTIs families abbreviation compounds References
18a,b
Multicyclic Tetrahydromidazo [4,5,1-jk][1,4] TIBO 5a, Tivirapine
scaffolds benzodizepin-2(1H)-one
19
Dipyridodiazepinone 1, Nevirapine
20
Indolyldipyridodiazepinone 6
21a,b
Thiazolobenzimidazole TBZ 7, NSC 625487
Thiazolo-iso-indolinone 8, BM 151.0836 22
23
Pyrrolobenzodiazepinone 9
24
Imidazodipyridodiazepine 10, UK-129,485
25
Arylpyrido(thio)diazepine 11, MEN 10979
26a,b
Pyrrolobenzoxazepinone 12
27
Indolobenzothiazepine 13
28
Imidazopyridazine 14
29
Trioxothienothiadiazine TTD 15, QM96521
30
Imidazoquinazoline 16
31
Pyrido[1,2a]indole 17, BCH-4989
32
Tricyclic benzothiophene 18, NSC-380292
33a,b
Coumarin 19, Calanolide A
33bd
20a, DCK
34
5H-Pyrrolo[1,2-b] PBTD 21
[1,2,5]benzothiadiazepine
35
Pyranoquinazolinones 22
36
Dihydro-1H-pyrido[3,2-b]indole 23, VRX-329747
37a,b
Benzo-fused Bisheteroarylpiperazine BHAP 2, Delavirdine
38
heterocycles Quinoxaline 24a, HBY 097
39a,b
Indole carboxamide 25, L-737,126
40
Benzothiadiazine 26,
41
Quinazolinone 27a
42
Benzoxazinone 3, Efavirenz
43
Benzothiadiazepine 28
44
Oxindoles 29a
45a
Quinolones 30
45b
31
45c
32
46
Benzimidazolones 33a
47
1-(2,6-Diuorobenzyl)-2-(2, BPBIs 34
6-diuorophenyl)benzimidazoles
48
Six-membered Diaryltriazine DATA 35
49a,b
heterocycles Diarylpyrimidine DAPY 4a, TMC125
50
core Diarylpyrazinone 36
51
Diarylpyridine 37
52
Diarylaniline 38
53
1-[(2-Hydroxyethoxy)methyl]-6- HEPT 39a, HEPT
(phenylthio)thymine derivatives
54
Alkoxy(arylthio)uracil 39b
55a,b
Dihydroalkoxybenzyloxypyrimidine DABO 40ac
56ac
Pyridinone 41a, L-697,661
57a,b
Benzylthiopyrimidine 42a, U-31355
(Pyrimidinethioethers)
58
Furopyridinylthiopyrimidinamine 42d, PNU-142721
59ac
Diarylamines (HetNHPhU) 43

HIV-1 NNRTIs
HIV-1 NNRTIs K K 5
E5
Table I. Continued
Chemical General Representative

scaffolds NNRTIs families abbreviation compounds References
60
Five-membered Thiadiazolyl dialkylcarbamate TDA 44, RD-4-2024
61a,b
heterocycles Highly substituted pyrrole 45a, 45b
62ac
core Azoles 46
63ac
Imidazole 47, S-1153
64
1,5-Diphenylpyrazole 48, PNU-32945
65
Diarylthiazolidinone 49a
66a,b
N-Aryl pyrrolidinone 50
67ah
Sulfanyltriazole/tetrazole 51a, VRX-480773
51b, RDEA806
68a,b
Thiazolidenebenzenesulfonamide 52ac
(Thio)amide a-Anilinophenylacetamido a-APA 53, Loviride 69
linker (a-APA, R89439)

70
containing Imidoyl thiourea ITU 54
71
scaffolds Thiocarboxanilide 55, UC-781
72ac
Phenethylthiazolylthiourea PETT 56a, Trovirdine
(LY 300046)
73
Quinoxalinylethylpyridylthiourea QXPT 56b, 6-FQXPT
74ad
Urea-PETT analogues 56c, MSC-204;
56d, MSC-372
(PETT-5)
75
O-Phthalimidoethyl- TC 57ac
N-arylthiocarbamate
76
Diphenyl Alkenyldiarylmethane ADAM 58a
77
scaffolds Tetrahydronaphthalene lignan 59a
78
Sulfonylbenzonitrile 60
79
Indazole 61a, 61b
80
Benzophenone 62a
81
Diaryl ether 63a
82
1-[2-(Diphenylmethoxy)ethyl]-2- DAMNI 64
methyl-5-nitroimidazole
83
Others Hexahydroxybiphenyl derivatives 65a, 65b
20 ,50 -Bis-O-(tert-butyldimethylsilyl)- TSAO 66, TSAO-m3T 84ac
30 -spiro-500 -(400 -amino-100 ,200 -

oxathiole-200 ,20 -
dioxide)pyrimidine
heterocyclic core scaffolds, ve-membered heterocyclic core scaffolds, (thio)amide linker

containing scaffolds, diphenyl scaffold, and so on. As shown in Table I, the prototype
leads or the promising candidates are selected as representatives in each class of NNRTIs
(Figs. 39).
As is well known, the current anti-AIDS drug research priorities are looking actively for
new drugs from the original leads and complex prescription for management of HIV infection
effectively, as well as against various mutant viral strains. In addition to the four approved
NNRTIs, a few more candidates are in clinical stage. Ideally, in order to be considered a bona
de candidate drug, a compound of interest must meet all the following criteria.10d (1) High
level of activity against key mutants (i.e. K103N and Y181C) resistant to other NNRTIs
without allowing breakthrough; (2) excellent oral bioavailability, and prolonged duration
6E6 K K ZHAN
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Me H
Me N Me F
N
Me N N
N N N N
F
Cl N S
N
S
N N
N H O O
H Me Me N
5a, Tivirapine (R 86183) 1, (Nevirapine, BI-RG-587) 6 7, NSC 625487
Me Me Me N
N
Me N
O MeO N N N
S
N S
N N N
N N S
H Me Me
O
O
8, BM +51.0836 9 10, UK-129,485 11, MEN 10979
O N
Me N
O S N
O
Cl N
N NH
N
O N O
H Me O
12 13 14
O O N Me Me
Cl
S N
N O
S N
7b
N O O OMe
N O 2a
O
O HO S
CN
MeO
15, QM96521 16 17, BCH-4989 18, NSC-380292
O
Me O
N
Me Me Cl S N
O
N
O O
Me CF3
Cl
O O O 21 NH
O 2N
O O O
Me OH Me N O
H
Me Me O Me
Me 22
19, (+)-Calanolide A O O O
Me O O N
Me O
CN
Me O
N
Me O H
20a, DCK 23, VRX-329747
Figure 3. Chemical structures of NNRTIs with multicyclic scaffolds.
of potency; (3) signicantly decreased toxicity; and (4) easy of synthesis and formulation.
Obviously, the more requirements a selected drug meets, the more success it will have in the
clinical setting and in the global market as the miracle drug for the treatment of AIDS.
HIV-1 NNRTIs
HIV-1 NNRTIs K K 7
E7
Me
Me
Me Me
HN
N O O
N
O O
O MeO N S S
H O
SMe Cl NH N
Me S N N
O N S N S
N O H N O H
CH SO H H
H
2, Delavirdine (U-90152) 24a, HBY 097 25, L-737,126 26, NSC 287474
OEt
Me
O
N O O Me
FC
Cl Cl Cl S N Br
NH O
Me O
N N N N
H H H O H
27a 3, Efavirenz 28 29a
Me
Me
R Me Me
Cl CO R O S O
X N O S
O Me
Cl R MeO OH Cl N
N O
H O
R = (CH ) CHCH , nPent N
N O O
R = Et, Me, Allyl H H
30 31 32 33a
F F
F
F F F F
N N
Cl N F
O N Me N
N F F
H Me
O O
33b 34a 34b
Figure 4. Chemical structures of NNRTIs with benzo-fused heterocyclic scaffolds.
3. COMMON FEATURES OF NNRTIs
NNRTIs, although belonging to a wide range of structurally diverse scaffolds, contain many
ubiquitous fragments in their structures and possess a common pharmacophore model,
including an aromatic ring able to participate in p-p stacking interactions, amide or thioamide
moieties capable of hydrogen bonding, and one or more hydrocarbon-rich domain that
participate in hydrophobic interactions. In addition, the interactions with RT show similar
binding mode which is considered reminiscent of a buttery with one body and two
hydrophobic wings.
A. Ubiquitous Fragments (Motifs) in NNRTI Scaffolds

The existence of ubiquitous motifs in NNRTIs is very similar with the concept of privileged
structures85,86 in medicinal chemistry. For instance, para-substituted aniline motif exists in
multicyclic-typed NNRTIs (i.e. tivirapine) and many second generation NNRTIs with
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N N N N
N N N N N
Me
Me Me Me Me
Me Me O N NH O N NH Me Me Me Me
N NH O N NH O NH
N
Br Me N O
N N
NH Me NH ON NH
35 4a, TMC 125 36 37 38
O O Me O
Cl
Me R'
HN HN Me HN
R'' R N
O N S O N S X N H
N
HO O Me O
Cl
O Me
40a, DABO (X = O) Me N O
Me Me 40b, S-DABO (X = S) H
39a, HEPT 39b 40c, N-DABO (X = N) 41a, L-697,661
Me
Cl Cl
Me
N N
Me H O
N
HN N S HN N S R
Het
O N N
42d, PNU-142721
H 43
42a, U-31355 (S)-(-)-enantiomer
Figure 5. Chemical structures of NNRTIs with six-membered heterocycles core scaffolds.
benzo-fused heterocyclic scaffolds (i.e. efavirenz, HBY 097), and (thio)amide linker con-
taining scaffolds (i.e. UC-781, trovirdine) (Fig. 10A). A diphenyl, substituted thiourea
functional group, a (thio)acetamide linker, and a nitrile-containing aromatic (not shown), are
also ubiquitous motifs in many NNRTI families (Fig. 10BD). Structural similarity is
remarkable among the NNRTIs with different chemical scaffolds (Fig. 10EG). Otherwise,
the usage of three different drug design strategies, bioisosteric principle, de novo design
approach, and pharmacophore-based virtual screening, resulted in the same quinolone
scaffold NNRTIs 3032, respectively, illustrating the structural similarity of NNRTIs.
Based on the fragment-based ligand discovery strategy,87 the ubiquitous motifs derived
from databases of known NNRTIs with high potency against WT and drug-resistant variants
of HIV-1 RT, high oral bioavailability and favorable pharmacokinetics, can be used as basic
fragments for the generation of privileged scaffolds libraries that are capable of providing
high-quality NNRTI hits. In fact, the computational tools of understanding bioactive mo-
lecular similarity has been employed in the colonization of the existing chemistry space for
each molecular scaffold and in association with de novo drug design45b,59a and classical
medicinal chemistry concepts (such as molecular hybridization) has assisted the rational
design of new drug-candidate prototypes against WT and key mutant viruses. The method
can be easy to put in place, and is fast enough to be iteratively applied to different sources of
drug-like molecules.
B. Molecular Modeling (From Buttery to Horseshoe)

On the basis of molecular modeling and X-ray crystallography investigations on nevirapine
(1), TIBO (5b) and 8b, Schafer et al. proposed a three-dimensional (3D) model describing the
HIV-1 NNRTIs
HIV-1 NNRTIs K K 9
E9
Me
Me
Me Me
N N
S N
OMe O
N O S
O Me O
N NH
Me O
Cl Cl
N
Me OMe Me N O
H
O O
44, RD4-2024 45a 45b
Cl Cl
N Cl
Me
R R
S N N
NH Cl
N
O NH O N
Me N N
O S
X N
Me Me CN O
X = CH, N
46 47, Capravirine (AG1549) 48, PNU-32945 49a
O NH
N N Cl
H O Me
N N S
N Br S R S
N
O N Me
O
R
MeO CN Me Me
O
52a: R = Cl. EC = 1.7 nM, SI > 15000
51a, VRX-480773, (R = SO NH ) 52b: R = Br. EC = 2.1 nM, SI > 12000
50 51b, RDEA806, (R = COOH) 52c: R = CN. EC = 1.8 nM, SI = 6100
Figure 6. Chemical structures of NNRTIs with five-membered heterocycles core scaffolds.

N
Me
N
Cl Me O Me
H O
N O Br
Cl Cl HN
Cl N
H Me S
Cl N NH
HN O N
H
Me NH S N S
H
53, Loviride (-APA, R89439) 54 55, UC-781 56a, Trovirdine (LY 300046)
Me Me
O O
N O
OH
O N
N O
X
F F F O
Br HN Br HN NC HN
N N N N S
S O O H
N N N
H H H 57a, TC-1, X = Cl, EC = 40 nM
56b, 6-FQXPT 56c, MSC-204 56d,MSC-372 57b, TC-2, X = Br, EC = 30 nM
(Active metabolite of PETT-4) (PETT-5) 57c, TC-3, X = I, EC = 20 nM
Figure 7. Chemical structures of NNRTIs with (thio)amide linker containing scaffolds.

10
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COOMe COOMe MeO Br NC CN

MeO OMe S
MeO F
O
Br Br OMe O S Me O
CN
MeO OMe R
OMe NH N NH
58 a 59a 60 61a: R = Me, RT IC = 50 nM

MeO 61b: R = Et, RT IC = 25 nM
O
H Cl CN Me
N
O O O
C N
O N

A B O O NH
N ON
MeO
Me N Me Cl
62a 63a 64, RS1478
Figure 8. Chemical structures of NNRTIs with diphenyl scaffolds.
OMe O
Br Me
O HN
O COOMe O N
O COOMe Me2(t-Bu)SiO O
H 2N
O R
O OSi(t-Bu)Me2
OMe S
O
O
65a: R = H
65b: R = Br 66, TSAO-m3T
Figure 9. Chemical structures of NNRTIs with other scaffolds.
structural elements that were critical determinants for anti-HIV-1 activity (Fig. 11)88: a
central lipophilic domain (body) to which are attached two hydrophobic (normally a
benzene ring and an extended p system) moieties (wings), as in a buttery-like
orientation. Moreover, an additional lipophilic region, such as a carbonyl or thiocarbonyl
group, should be adjacent to the benzene ring. Other NNRTIs, such as a-APA, DABO, TBZ,
and TTD, are examples of agents conformationally related to nevirapine and TIBO. Taking
account the buttery-like conformation as determinant for anti-HIV-1 activity, many
novel families of NNRTIs were initially designed, such as 1-[2-(diarylmethoxy)ethyl]-2-me-
thyl-5-nitroimidazoles (DAMNIs).
Another buttery-like model was derived utilizing eight well-known NNRTIs, i.e. ne-
virapine (1), delavirdine (2), efavirenz (3), indole carboxamide (25), benzothiadiazine-1-oxide
(26), thiocarboxanilide (44), loviride (53), and trovirdine (56a).89 As shown in Figure 12, the
3D-pharmacophoric distance model proposed may be considered reminiscent of a butter-
y with a hydrophilic center (body: amide or thioamide groups) and two hydrophobic
outskirts (wings), one of which is usually substituted by a halogen atom.
HIV-1 NNRTIs K E11
A C NH
N
R
Br N
HN
N O (S) Cl N S
H
N N S
H
PETT (LY 300046) U-31355
B
Me Me
R R
N O
X Me S
X = C, O, SO N
Cl N
S N S
H
N
H
R 86183 NSC 287474
D Me Me N O NH
Cl
Me
Me N
N N
S S N
Cl
N N N MeO
S S
Me O
O O
8, BM +51.0836 11, MEN 10979 49a 50
N N Cl
H H
N N
Br N S O O
C
O O
SO NH
A B
MeO
Me N Me
51a, VRX-480773 62a
Me
E Me
Me Me Me
O N
Me O O
O S Me
Cl N Cl N Cl Me
O S
N N N S
H H H
R 86183 55, UC-781
33
F O
Me CN
Me NC
R R
F
Me Me N
O NH
N NH
HN NH
X N
N N
X = CH, N O
35 46 56d, MSC-372
Me
G Me
Me Br
Me
Me Me
N O
O O S O
O S
S Me O N O S Me O
O O S Me
Cl NH
NH MeO OH Cl N
CN
N O
N Me N
O H O N
H O H
O NH
25, L-737,126 45b 32 33a 60
Figure 10. Some ubiquitous fragments (motifs) and structural similarity in different NNRTI scaffolds: (A) para-substituted
aniline motif; (B) diphenyl scaffold; (C) substituted thiourea; (D) (thio)acetamide. [Color figures can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]

E12 K ZHAN ETAL.
Me
Me
Me
N
N N N
Lipophilic
S region
Benzene ring Extended -system
N or aromatic ring
N N
H O S
Me 4.5--5A
N
H O CH
O 108--115
(Thio) carbonyl Methyl or other group
1, Nevirapine 5b, TIBO 8b or sulphonyl Linked at -system
Figure 11. The common three-dimensional model derived from the comparison of 1, 5b, and 8b (see text). [Color figures can
be viewed in the online issue, which is available at wileyonlinelibrary.com.]
It must be pointed out that these two buttery-like molecular models were derived from
ligand-based pharmaphore modeling. As a wealth of crystal structures of RT-NNRTI
complexes were reported,9092 the buttery-like conformation of NNRTIs with different
structural classes has been conrmed by crystallographic analysis. For instance, the rst-
generation NNRTI nevirapine and the recently approved etravirine can be superimposed in a
two-wing binding mode (compare the superposition gure of nevirapine with etravirine).12
Comparing the conformation of ten NNRTIs (nevirapine, delavirdine, efavirenz, a-APA,
BM121.1326, 9-Cl-TIBO, PETT-2, UC-781, MKC-442, and capravirine (S-1153)) when
bound with RT also disclosed a high degree of inhibitor overlap causing a buttery-like
conguration separated by a linker (body), where planes of the wings are separated by
1201 (compare two orthogonal views of ten NNRTIs in NNIBP).93
The RT-bound conformation of the ITU/DATA/DAPY NNRTIs resembles a U or
horseshoe, in contrast to the above-mentioned buttery-like shape.49b
There are important differences in the conformations of these two models (buttery
and horseshoe) and specic positioning within the NNIBP. For instance, the horseshoe
model could adapt to the plasticity and changes of the NNIBP better, which appear to be
critical for potency against WT and a wide range of drug-resistant mutant HIV-1 RTs.
C. 3D Pharmacophore Model of NNRTIs

Based on the crystallographic structures of RT-NNRTI complexes and computational stu-
dies, it has been demonstrated that the buttery-like or horseshoe NNRTIs also share
the common binding mode with NNIBP (the key interactions involved in binding sum-
marized in Table II)94,95 and 3D pharmacophore model (illustrated in Fig. 14),96,97 which is
the spatial arrangement of key chemical features: hydrophobic domain, hydrogen bond
acceptor, and donor. The hydrophobic domain lls the hydrophobic subpocket consisted of
the residues Y181, Y188, F227, and W229 (Fig. 13). The hydrogen bond acceptor and donor
form a key hydrogen bond with the backbone imino and carbonyl groups of K101 (or K103)
residue (directly or via a structural water molecule). The derived pharmacophore model can
facilitate insight into the detailed interactions between NNRTIs and RT, and to design the
next generaction of NNRTIs.
As is well known, perceiving a pharmacophore is the rst essential step towards un-
derstanding the receptorligand interaction. Other similar pharmacophore models for
NNRTIs were also obtained.45c,46,98100 As the pharmacophore-based virtual screening has
evolved into one of the well-established computational tools in rational drug design, this
technology could be used for obtaining new potentially active NNRTIs, lead optimization, as
well as combinatorial library focusing (will be described in detail in the following section).
HIV-1 NNRTIs K E13
Me
Me
HN
N
N
N
O O
N N H FC S
Cl O
Me S N N O Cl NH
O
N N N O
H O O N O
Me CH SO H H H
H
1, Nevirapine 2, Delavirdine 3, Ef avirenz 25, L-737,126
Me
Me N
N Cl Me O
S N
O O H
S N
O N
N Br HN
N
Cl Cl Cl S
N S HN O
H N
H
Me
26, NSC 287474 44, RD4-2024 53, Loviride 56a, Trovirdine
Molecular mechanics calculations
Geometrical optimization
Uniform sampling of low energy conformers
Mapping the essential structural components
Hydrophilic site
A
4.2 - 6.7 A 9.12 - 9.44 A
114-119
B C
4.25 - 7.6 A
Lipophilic site Lipophilic site
Figure 12. Schematic representation of the pharmacophoric distance map derived from eight well-known NNRTIs.89 In general,
NNRTIs consistoftwo hydrophobic moieties (wing I and wing II) connected by a polar central body. [Color figures can be viewed inthe
online issue, which is available at wileyonlinelibrary.com.]
D. General Types of NNIBP

There are subtle differences in the conformation of the NNIBP which mainly rely on the
NNRTI itself. The size and volume of the NNIBP are remarkably affected by the re-
positioning of b10 strand (residues 232234) and b11 strand (residues 239241) and the
moving of the P236 hairpin loop, as veried by crystallographic studies.101 Consequently,
it is commonly accepted that various NNRTI pockets can be divided into two discrete
binding modes. The rst mode is a small NNRTI (such as nevirapine)-type binding pocket
(PDB code 1VRT) in which there is a main chain hydrogen bond between the carbonyl

E14 K ZHAN ETAL.
Table II. The Key Interactions Involved in Binding to HIV RT and Denition of Pharmacophore
Points94,95
Pharmacophore
points Groups Interaction
Hydrogen bond OH, SH, NH Donor to K103 (1EP4, 1KLM)

donors or K101
Hydrogen bond (Thio)carbonyl, ester, sulfone O in ether, Acceptor to K103 (1EP4, 1KLM)
acceptors Pyridine N atom, N, O in aromatic or K101
5/6-membered rings
Hydrophobic Aliphatic or aromatic rings, Double and Hydrophobic interaction with Y188,
domains triple CC bonds, CF3, Aliphatic chains Y181, W229, F227, L100, L234,
V106, Y318
W229 Wing I Wing II

CN CN
Y188 HN
OH Me Me
Y181 Hydrophobic domain O N N
OH Me H
Cl N
Me Br
NH2
N
TMC125 (4)
Me N N
H Hydrogen bond donor
9-Cl-TIBO (5b)
S
Hydrogen bond acceptor O
H
N
K101
Figure 13. Positioning of NNRTI binding into NNIBP by mapping of the pharmacophore points (exemplified by 9-Cl-TIBO
and TMC125).96,97 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
oxygen of P236 and the nitrogen of K103. The second mode is a larger NNRTI [such as
delavirdine (PDB code 1KLM) or 1-(2-hydroxyethoxymethyl)-6-(phenylthio) thymine
(HEPT)]-type NNIBP in which there is no hydrogen bond between P236 and K103.101,102
These bulkier NNRTIs bind with the RT in an expanded volume relative to smaller in-
hibitors and contain members that extend from the common NNIBP toward a exible
protein/solvent interface (Fig. 14), providing a valuable clue for drug design (will be
described in detail in the following section).103
4. THE NNRTI LEAD DISCOVERY APPROACHES
Lead discovery is one of the most considerable components in rational drug design, and
represents a major research area of medicinal chemistry today. There are two basic
HIV-1 NNRTIs K E15
Figure 14. Positioning of delavirdine in the NNIBP (PBD code:1KLM).101 [Color figures can be viewed in the online issue, which
is available at wileyonlinelibrary.com.]
approaches to obtain original leads, namely, de novo design and database screening.
Although de novo design is conceptually more attractive, high-throughput screening (HTS) of
compound collections is still the predominant approach in drug lead exploration, including
NNRTI lead discovery.
A. HTS
In the pharmaceutical industry, database HTS is frequently applied at the beginning of a
drug discovery program to detect novel hits.104,105 The combinatorial chemistry strategy
together with the HTS approach has permitted the discovery and optimization of novel anti-
HIV lead compounds.106 Some novel and diverse NNRTI leads discovered through HTS
using the cell-based HIV replication or enzymatic assay (presented in Fig. 15), such as
benzophenone (62),80 sulfanyltriazole (51c and 51d),67b,c sulfanyltetrazole (51e and 51f),67d
oxindole (29),44 tricyclic benzothiophene (18),32 N-aryl pyrrolidinone (50),66a and thiazoli-
denebenzenesulfonamide (52d and 52e),68a are of great value for the discovery of the next
generation NNRTI candidates.
B. Natural Products
Nature has always provided a wealth of drugs for various disease.107 Natural products with
promising anti-HIV properties have been revealed.108110 Over the past decade, signicant
progress has been made in the investigation of the medicinal plants as novel NNRTIs. These
plant-derived naturally occurring compounds belong to a broad range of diverse structural
families, e.g. avonoids, coumarins, terpenes, tannins, lignans, alkaloids, polysaccharides,
and naphtha(anthrax)quinones.107110 Most of them can serve as leads for developing novel
RT inhibitors that may be developed into anti-HIV candidates. This section described
representative examples of the successful use of chemical modication or molecular simpli-
cation strategy in the discovery of new leads from bioactive natural products.
E16 K ZHAN ETAL.
H N N N N Br
N H H
O O N N
Me N S Me N S
O
O O
Me
MeO
62a Me N Me 51c 51d
Me Me
OEt
N N Cl N N NO N
H H O
N N O
N N 7b
N S N S
Br OMe
Me Me O O 2a
O O
S
N
H MeO
51e 51f 29 18, NSC-380292
Me
IC (WT RT Pol) = 5 nM 2aS,7bS- and 2aR,7bR enantiomers
IC (WT RT Pol) = 5 nM IC (K103N) = 20 nM EC = 75 nM
EC = 1.24 M, SI > 800
IC (K103N) = 15 nM IC (K103N/Y181C) = 849 nM
O NH
N
Me O Me O
S N S N
Me S NO S NO
MeO O
Me N O Me N
O Me Me
Me Cl
50 52d 52e
EC = 125 nM EC = 8 5 nM EC = 48 nM
Figure 15. Examples of representative NNRTIs discovered from HTS.
OH
HO
O
OMe
HO
O O Br
OH
O O O COOMe
HO O
OH O COOMe
OH OH
O
HO O
O R
OH
HO O
OMe
Hexahydroxybiphenyl
O
HO 65a: R = H, EC 50 = 0.52 ug/mL, SI > 190
67, Ellagitannin punicalin 65b: R = Br, EC 50 = 0.23 ug/mL, SI > 480
OH
Figure 16. The discovery of hexahydroxybiphenyl NNRTIs.
As early as in 1990s, the hexahydroxybiphenyl compounds 65a and 65b (Fig. 16), derived
from tannins ellagitannin punicalin (67), were identied as a unique NNRTI family.83,111
With biologically active lignans, phenylpropanoid dimer compounds of plant origin, as a
starting point, synthetic tetrahydronaphthalene (THN) lignan derivatives 59a and 59b have
demonstrated potent anti-HIV activity (Fig. 17).77
Naturally occurring Calanolides112ad and Inophyllums (mainly isolated from
Calophyllum lanigerum33a and the Malaysian tree, Calophyllum inophyllum,113 respectively),
HIV-1 NNRTIs K E17
H H
MeO O
S S
MeO O
H H
OMe OMe
MeO OMe OMe

OMe OBz
59a 59b
EC50 = 0.15 M, SI = 161.6 EC 50 = 1.09 M, SI > 769
Figure 17. Lignans-based NNRTIs.
Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me
O O O O O
O O O O O O O O O O O O O O O
Me OH Me OH Me OH Me OH Me OH
Me Me Me Me Me
Me Me Me Me Me Me Me
Me
O O Me O O
O O O O O O O O O O O O
Y
Cl
O Me X Me OH Me O
Me Me Me
Figure 18. The structures of Calanolides and Inophyllums. [Color figures can be viewed in the online issue, which is available
at wileyonlinelibrary.com.]
as well as their structural analogs,114 represent novel coumarin-based NNRTIs (Fig. 18). In
particular, (1)-calanolide A is unique in inhibiting HIV-1 Y181C isolates.112b The (1)-cala-
nolide A also displays additive to synergistic anti-HIV activity with other antiviral agents to
suppress mutant strains. Nevertheless, its low potency against HIV-1 is likely to account for the
limitation in clinical trials although it was proved to be well tolerated in phase Ia/Ib trials.112c,d
Thus, many structural modications on (1)-calanolide A with the aim of improving
inhibitory potency have been performed. Very recently, 10-chloromethyl-11-demethyl-12-
oxo-calanolide A, 19f, was reported, which shows druggable properties with higher oral
bioavailability (32.7% in the rat), tolerable toxicity upon a single oral dose administration in
mice, and interesting resistance proles (especially the feature of high inhibitory potency
against the WT and Y181C mutant HIV-1 at an EC50 5 7.4 and 0.46 nM, respectively).115
Taking the natural product, suksdorn (68) (Fig. 19), which was isolated from the fruit
of Lomatium suksdori,116 as a lead compound, further modications led to the discovery of
3,4-di-O-(S)-camphanoyl-(1)-cis-khellactone (20a, DCK) and its analogs,117130 such as
E18 K ZHAN ETAL.
R2
R1
O O O
Me
O O O Me O Me
Me Me
O O
Me O Me Me O O 20a, R1 = R 2 = H (DCK)
O O Me 20b, R1 = H, R 2 = Me
O
O Me 20c, R1 = CH 2OH, R2 = Me (HMDCK)
Me O
Me 20d, R1 = CH 2CN, R2 = Me
Me O
68, Suksdorfin
Figure 19. The novel suksdorfin derivatives as potent NNRTIs.
4-methyl-DCK (20b), 3-hydroxymethyl-4-methyl-DCK (20c, HMDCK), and (30 R,40 R)-3-

cyanomethyl-4-methyl-DCK (20d), which belong to a novel NNRTI family (Fig. 19). The
structural optimization of DCKs is still a research focus in the current anti-HIV drug
discovery eld.131
Especially, DCK derivative 20d, which contains a cyano group, not only exhibited
promising potency against WT HIV-1 in H-9 lymphocytes assay but also showed improved
drug resistance proles. It also has mediocre oral bioavailability, mediocre cell permeability,
and low systemic clearance.130 Its design was based upon the computational studies,132
coupled with the fact that a cyano group demonstrates good metabolic stability under most
conditions. This cyano group is also a good H-bond acceptor and can favorably interact with
key residues on the NNIBP, which are determinant requisites for the afnity of several
NNRTIs.133 These results suggest that natural products combined with rational drug design-
based modications and analogs synthesis could provide promising lead molecules for the
development as clinical trial candidates.
In summary, structural modication (simplication) of a natural product has afforded a
practical way in theory to nd novel NNRTI leads with promising antiviral potency and less
toxicity. However, identifying novel NNRTIs by random screening of natural product
libraries and then optimizing them by systematic chemical modications are highly time- and
resource consuming. Therefore, faster and more efcient approaches that facilitate and
shorten the novel NNRTI discovery process would be extremely benecial.
C. Virtual Screening
Virtual screening is becoming a major source in the discovery of hit- and lead-com-
pounds.134136 Several approaches of virtual screening, such as molecular docking and
pharmacophore-based searching algorithms, are gaining acceptance and are applied to dis-
cover more potent NNRTIs. Numerous related software tools have been developed. In this
section, we will describe several examples of different virtual screening approaches for
NNRTI lead discovery.
1. Docking-Based Virtual Screening

Docking-based virtual screening is a widely used computational tool in hit identication and
lead optimization, which dock small molecules into the binding sites of macromolecular
targets and score the targetligand binding afnity.137
Sangma et al. used a docking and neural network combined approach to screen active
compounds targeting HIV-1 RT and PR from the Thai medicinal plants database.138 The
HIV-1 NNRTIs K E19
results show that this combined approach allows to execute the successive screening and to
minimize the analyzing step from the docking and scoring procedure.
In a recent report, virtual screening of the Maybridge library of 70,000 compounds was
carried out using a similarity lter, docking, and molecular mechanics-generalized Born/
surface area postprocessing to search for novel NNRTIs. Although known NNRTIs were
retrieved, purchase and evaluation of top-scoring representative compounds from the library
failed to obtain any active HIV inhibitors.62a
Hierarchical lters, from simple structural and PK lead lters (e.g. molecular weight,
number of rotatable bonds, and number of hydrogen bond acceptors/donors) to high-
throughput rigid docking were applied to seek the National Cancer Institute (NCI) database
for HIV-1 RT hits. Finally, in vitro assay, a novel molecule NIC 14129 (69), was identied as
the most efcient hit for HIV-1 RT inhibition (Fig. 20).139
To discover NNRTIs that are effective against both WT virus and Y181C mutations,
docking-based virtual screening using standard-precision scoring and the more computa-
tional intensive extra-precision scoring with the Glide program was carried out using three
RT proteins (PDB entries 1RT4, 2BE2, and 1JLA) and more than 2,000,000 commercially
available compounds. The structures 1RT4 and 2BE2 are for WT RT with different con-
formations of Y181, while the protein 1JLA contains the Y181C mutant. Among the
purchased compounds, 70 shows moderate inhibitory activity against both the WT and
Y181C-mutant HIV-1 in low micromolar level, while 71 has 7.5 mM activity against the
O CN
Me H N S
N N
N Me
4 NH O
O N
O N N
O
Me HO NH N
69, NIC 14129
IC = 18.9 M Me O N O
H
Nevirapine IC = 4.20 M 70 71 72
S N Br
O H
N N S
S
MeO HN
O N HN
N
H
73 S
EC = 374 nM O
MeO HN
SI > 446 OMe 74a Me
HN
EC = 3.0 M
Me
O
S
Cl OMe Me
Me HN 74c
Me Me HN EC = 168 nM
O S SI > 345
N
O O
MeO OH Cl 74b Me
EC = 2.6 M
O

32
H
S N
NH
O
S
O
O
75, NAPETA
Figure 20. The structures of NNRTIs obtained using virtual screening.

E20 K ZHAN ETAL.
Y181C mutant, and 72 is a 4.8 mM NNRTI toward the WT virus. This research illustrates a
viable protocol to uncover anti-HIV agents with improved resistance properties.140
The virtual screening by docking a large compounds library (Leadquest 3) into two RTs
(PDB entries 1FK9 and 1DTQ) led to initial identication of several potential compounds
(i.e. 73, 74a, and 74b) with effects against the RT-associated DNA polymerase activities and
the HIV-1 pseudovirus infection in susceptible cells. Moreover, combining functional groups
of two structurally related inhibitors 74a and 74b resulted in a more potent inhibitor 74c that
inhibited the RNA-dependent DNA polymerase activity of recombinant HIV-1 RT with an
IC50 value of about 510 nM. This compound also suppressed the infection of HIV-1 pseu-
dovirus in human lymphocytes with an EC50 value of about 168 nM.141 It should be noticed
that these structures have high similarity to the known PETT family.
Through docking-based virtual screening of a large library of 50,000 compounds, N-f2-[4-
(aminosulfonyl)phenyl]ethylg-2-(2-thienyl)acetamide (NAPETA, 75) was identied as novel
HIV-1 RT inhibitor, which interfered with the formation of the RT-DNA complex. This
mechanism is different from that of the classical NNRTIs used for treating HIV infection.142
2. Pharmacophore-Based 3D Database Searching
Once a bona de drug against a known target has been identied, computational approaches,
such as 3D pharmacophore-based database searching, can play a pivotal role in the discovery
of novel leads with different chemical scaffolds. The large number of successful applications
of 3D pharmacophore-based searching in medicinal chemistry clearly demonstrate its utility
in the modern drug discovery paradigm.143,144
As early as 1998, a 3D stereoelectronic pharmacophore derived from a 3D-QSAR
investigation was reported as the foundation of the development of a two-phase data-mining
methodology to seek novel NNRTI leads.145
In 2007, a 3D structure-based pharmacophore model for DAPY NNRTIs was used to
screen large chemical databases (CAP Complete 2004 and Derwent-WDI2005). The obtained
hits were further ltered by taking into account the tness score and by using Lipinskis rule
of ve in addition to molecular docking studies (Glide program). Finally, six compounds
were selected for assaying of their inhibitory potency against HIV-1 RT. In particular,
compound 32, which belongs to the quinolin-2(1H)-one scaffold, showed an IC50 value
(200 nM) comparable to that of nevirapine (180 nM).45c
It must be pointed out that pharmacophore-based virtual screening by itself may not
always guarantee a successful identication of potent inhibitors against HIV-1 RT and may
therefore require additional complementary approaches. The hierarchical multiple-lter
database searching strategy combined many cheminformatic tools is an attractive strategy in
drug lead exploration. Two efcient approaches by using hierarchical database screenings are
presented in Figure 21.99,146
Although the applicability of virtual screening methodology has been well established, it
seems that there are still no successful projects of NNRTIs drug discovery in which virtual
screening has been the pivotal contributor.
D. De Novo Design of NNRTIs

De novo drug design is an active area of structure-based rational design approach, which
relies only on prior knowledge of the 3D structure of target to design entirely new lead
compounds with desired properties.147 Two categories can be divided for de novo design:
atom-based and fragment-based approaches. The fragment-based method shows more
attractive as a virtual structure can be easily constructed from combinatorial building blocks.
Since the discovery of NNRTIs, crystal structures of WT and mutated RT have been
used extensively in the de novo design of novel NNRTIs.148 However, the considerable
HIV-1 NNRTIs K E21
Figure 21. Flowchart representation of the hierarchical multiple-filter database searching strategy. (A) Hierarchical database
screening combined sequentially a pharmacophore model, multiple-conformation rigid docking, solvation docking, and mole-
cular mechanics-Poisson--Boltzmann/surface area (MM-PB/SA) sequentially.99 (B) Virtual screening by pre-filter pharmacophore
hypotheses and docking.146 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Four RT crystal structures: WT, Y181C, K103N, L100I + K103N
Search in each structures for fragments that bind to NNRTIs binding site
Identified fragments that appears in all structures
Build a molucule by linking cross reacting fragments
Minimize and dock final molecule to each structure separately
Synthesize and test various derivatives based on the designed pharmacophore
I O
76
Figure 22. Outline of the design process of new NNRTIs.149 [Color figures can be viewed in the online issue, which is available
conformational exibility of RT has complicated the traditional structure-based de novo drug

design approach for the discovery of novel NNRTIs, because no one would ever predict the
formation of the allosteric binding pocket just looking for the unbound structure.
In 2007, a successful de novo drug discovery of NNRTI was reported (Fig. 22).149 First,
the authors searched small fragments capable of interacting with each one of four RT pro-
teins (WT and Y181C, K103N, L100I1K103N mutations), using the Ludi module (Cerius2
LUDI user guide; San Diego, CA, 2003), a program widely used to dock small molecular
E22 K ZHAN ETAL.
fragments in target binding sites for the de novo design approach. Then, these fragments were
combined to build a core scaffold. Out of 27 synthesized compounds, four had low micro-
mole activity against the DNA polymerase activity of RT (IC50 value o10 mM). The most
potent compound 76 shows high RT inhibitory activity with (IC50 value: about 3.5 mM),
meanwhile, its potency against clinically relevant drug resistance mutants was more ef-
ciently than that of nevirapine.
Factors important for tight binding of inhibitors and resilience to mutations were elu-
cidated based on the detailed analysis of a broad range of crystal structures of RT in
complexing with various NNRTIs together with data on drug-resistant HIV-1 mutations.
These information were used to the structure-based (fragment-based methods) discovery of a
novel series of quinolone NNRTIs 31ad. Several of them retain high activity against the
Y181C and L100I mutated RT (Table III). Crystal structure analysis conrms the predicted
binding modes.45b
The ligand-growing program BOMB (Biochemical and Organic Model Builder,
Jorgensen, W. L. BOMB, v 2.5; Yale University: New Haven, CT, 2004.) is used to construct
molecules by adding layers of substituents to a scaffold that is isolated or that has been
placed in a binding site. De novo design of NNRTIs with the program BOMB based on
diarylamines (HetNHPhU) scaffold resulted in the identication of compound 77
(Het 5 2-thiazolyl and U 5 dimethylallyloxy) as a promising original hit (Fig. 23). As
described below, this compound was further optimized to multiple highly potent NNRTIs.59a
Table III. Anti-RT (WT and Mutant) Activity (IC50, mM) and Antiviral Activity (EC50, mM) of
Quinolone Derivatives
Cl X
Cl R 31a: R = Pr, X = O
31b: R = i-Pr, X = O
N O 31c: R = Pr, X = S
H
N O 31d: R = Pr, X = SO
Popular fragment H
Nevirapine-resistant
Compd RTWT RTY181C RTL100I HIV-1IIIB HIV-1
31a 0.71 1.13 1.36 0.035 0.607

31b 0.63 2.50 1.96 0.051 0.710
31c 0.24 0.86 1.61 0.100 0.368
31d 0.38 1.26 2.38 0.242 2.210
Nevirapine 0.30 4100 4100
Me
U
Me O
BOMB
S
Het Ph
N N N
H H
Het-NH-Ph-U 77: EC50 = 10,000 nM
Figure 23. The discovery of diarylamine NNRTIs using BOMB. [Color figures can be viewed in the online issue, which is

HIV-1 NNRTIs K E23
Because the Gordian knot of most de novo design methods may be synthetic in-
accessibility, an advance de novo design program SYNOPSIS providing a synthesis route for
each generated molecule has been developed.150 This novel program has been successfully
applied to design several NNRTIs showing HIV inhibitory activity in vitro.150
5. OPTIMIZATION STRATEGIES OF NNRTI LEADS
In the NNRTI modication process, the combination of traditional medicinal chemistry,

computational chemistry, and crystallographic studies led to the identication of numerous
promising candidates, which were active against both WT and drug-resistant variants of RT.
A. Crystallographic Studies and Implication for Modification of NNRTIS

Nowadays, the course of drug development for the treatment of AIDS is being revolutionized
by high-resolution crystallographic structures of keyproteins in the HIV-l life cycle. Espe-
cially, crystal structures of WT and drug-resistant mutants of HIV-1 RT have been used
extensively in the design of novel NNRTIs. The structural information reveals the important
interaction mode of inhibitor, indicating the essential aspects determining their binding af-
nity and generates new ideas about opportunities for improving drug efcacy.151
1. The Identication of Tolerant Region in NNRTIS or NNIBP
The identication of the tolerated region in the lead compounds using the structure biology
information of HIV-1 RT/NNRTI complexes is a premise that allows rational optimization.
In view of the plasticity of NNIBP, a composite binding pocket model, integrating all
available crystallographic information on the NNIBP of HIV-1 RT,152154 was used to
rationally design potent inhibitors with improved proles against drug-resistance mutants of
HIV-1 RT. This composite binding pocket was successfully demonstrated as a powerful
tool to handle exibility of the NNIBP and to identify specic domains (the potentially
usable space) for structural optimization of the inhibitors. Based on the obtained results,
several novel, highly potent NNRTIs with broad-spectrum antiviral activity were identi-
ed.155159
On the basis of the crystallographic studies on binding of larger NNRTIs, the P236
hairpin loop in RT is closer to the apo conformation, forming a more open pocket; this
represented a tolerant region for introducing additional groups to the binding NNRTIs
(described in the earlier section).160
Additionally, two relatively inexible residues at the pocket entrance, V179 and L100,
manage the openness of the entrance and form the fortress of the inhibitor-unbinding channel,
which therefore was regarded as another attracting tolerant region and could be exploited by
diverse groups, giving an additional contribution to the generation of the allosteric NNIBP.161
For instance, the 5,6-positions in the central pyrimidine ring of DAPY NNRTIs162,163 and the
5-position in the pyrimidone ring of HEPT NNRTIs164 are well accommodated in a small
cavity consisting of V179 side chain, respectively, which has been validated by crystallographic
studies (Fig. 24) and further chemical modications (Figs. 25 and 26).
In summary, the plasticity of NNIBP resulted in the discovery and/or validation of the
tolerated region in NNRTIs or NNIBP using crystallographic studies, which provides a
broad space for the discovery of new generations of NNRTIs. It seems possible to exploit the
tolerated region of NNIBP to gain specic proteinligand interactions to accommodate
substantial modications of the NNRTI molecule which improve its pharmacokinetic
properties or to construct multi-target ligand165,166 by incorporating another bioactive
moiety without a signicant deprivation of binding afnity.
E24 K ZHAN ETAL.
Figure 24. TMC125 (A) and TNK-6123 (compound 39e) (B) in the NNIBP (PDB code for TMC125 and TNK-6123: 3MEC,
1C1C).151,164 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
CN CN CN CN CN CN Me CN Me CN
Me Me Me Me Me Me Me Me Me Me
O N NH O N NH O N NH O N NH O N NH
N N N N N
Br HN N
NH NH N NH
HO
V179 V179 V179 V179 V179
4d 4e 4f 4g
4c
EC < 10 nM EC < 10 nM EC < 10 nM EC < 10 nM (WT)
(WT, L100I+K103N) (WT, L100I+K103N) (WT, L100I+K103N) 10 nM < EC < 100 nM
(100I+K103N)
Figure 25. Diverse bicyclic heterocycle DAPYanalogs.163 [Color figures can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
O V179 O Me V179 O Me V179 O Me V179

Me
HN HN Me HN Me HN Me
O N S O N O N O N S
O O O O
HO
Me Me
39a, HEPT 39c, TNK-651 39d, MKC-442 39e, TNK-6123
Figure 26. HEPT and the second generation pyrimidine diones. [Color figures can be viewed in the online issue, which is
2. Structural Biology Explanation of NNRTIs With Resilience to Mutations

We gained a thorough understanding of the structural biology of HIV-1 RT/NNRTI com-
plexes and the data on drug-resistance mutations, inherent conformational exibility, and
positional adaptability of NNRTIs,72c,167169 forming extensive hydrogen bonding170 or
HIV-1 NNRTIs K E25
other key interactions171 with the main chain. This has allowed us to target highly conserved
residues in the HIV-1 RT167,172 and to exploit unconventional mechanisms for NNRTI-
mediated inhibition of RT.173175 These are important factors for the design of inhibitors
with improved resilience to mutations.
Therefore, only using these information as a staring point would the application of the
following described medicinal chemistry strategies be highly effective.
B. Medicinal Chemistry Strategies in the Modification of NNRTIs

In this section, successful applications of medicinal chemistry strategies (bioisosteric re-
placement, molecular hybridization, scaffold hopping, design of multiple ligands, and mul-
tivalent drug design) for NNRTI modications are reviewed.
1. Bioisosterism Principle: Me-Too

Bioisosteric replacement is an excellent tool for lead optimization to produce the desired
potency, selectivity, and the required ADME proles for a marketable drug.176ac The use of
bioisosteres in NNRTI lead optimization is illustrated by some recent examples from the
literature.
Case 1. Diarylazine-based NNRTIs
Taking a-anilinophenylacetamido (a-APA) as the original lead compound,69a further
optimization carried out by Janssen and his colleagues led to the discovery of the imino-
thiourea (ITU) analogs (i.e. 54, IC50(LAI) 5 3 nM)70 to the diaryltriazine (DATA) analogs (i.e.
35, IC50(LAI) 5 0.3 nM)48 and the diarylpyrimidine (DAPY) analogs (i.e. 4c, TMC120),
successively.49 The rst DAPY compound, dapivirine (TMC120), is being pursued for its
microbicidal potential. The second DAPY compound etravirine (TMC125) (Fig. 27),177
which has been recently approved (Intelences) for clinical use, and the third DAPY com-
pound (R278474) (35) corresponds to rilpivirine (TMC278) (Fig. 27),178 which is expected to
be approved soon for clinical use. Thus, the structural modications of the DAPY series are
still a research hotspot.179182 Recently, using the isosteric replacement strategy, pyr-
azinone,50 diarylpyridine,51 and diarylaniline compounds52 were discoveried as novel scaf-
folds of potent NNRTIs, active against both WT and drug-resistant HIV-1 strains.
Especially, the diarylpyridine 37 showed low nanomolar EC50 values and high SI values
(410,000) against HIV-1 IIIB, NL4-3, and RTMDR1.51 The diarylaniline 38 inhibited WT
HIV-1 strains with low nanomolar EC50 values of 0.0030.032 mM and inhibited several
drug-resistant strains with EC50 values in 0.0050.604 mM range.52 In addition, the pyridine
or substituted aniline ring replacement offers a more convenient and shorter synthetic route,
using inexpensive commercial reagents, compared to the synthesis of DAPY derivatives
TMC125 and TMC278.
Case 2. Efavirenz analogs
Efavirenz (DMP 266, L-743,726, SustivaTM) is one of the four approved NNRTI drugs
for the treatment of HIV-1 infection, which belongs to the series of benzoxazinones, struc-
turally related to the rst subset of NNRTIs developed by Merck and based on a quina-
zolinone skeleton. The development of quinazolinone derivatives started from the lead
L-608,788 (78), unstable under screening conditions (Fig. 28).41 Researchers have continued
to develop additional potent NNRTIs with other ring systems, structurally related to efa-
virenz, such as dihydroquinazolinone skeleton (DPC 961, DPC 963, DPC 082, and DPC
083),183187 cis-3-alkylbenzoxazepinone skeleton (79a, 79b),188 and benzothiadiazine skeleton
(80).189 They showed antiviral activity in the nanomolar range. Based on the structural
features of efavirenz (3), HBY-097 (24), and oxindole 29b, a quinolone scaffold (30b) was
obtained as a good surrogate of efavirenz.45a
E26 K ZHAN ETAL.
N N N N
Me Me
Cl Cl Cl Cl Me Me Me Me
H H
N NH N NH N NH HN N NH
NH S NH N N N N
54 N
35 4c, TMC 120
(1998)
N N N N N N N N
Me Me Me Me Me Me Me Me
O N NH O N NH O N NH O NH
N NH
Br Me N O NH ON
NH Me
36 37 38
4a, TMC 125 Pyrazinones (2005) Diarylpyridine (2009) Diarylaniline (2010)
(1999)
IC (LAI) = 6 nM EC = 1.4 nM; SI = 22,700
IC (K103N + Y181C) = 63 nM (HIV-1 ,MT-2 cell)
EC = 0.68 nM; SI = 13,206
N (HIV-1 , TZM-b1 cell)
EC = 0.96 nM; SI = 9,354
N (HIV-1 ,TZM-b1 cell)
Me Me
HN N NH
4b, TMC 278

(2001)
Figure 27. The chemical evolution of diarylazine-based NNRTIs (Arrows represent development timelines). [Color figures can
be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Case 3. Capravirineanalogs
Imidazole compound capravirine (47, formerly known as AG1549 and S-1153) displayed
potency at subnanomolar concentrations in vitro against a broad-spectrum of HIV-1 strains
(EC50 values: 0.710.3 nM).63ac Unfortunately, capravirines development was discontinued
due to poor results in clinical trials and complex interactions with other anti-HIV ther-
apies.63ac In the continued modication of capravirine, novel arylthio isopropyl pyr-
idinylmethylpyrrolemethanol (AThP) derivatives were found to be active to block the
replication of HIV-1 in infected cells in the concentration range of 0.00853 mM.190ab Com-
pounds 81a and 81b were the most two active derivatives in cell-based assays with similar
inhibitory effects and SI to that of capravirine (EC50 5 8, 7, and 3 nM; SI 5 6,250, 16,357, and
7,000, respectively).190ab Compound 81b retained impressive activities against clinically
important drug-resistant RT carrying K103N, Y181I, and L100I mutations.190b 5-Aryloxy
imidazole 82, achieved by removing a metabolically vulnerable pyridine ring and replacing a
vulnerable sulfur atom with oxygen, illustrates the impressive overall prole against both WT
RT and the clinically relevant mutations K103N and Y181C and remarkable improvement in
potency and metabolic stability over capravirine.191,192 Recently, a new series of S-1153 analogs
HIV-1 NNRTIs K E27
OEt H
Cl Cl Cl OEt
NMe NMe NH H
O
N S N O N O Cl
H H H
27a O
78, L-608,788 27b
IC = 12 nM N
H
29b
Me Me
O O
FC FC FC
Cl MeO N
NH NH O
X X SMe
N O N O N O
H H H N O
H
27c, DPC 961 (X = 6-Cl) 27e, DPC 083 (X = 6-Cl) 3, Efavirenz
24, HBY-097
27d, DPC 963 (X = 5,6-diF) 27f, DPC 082 (X = 5,6-diF)
Me
Efavirenz: EC = 38 nM Me R O
DPC961: EC = 32 nM
DPC083: EC = 23 nM Cl Br
NH
OEt
FC FC S O
N N O
Cl O Cl O H O H
Me Me 80 30b
EC = 182 nM
N N
H O H O
79a 79b
EC = 82 nM EC = 46 nM
Figure 28. The discovery and development of Efavirenz. [Color figures can be viewed in the online issue, which is available at
were studied, in which the imidazole ring is replaced by a pyrazole moiety. Several of these
derivatives (such as compound 83a) displayed the excellent broad spectrum anti-HIV acti-
vity.193a,b Especially, compound 83b (UK-453,061, lersivirine) was selected for further clinical
evaluation due to its very impresive potency against an interesting panel of key HIV-1 mutants,
safety, pharmacokinetic, and pharmaceutical proles (Fig. 29).193ce
Case 4. Sulfanyltriazole/tetrazolederivatives
Sulfanyltriazole/tetrazole derivatives were newly emerging HIV-1 NNRTIs with low
nanomolar intrinsic potency against the RT and anti-HIV activity cell-based assay.67ag
Currently, a number of compounds derived from this triazole/tetrazole scaffold are being
considered for further clinical trials for the treatment of HIV infection.67h Molecular mod-
eling indicated that the triazole/tetrazole moiety stays in the center of the NNIBP, anchoring
the substituents in the scaffold into the optimal space for interactions with NNIBP, which are
in agreement with the present insights of SAR and provide valuable avenues for the future
optimization of novel analogs as promising candidates for the treatment of AIDS.67a Based
on these analyses, additional and potentially more potent scaffolds have been designed and
synthesized independently in our194 and other195 laboratories (Fig. 30). Some derivatives
demonstrated high potency in inhibiting HIV-1 proliferation at nanomolar concentrations.
Case 5. Diaryletherderivatives
Taking advantage of the solvent exposed region (in the RT/solvent interface) of NNRTIs
as a means to incorporate solubilizing groups and to further optimize physico-chemical
properties and pharmacokinetics led to the discovery of novel structurally diverse diaryl ether
derivatives, such as indazole 63a,81 pyrazolopyridine 93 (MK-4965),196 pyrazolopyridazine
E28 K ZHAN ETAL.
Pyrrole core O
Me Me
Me Me
HN
HO O
N
S S S
O O N N N
Cl Cl
NH
Cl Me Cl
N N N
47, Capravirine 81a 81b
Designed to improve
metabolic stability Me Pyrazole core
Me Me Me
N N N
O O
N N
N
HO HO HO
CN Me Cl CN
Me Me
NC Cl NC
82 83a 83b, UK-453,061 (lersivirine)
EC =10 nM
EC =33 nM (WT) EC = 4 nM (WT)
CC >100 M
Figure 29. Optimization strategy for capravirine. [Color figures can be viewed in the online issue, which is available at wi-
leyonlinelibrary.com.]
94,197a pyridazinone 95,197b triazolinone 96,197c 97, 98,197d imidazolinone 99, 100, benzo-
[d]imidazolinone 101, imidazopyridinone 102, 103, imidazo[4,5-c]pyridazine 104, pyridone
105, pyrimidones 106, 107,197d pyrazole 108,198 and oxadiazole 109,199 which were regarded
as classic bioisosteres (Fig. 31). These analogs have high levels of activity against HIV-1
bearing WT strain and a panel of key mutations, and some of them show excellent oral
bioavailability and favorable pharmacokinetics.
Case 6. Modications of other NNRTIs based on bioisosterismprinciple
1-[2-(Diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs) is an unique and
highly potent family of HIV-1 NNRTIs.82,200 Replacement of one phenyl group of lead
compound RS1408 (64) with heterocycles, such as 3-pyridinyl (110) or 2-thienyl (111), led to
novel DAMNIs with increased potency (Fig. 32). In HIV-1 WT cell-based assay, compounds
110 and 111 were found to be 2.5 and 6.7 times more active than compound 64. Compound
111 (IC50 5 8.25 mM) was also found more active than efavirenz (IC50 5 25 mM) against the
K103N mutant RT, suggesting for this compound a potential addition in efavirenz-based
anti-HIV regimens.201
A bioisosterism principle-based alteration, focusing on the replacement of the benzylthio
group of pyrimidine thioether NNRTI 42a,57a by different heteroaromatic systems, led to the
identication of PNU-142721 (42) as a clinical candidate (Fig. 33).57b,c,58
(7)-6-Ethyl-6-phenylpyrrolo[2,1-d][1,5]benzoxazepin-7(6H)-one (12) is the prototype of
pyrrolobenzoxazepinone NNRTs.26a Structural modications based on the bioisosterism
principle, dictated by docking studies, prompted the discovery of pyrrolopyridooxazepinones
(PPOs) analogs 112ac featuring a meta-substituted phenyl or a 2-thienyl ring at C-6 and a
pyridine system in place of the fused-benzene ring in the lead compound with a signicantly
improved pharmacological properties, in terms of efcacy, broad spectrum, and low cyto-
toxicity (Fig. 34). Compared with the lead 12 and nevirapine, PPOs 112ac displayed higher
inhibitory activity against WT RT and several key clinical RT mutations: L100I, K103N,
HIV-1 NNRTIs K E29
N S X N X N Se X
H H H
N N R N N N
S N S S
R2 O R2 O R2 O
Y Y Y
84 85
R4 86
R4 R4
Novel scaffolds discovered in our lab
Bioisosterism Principle
N N N N Br
H H
N N
Me N S Me N S
O O
Me
51c 51d
EC50= 2.053 M (WT) EC50 = 0.1 M (WT)
EC50= 1.3 M (K103N/Y181C)
Me
N N Cl N N NO2
H H
N N N N
N S N S
Me Me O O
51e 51f
IC50 = 5 nM (WT) IC50 = 9.5 nM (WT)
Me IC50 = 766 nM (K103N/Y181C)
Bioisosterism Principle
N X X N X
H H H
N N N N Me N N
N S N S S
R2 O R2 O R2 O
Y Y Y
87 88 89
R4 R4 R4
S X O X HN N X
H H H
N N N N Me N
S S S
R2 O R2 O R2 O
Y Y Y
90 91 92
R4 R4 R4
Novel scaffolds discovered in other labs
Figure 30. The structures of sulfanyltriazole/tetrazole derivatives. [Color figures can be viewed in the online issue, which is

E30 K ZHAN ETAL.
F
NC O O NC O O NC O N
NH
Cl N Cl N Cl
Cl NH Cl NH Cl N
63a 93 94 N
N
HN EC (WT): 1 nM
EC (wt): 4.7 nM EC (WT): 1.35 nM EC (K103N/Y181C): 5 nM
EC (K103N/Y181C): 141 nM EC (K103N/Y181C): 84 nM
F F F
O
NC O N NC O N NC O
NH N
NH NH
N N
Cl O R Me Br Me
R 95 Me Cl 96 O O
Cl
R= Cl, Br, Me, Et, c-Pro 97
R = F, OMe, CN
IC (WT) = 7 nM, IC (K103N/Y181C) = 5 nM
EC (WT): 1 nM EC (WT): 2-11 nM
EC (K103N/Y181C): 4-40 nM EC (WT) = 3 nM, EC (K103N/Y181C) = 28 nM
EC (K103N/Y181C): 20-40 nM
F 98a: F
O O
NC O IC (WT) = 45 nM, IC (K103N/Y181C) = 13 nM NC O
N N
NH EC (WT) = 14 nM, EC (K103N/Y181C) = 55 nM NH
Br N 98b: Br
R
IC (WT) = 55 nM, IC (K103N/Y181C) = 12 nM Cl O
Cl 98a, R = H 99
98b, R = Me EC (WT) = 11 nM, EC (K103N/Y181C) > 100 nM
IC (WT) = 9 nM, IC (K103N/Y181C) = 11 nM
EC (WT) = 4 nM, EC (K103N/Y181C) > 100 nM
F F
O F
NC O NC O N
N NC O
NH N
N NH
Br Me Br NH
O Br O
Cl O Cl 101
100 Cl 102
IC (WT) = 6 nM, IC (K103N/Y181C) = 7 nM IC (WT) = 13 nM, IC (K103N/Y181C) = 8 nM IC (WT) = 5 nM, IC (K103N/Y181C) = 4 nM

EC (WT) = 4 nM, EC (K103N/Y181C) = 11 nM EC (WT) = 5 nM, EC (K103N/Y181C) = 46 nM EC (WT) = 0.4 nM, EC (K103N/Y181C) = 6 nM
F F F
N
NC O NC O NC O
N N N N
NH NH Br O N
Br O Br O H
Cl 103 Cl 104 Cl 105
IC (WT) = 6 nM, IC (K103N/Y181C) = 5 nM IC (WT) = 5 nM, IC (K103N/Y181C) = 4 nM IC (WT) = 19 nM, IC (K103N/Y181C) = 18 nM

EC (WT) = 3 nM, EC (K103N/Y181C) = 20 nM EC (WT) = 4 nM, EC (K103N/Y181C) = 38 nM EC (WT) = 25 nM, EC (K103N/Y181C) > 100 nM
F F
107a:
NC O Me NC O R IC (WT) = 4 nM, IC (K103N/Y181C) = 4 nM
N N
EC (WT) = 1 nM, EC (K103N/Y181C) = 19 nM
Br O N O Br O N O 107b:
H H
Cl 106 Cl
107a, R = H IC (WT) = 3 nM, IC (K103N/Y181C) = 3 nM
IC (WT) = 6 nM, 107b, R = Me
EC (WT) = 1 nM, EC (K103N/Y181C) = 11 nM
107c, R = Cl
EC (WT) = 5 nM, EC (K103N/Y181C) = 66 nM 107c:
IC (WT) = 4 nM, IC (K103N/Y181C) = 4 nM
N
EC (WT) = 2 nM, EC (K103N/Y181C) = 10 nM
F
NC O O NH
NC O O R2
N
N N
Cl Cl R
Cl Cl
108 109
IC (WT) = 4.5 nM, IC (L100I) = 21.9 nM IC (WT) < 10 nM, IC (K103N) < 10 nM,
IC (K103N) = 19.7 nM IC (V106A) < 10 nM,IC (Y181C) < 10 nM
Figure 31. Diaryl ether-based antivirals. [Color figures can be viewed inthe online issue, which is available at wileyonlinelibrary.com.]

HIV-1 NNRTIs K E31
Me Me Me
O O O
N N N N N N
O 2N O 2N S O 2N
N
64, RS1478 110 111
EC50 = 200 nM, SI >500 EC50 = 80 nM, SI >1250 EC50 = 30 nM, SI >3333
Figure 32. The strategy to the optimization of DAMNIs. [Color figures can be viewed in the online issue, which is available at
Cl Cl Cl
N N N
Me H
N
H2N N S H 2N N S R H 2N N S
42a 42b: R = CONMe 2, EC90 = 90 nM (WT) 42d, PNU-142721 O

42c: R = CONEt 2, EC90 = 20 nM (WT) (S)-(-)-enantiomer
Delavirdine: EC90 = 30 nM (WT) IC50 = 20 nM (WT)
IC50 = 22 nM (P236L)
Figure 33. The strategy to the development of PNU-142721. [Color figures can be viewed in the online issue, which is available
N N N N N N N
O O O O
Me Me Me Me
O O O O
S
Me
12 112a 112b 112c
CEM-SS cells, EC50 = 470 nM, SI = 11 EC50 = 69 nM, SI = 56 EC50 = 150 nM, SI >13 EC50 = 27 nM, SI >75
C8166 cells, EC50 = 800 nM, SI = 12.5 EC50 = 54 nM, SI = 111 EC50 = 1200 nM, SI = 16.6 EC50 = 270 nM, SI = 26.7
Figure 34. Structural modification of pyrrolobenzoxazepinone NNRTIs. [Color figures can be viewed in the online issue, which
is available at wileyonlinelibrary.com.]
Table IV. Inhibition of WT HIV-1 and Several Key RT Mutations
Ki (mM)
Compd WT L100I K103N V106A Y181I Y188L
12 0.19 0.75 7.7 3.9 410 410

112a 0.022 0.04 0.3 0.07 4 1.5
112b 0.093 0.09 0.045 0.09 0.43 0.475
112c 0.021 0.044 0.03 0.4 1.2 1.5
Nevirapine 0.4 9 7 10 36 18
V106A, Y181I, and Y188L (Table IV). The antiviral activity and the synergistic antiviral
properties of 112a and 112b with AZT suggest a potential therapeutic usefulness in combi-
nation with NRTIs, against clinically signicant NNRTI-resistant HIV-1 strains.26b
E32 K ZHAN ETAL.
Table V. Anti-HIV Activities and Metabolic Stability of Cosalane Analogues
EC50 (mM) CC50 (mM)
HIV-1RF HIV-1IIIB IC50 CEM-SS MT-4 t1/2

Compd (CEM-SS cells) (MT-4 cells) (mM) cells cells (min) References
a b a a b b 202,203a
58b 0.013 0.6 0.3 31.6 160 5.8
204,205b
58c ND 1.8 ND ND 4224 55.3
206
58d 2.7 ND ND 16.3 ND 22.1
207
58e 0.7 0.24 0.67 2.9 12.4 3,641
207
58f 0.36 0.42 0.39 2.8 6.4 331
208
58g 0.05 0.14 0.47 5.7 7.0 864
209
58h 0.04 0.02 0.91 0.5 1.09 3.46
209
58i 0.6 41.1 0.63 1.2 41.1 51.4
210
58j 0.03 0.09 0.02 5.1 16.86 1.3
a represents that the date is from reference 202 or 203; b represents that the date is from reference 204 or 205.
The potential clinical utility of the alkenyldiarylmethanes (ADAMs) NNRTIs could be

affected by the metabolic instability of ester moieties that are prone to be hydrolyzed by
human nonspecic esterases.202,203 The replacement of labile esters with some bioisosters,
such as thioesters,204 various heterocycles,205209 and nitriles,206 led to the successful devel-
opment of several sub-micromolar NNRTIs that exhibited increased metabolic stability in
rat plasma relative to their parent analogs (Table V). Especially, ADAM 58e demonstrated
improved metabolic stability in rat plasma (t1/2 5 61 hr) along with the potency to inhibit
HIV-1 RT and the replication of HIV-1IIIB and HIV-1RF strains in cell assay at sub-
micromolar concentrations.207 Although the rat plasma half-lives of benzoxazolone deriva-
tive 58j was not optimized when compared to the prototype compounds, it was identied as
one of the highly potent compounds, which inhibited the replication of both HIV-1IIIB and
HIV-1RF with EC50 values of 90 and 30 nM, respectively, and inhibited HIV-1 RT with an
IC50 value of 20 nM (Fig. 35).210
In summary, a large number of exemplications show that the bioisosterism principle is
one of the most widely used medicinal chemistry strategies in NNRTI modications.
However, like any tool used in modern drug discovery, the bioisosterism principle has lim-
itations that require researchers with experience, insight, and creativity to use it intelligently
in the solution of the practical problems encountered in drug discovery.
2. Molecular Hybridization Concept: Me-Better

Molecular hybridization is a novel concept in drug design and optimization based on the
combination of basic structural elements (the pharmacophores) of different bioactive sub-
stances to obtain a new hybrid entity with improved afnity and potency, when compared to
the prototypes.211,212 The conceptual approach illustrated by many examples of NNRTI
hybrids, such as capravirineefavirenz hybrid 61,79 HBYefavirenz hybrid 113,213 pyr-
idinoneefavirenz hybrid 114,214 pyridinoneHEPT hybrid 115,215ad and pyridinoneDAPY
hybrid 116,216a,b promises to be broadly useful in the search for new chemical entities and can
contribute greatly to improve the speed and overall efciency of drug optimization.211,212
Figure 36 shows the recent adcances in the discovery of novel NNRTI platforms based on the
rational hybridization of two structurally distinct leads.
The discovery of aryl phosphinate-indoles 117a (IDX-899) and 117b was the result of
coordinated medicinal chemistry principles involving bioisosterism principle and molecular
hybridization (Fig. 37).217 In the structure of RTK103N/Y181C-117b complex, the newly
HIV-1 NNRTIs K E33
OMe
Me Me
Me Me N F
S O S O Me
O OMe
O OMe
MeO OMe Me N
OMe O
N Me
O O
Cl Cl Me
N
N O
58c O N
58d O 58e
Me
MeO O
MeO O MeO O MeO O S O

Me Me Me
O OMe MeO OMe OMe
O
N N
Me Cl Cl Me
MeO MeO
N
N O N
58f O 58b 58g N
MeO O
Me Me
MeO O MeO O O OMe

Me Me Me
OMe OMe O OMe
O O
N N O
Me N Me
Me
MeO MeO Me
O OMe N 58j MeO O

58i
58h
O
O
Figure 35. The strategy to improve the metabolic stability of ADAMs. [Color figures can be viewed in the online issue, which is
introduced 3-substituent CH= =CHCN of the phenyl points directly to the highly conserved
W229. This must have contributed to its high potency. Because of its favorable safety prole
and predictable pharmacokinetics,217b a phase II clinical evaluation of IDX-899 has been
initiated recently.217c
As one of the most valuable structural modication tools useful for the discovery of new
ligands, the molecular hybridization approach has been successfully exploited across
different NNRTIs families and may be an effective strategy in the discovery of the next
generation NNRTI candidates.
3. Scaffold Hopping (Chemotype Switching): From One Hit to Another Attractive Series
Scaffold hopping has been recently reviewed and dened.218ae In chemoinformatics,
searching for compounds with structural diversity and common biological activity is entitled
scaffold hopping. On account of the structural similarity of NNRTIs families, scaffold
hopping or chemotype switching via dismantlement and simplication of known NNRTIs is
signicant since it can be used to produce alternative scaffolds with improved efciency and
E34 K ZHAN ETAL.
CN
Capravirine-efavirenz hybrid HBY-efavirenz hybrid
Me Me
NC O R
F O O Me
N
F N Et O O
N
H
61a: R=Me, RT IC = 50nM N
61b: R=Et, RT IC = 25nM N O CF
H
24b, HBY1293/GW867 N O
H
IC = 45 nM;
IC = 4.8 nM
Cl
113
FC
Cl
Cl S O
Me
N N O
Me H FC
N
3, Efavirenz Me O
N
O Me
Me N O
HN R H
O 114: IC = 32 nM
47, Capravirine N Pyridinone-efavirenz hybrid
X
Me O Me
R
Me N O
H
41a, L697,661: X = NH, R = Cl
41b, L-696,229: X = CH , R = H X Me
R
Me
Me N O 115
H
S
Pyridinone-HEPT hybrid
Me
O N a: R = COOEt, X = S. EC = 3 nM, SI > 3333
b: R = NO , X = S. EC = 6 nM, SI > 1666
O N O c: R = NH , X = CO. EC = 6 nM, SI > 1666
H d: R = NHCHO, X = CH . EC = 3 nM, SI > 3333
OH e: R = N(Me) , X = CH . EC = 0.2 nM, SI > 5000
39a, HEPT
f: R = I, X = O. EC = 1.3 nM, SI = 9000 (LAI);
EC = 3 nM (K103N); EC = 20 nM (Y181C)
a: R = -CN, X = C(=O), R = R = Me R
EC (nM) = 2 (LAI), 6 (K103N),
40 (Y181C), 398 (Y188L) 116 R
SI = 6310 (LAI)
b: R = -C=C-CN, X = C(=O), R = R = Me X
EC (nM) = 1 (LAI), 2 (K103N),
N
16 (Y181C), 158 (Y188L) Me R Me Me
SI = 10,000 (LAI) R
c: R = -C=C-CN, X = CH , R = Me, R = Et NH
Me N O N
EC (nM) = 1 (LAI), 2 (K103N), H X
32 (Y181C), 251 (Y188L) N
SI = 10,000 (LAI)
d: R = -C=C-CN, X = CH , R = Me, R = -(CH ) OMe N N Y
H
EC (nM) = 1 (LAI), 20 (K103N),
40 (Y181C), 316 (Y188L) 4a, TMC125: R = -CN, X = Br, Y = NH
Pyridinone-DAPY hybrid 4b, TMC278: R = -C=C-CN, X = Y = H
SI = 10,000 (LAI)
Figure 36. Representative cases of hybrid NNRTIs. [Color figures can be viewed in the online issue, which is available at
unexpected side effects. In this section, the current use of scaffold hopping in the NNRTI
optimization is reviewed based on the representative examples of scaffold hopping in the
literature.
HIV-1 NNRTIs K E35
N Me
N
O O
S X MeO
O P
Cl NH2 Cl NH2
Me Me
HN N NH
N O N O
H H
N 117a, X= H
25, L-737,126 4b, TMC 278 117b, X = F
W229 Y188
Me
N
F227
V106 O
L234 F MeO
P
Cl NH2
H235 O L100
N O
P236 Y318 H
H
O N
N103
K101
Figure 37. Strategy for phosphoindole NNRTI discovery and schematic structure of RTK103N/Y181C with117b.217a,b [Color figures
can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
DAMNI derivative RS1478 (64), an open-analog derived from thiazoloisoindolone 8b by

disruption of two nitrogen linkages of the thiazolidine ring, was identied as a potential
NNRTI candidate for anti-HIV-1 assays. Imidazole was chosen as a terminal ring because of
its presence in the structures of many tricyclic NNRTIs.82
LY300046-HCl (56a), a phenethylthiazolylthiourea (PETT) analog, obtained from the
dismantling of the rigid tricyclic nucleus of the tetrahydroimidazobenzodiazepinthione
(TIBO) derivative (Fig. 38), was more inhibitory to the Y188, Y181, and L100 mutations of
HIV-1 RT than was the parent compound 9-Cl-TIBO. Besides the minimal pharmacophoric
moieties of the TIBO structure necessary for antiviral activity, the presence of an additional
torsional freedom degree in LY300046 relative to earlier rigid TIBO analogs also probably
contributes to the excellent resistance proles of LY300046.72c
By dismantling the rigid tricyclic nucleus of the thiazolobenzimidazole (TBZ) prototype
lead, 2,3-diaryl-1,3-thiazolidin-4-one (49a),65 1,3-dihydro-2H-benzimidazol-2-one (33b),98
and 1-(2,6-diuorobenzyl)-2-(2,6-diuorophenyl)benzimidazole (34a)47ac were developed
as new NNRTIs, which proved to be more active than TBZs in inhibiting HIV-1
proliferation. These compounds can be envisaged as open models of TBZs since they keep
the basic pharmacophoric elements of the TBZs necessary for the HIV-1 RT inhibitory
activity.
The above mentioned and some other typical examples167169 indicated that the con-
formational exibility and positional adaptability of an NNRTI can contribute to the
inhibitor retaining efcacy against a variety of drug-resistant HIV-1 strains. It is worth
E36 K ZHAN ETAL.
A Me B S S
O HN HN
Disconnect N N
S N Disconnect HN
ON Me CH
N
Cl N Cl HN
O Me Me
64, RS1478
8b 5b, 9-Cl-TIBO (R82913)
Me Me
EC = 200 nM, SI >500
Isolation of potential
pharmacophore
S
C F F S
HN HN
2 HN HN
F Disconnect: 2 F
S F N
N
N N
EC = 1100 nM, HCl
N Br
1 SI = 45 N
7, NSC 625487 F 56a, LY300046 hydrochloride
Disconnect: 2 Me 34a
Disconnect: 1
F
Cl Cl
F
Cl N
S
Me N N O
N
O 33b H
49a EC = 240 nM, SI > 1766
Figure 38. The discovery of DAMNIs (A),82 PETTs (B),72c 2,3-diaryl-1,3-thiazolidin-4-one (49a),65 1,3-dihydro-2H-benzimida-
zol-2-one (33b)98 and1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (34a)47a--c (C) by dismantling of the rigid tricyclic
nucleus of the prototype leads. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
highlighting that, in certain NNRTIs, reduced conformational exibility could also improve
inhibitory potency against HIV and RT enzyme together with selectivity, provided that the
conformationally restricted analogs with at least one conformation, among a few en-
ergetically allowed conformations, could be recognized by the binding site.219
Analysis of the bound conformation of tetra(tri)azole-based NNRTIs via molecular
modeling and NMR permitted the scaffold hopping from azoles to novel tertiary thio-
carbamate-based NNRTIs. Although these compounds did not provide the ideal improve-
ment in metabolic stability, they represent a novel, potent family of NNRTIs with a broad
spectrum of antiviral activity.67e,195f Analysis of the SARs of the thiocarbamate-based
NNRTIs contributed to the design of novel tetrahydroquinoline derivatives as potent
NNRTIs with nanomolar intrinsic activity against the WT and key mutant RTs and potent
anti-HIV activity in infected cells. In addition, the sulfur methylene linker was replaced with
a cis-cyclopropyl ring. A modeling study demonstrated that the conformation of a cis-
cyclopropyl amide could mimic the thiocarbamate.220
Also, the SAR conclusion, crystallography, and molecular modeling of tetra(tri)azole
and benzophenone-based NNRTIs permitted the scaffold hopping to a novel series of diaryl
ether NNRTIs which have excellent potency against WT and key mutant viruses (Fig. 39).221
Further systematic optimizations of the lead structure 121 resulted in the discovery of
compound 63a, which is the prototype of a potent and novel NNRTI family. In Figure 40, as
hypothesized, the two pyrrolo nitrogen atoms of the indazole moiety could be used as a
surrogate for the amide group, which appear to form two direct hydrogen bond interactions
with the carbonyl and imino of the backbone of K103.81
Following up on the aurintricarboxylic acid (ATA) lead, Mark Cushman and his cow-
orkers then described an ATA derivative cosalane (Fig. 41), in which one salicylic acid
HIV-1 NNRTIs K E37
O Cl O Cl
H H
Me N N
N S N S
Me Me O Cl O
SO2NH2 SO2NH2
118a
119
IC50(wt): 8 nM IC50(wt): 1 nM
IC50(K103N): 9 nM IC50(K103N): 1 nM
Me IC50(Y181C): 80 nM Cl IC50(Y181C): 4 nM
O Cl
H
N O Cl
Me N S H
N
Cl O N cis
Cl O
118b 120 SO2CH3
CH2COOH
IC50(wt): 34 nM IC50(wt): 18 nM
IC50(K103N/Y181C): 35 nM IC50(K103N): 18 nM
Me Me
Me Cl IC50(Y181C): 99 nM
Tertiary thiocarbamate-based NNRTIs
Tetrahydroquinoline-based NNRTIs
Scaffold hopping
Me
N N Cl H
H N
X N O O
N S
R O
R6 R2 O SO2NH2
SO2NH2
X = N, CH
R1 Cl
R4 Tetr(tri)azole-based NNRTIs
Benzophenone-based NNRTIs
Scaffold hopping
Cl
Y181/Y188/W229 H Y181/Y188/W229 C
N
CN O Scaffold hopping CN O
O N NH
SO2NH2
A B
O
Cl O H Cl O H
N N
Cl Solvent Cl Solvent
K103 K103
121 63a
V179 V179
IC50(wt): 0.14 nM IC50(wt): 1.35 nM
IC50(K103N): 0.21 nM IC50(K103N): 1.12 nM EC50(wt): 4.7 nM
IC50(Y181C): 0.28 nM IC50(Y181C): 2.62 nM EC50(K103N/Y181C): 141 nM
Diaryl ether-based NNRTIs Diaryl ether/pyrazole-based NNRTIs
Figure 39. Scaffold hopping paradigm for tetr(tri)azole-based NNRTIs and proposed binding mode for compounds 121
and 63a.67e, 195f, 220 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
moiety is replaced by one cholestane group. Alkenyldiarylmethanes (ADAMs), structurally

related to cosalane, represent an addition to the group of NNRTIs.222 The crystallographic
studies revealed that ADAMs are highly hydrophobic and the shape of the NNIBP is unique
among other disclosed NNRTI-RT crystal structures.223
E38 K ZHAN ETAL.
Figure 40. The X-ray crystal structure of compound 63a (blue) in the WT-NNIBP (2.7 resolution, PDB code is 3C6U). (Hydrogen
bonds are shown as broken lines).81 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
OH OH OH OH
Cl Me
O O
Me
OH Me Scaffold hopping
OH OH
Me
O Me
O O
HO O HO
Cl
122, Aurintricarboxylic acid 123, Cosalane
MeO O MeO O MeS O

Me
MeO OMe O OMe
N
Cl Cl Me
MeO
OMe OMe
Br O N
O 58b 58g
Scaffold hopping N
MeO O
OMe Me
O O
MeO O OMe
Me Me Me
MeO OMe
O O OMe
Br 124 O
N
Me N Me
EC = 7.1 5.0 M
(HIV-1 /CEM-SS cells) MeO Me
58h O OMe 58j MeO O
Figure 41. Historical synopsis of the discovery and development of the ADAM-type NNRTIs. [Color figures can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]

HIV-1 NNRTIs K E39
4. The Usage of the Tolerant Region in the Modication of NNRTIs

(a) To improve pharmacokinetic properties
Interestingly, certain moiety in many NNRTI families sits between V106 and P236, and
points toward the solvent-exposed region. Consequently, this feature should be benecial for
the modulation of the physicochemical properties of the NNRTIs.
GW678248 (62b), a novel benzophenone NNRTI, potently inhibits WT and mutant RTs
in enzyme inhibition assays, with an IC50 between 0.8 and 6.8 nM. An N-propionyl sulfo-
namide derivative GW695634 (62c), designed as amide prodrug of GW678248, displayed
improved solubility and bioavailability in clinical trials (Fig. 43).224
The N-2 position of pyridazinone 95c, a potent NNRTI that has limited aqueous so-
lubility, was derivatized into a set of hydroxymethyl esters and carbonates as well as one
phosphate. These derivatives served as prodrugs to effectively deliver 95c to rat plasma upon
oral treatment at 50 mg/kg. Increases of 4.3- to 8.6-fold in 24-hr exposure of 95c (over that of
prototype) were observed, while the prodrugs and the hydroxymethyl derivative 95c-1 were
undetectable.225
An N-pyridinyl pyrimidinedione (KRV-2110, 39f) was previously identied as a potent
NNRTI (Fig. 42).226a However, pharmacokinetics in three animal models (rat, dog, and
monkey) demonstrated that once-daily dosage in humans was unlikely. Endeavor to improve
the suboptimal pharmacokinetic prole of 39f led to the discovery of compounds 39g and
39h, which represent the promising compounds in this series with similar antiviral potency as
inhibitor 39f and improved pharmacokinetics that may support once-daily dosage.226b,c
In the tetrazolyl series, it has been demonstrated that the introduction of substituents
(i.e. alkynyl fragment) at the para position of the anilide in 51f led to substantial improve-
ment in the overall physicochemical proles of the molecule while keeping excellent potency
against the K103N/Y181C double mutant RT. As shown in Figure 42D, extensive SAR and
pharmacokinetic evaluation resulted in the discovery of candidate 51i with favorable oral
bioavailability and PK properties in rats.67f
(b) Multiple ligands design strategy

Designed multiple ligands (DML), an emerging and appealing drug discovery strategy, using
a single chemical entity to inhibit multitargets, should be effective in improving patient
compliance, reducing problems of dosing complexity, drugdrug interactions and toxicities,
as well as diminishing the likelihood of virusdrug resistance.166 The exploration of DML
strategy should be valuable in anti-HIV drug discovery.166
Apparently, the key to rational DML strategy would be to identify a tolerant region in
the drug target. Crystallographic studies have shown that the phenyl group in the N-1
substituent of the HEPT type of NNRTIs and the methylsulfonamide group at the C-5
position of delavirdine are situated in an open area (the solvent-exposed region) controlled by
the P236 loop where structural alternations could be tolerated. Based on these general
knowledge and the DML strategy,165,166 several series of RT/IN (integrase) dual inhibitors
were designed and synthesized via incorporation of an IN pharmacophore element to this
tolerant region of a known potent NNRTI (Fig. 43), and many inhibitors demonstrate
activity against RT at low to submicromolar range, and against HIV at nanomolar range
(compounds 126a and 126b), which also conrms that the introduction of a second phar-
macophore to these NNRTIs does not seriously impair their binding with RT. In addition,
moderate anti-IN activity was also observed.227ad
Undoubtedly, the growing efforts in recent years to discover multitarget agents resulting
from the rational combination of pharmacophoric moieties of different known lead com-
pounds will bring a new perspective for the treatment of AIDS.
E40 K ZHAN ETAL.
A Me
Me
H H
N N
O O O O
H
NC O NH2 NC O N
S S Me
O O O O
O
Cl Cl Cl Cl
62b, GW678248 62c, GW695634

B
F F
NC O N NC O N
NH N O
Cl O Cl O
CN 95c Me CN 95c-1 ~ 95c-9 Me
O O O O
OH P NH2
H ONa N
ONa HCl HCl
O
95c-1 95c-2 95c-3 95c-4 95c-5
O O O O O
H
NH2 N NMe2 N
O O
HCl HCl
HCl HCl
95c-6 95c-7 95c-8 95c-9
C O Me O Me O Me
HN Me HN Me HN Me
O O O
O N O N O N
H2N
N N
Me CN Me CN Me CN
F F
39f, KRV-2110 39g 39h
D
N N Cl N N Cl
H H
N N N N H
S S N
N N NH
51g: R =
Cl O Cl O Me Me O
H R OH
51h: R = N
51f H
Me Me O
EC (WT) = 82 nM O
EC (K103N/Y181C) = 505 nM
t = 4 min (RLM) 51g: EC = 1.1 nM(WT); 8.1 nM(K103N/Y181C)
51i: R = OH
t = 109 min (RLM)
51h: EC = 1.6 nM(WT); 13 nM(K103N/Y181C) Me Me
t = 79 min (RLM) O O O
51i: EC = 7.1 nM(WT); 58 nM(K103N/Y181C)
S
t = 90 min (RLM) N Me
51j: R =
51j: EC = 4.2 nM(WT); 27 nM(K103N/Y181C) H
Me Me
t = 82 min (RLM)
Figure 42. Successful cases of NNRTIs modifications in the tolerant region to improve pharmacokinetic profiles. [Color figures
can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

HIV-1 NNRTIs K E41
O Me
Me
HN
O N
RT IC = 0.016 M O RT IC >100 M
O IN IC > 100 M IN IC =0.093 M
OH
HIV-1 EC = 0.016 M HIV-1 EC =0.16 M
O OH
RT inhibitor SI> 610 IN inhibitor 125 SI> 61
39e,TNK651
O O Me Me
Me Me
HN HN
O N O N Me
Me
O O O O
126a OH 126b OH
O OH O OH
RT IC = 0.024 M RT IC = 0.028 M
IN IC = 4.4 M IN IC = 14 M
HIV-1 EC = 0.0097 M HIV-1 EC = 0.014 M
RT/IN dual inhibitor
SI> 1000 SI> 710
Figure 43. Discovery of RT/IN dual inhibitors 126a and 126b against RTand IN, combining RT inhibitor 39e with IN inhibitor 125.
[Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
(c) Multivalency drug design strategy (to form additional proteinligand interactions)
By the classical concept for drug design, a favorable inhibitor should efciently enter and
maximally occupy the binding site, thus interacting effectively with the residues around the
binding pocket.228 Therefore, the larger the NNRTI, the stronger is the interaction with
residues around the NNIBP, provided that the NNRTI can enter efciently inside the
NNIBP. This is partly supported by docking studies that the overall shape and chemical
structure of larger second generation NNRTIs enables them to occupy more space in the
NNIBP than the smaller and less active NNRTIs such as nevirapine,229 and thereby form
additional proteinligand interactions, especially the strong interactions of the drug with the
conserved regions or polypeptide backbone in the NNIBP, which is regarded as a primary
strategy to improve the potency of NNRTIs against resistant mutations.
This is consistent with the concept of multivalency, that using one entity to bind
multiple targets or binding additional sites in one target, simultaneously, could result in a
signicantly improved efciency.230,231
For example, several novel 8-substituted nevirapine-based analogs (127ah) display ex-
cellent broad antiviral activity against a panel of prevalent RT mutants and excellent
pharmacokinetic proles (Fig. 44).232235 Especially, BILR 355 BS (127h) was once advanced
into Phase II clinical trials in 2005.236 X-ray crystallographic study reveals that while the
dipyridodiazepinone core of BILR 355 BS and its analogs bind in an overall similar con-
formation to that of nevirapine, it has a greater ability to accommodate its orientation in the
NNIBP of the mutants. Additionally, the extended C-8 substituent off the dipyr-
idodiazepinone core likely make additional favorable binding contacts with RT (including
E42 K ZHAN ETAL.
Me Me Me Me
O O O
N N N
8 N Cl N Cl Cl
N N S N N
N N N N
Me Me
Me
127a 127b 127c
Me Me Me
O H O O
N N N
Me
N Cl N Cl N Cl
N N N
N S N O N O N
Me Me Me
Me 127d 127e 127f

N N
O O
Me Me
O O
N N
N N N N
Me O N O N
Me Me
127g 127h
N
HO O
O
Figure 44. 8-Substituted nevirapine-based NNRTIs. [Color figures can be viewed in the online issue, which is available at
Me Me
O Me O Me
I I
Me S
O
Me N O Me N O
H H
1152f 115g, R221239
Figure 45. Pyridinone NNRTI115 g (R221239) and its contacts with RT (PDB code: 2BE2). [Color figures can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
P236 and K103 backbone) that may stabilize binding of these 8-substituted analogs even in
the presence of NNRTI-resistance mutations.236
Compared with pyridinone derivative 115f,208d R221239 (115g) contains a exible linker
and a connected furan ring which permits close contacts with V106, F227, and P236. These
additional interactions appear to enhance the inhibitory activity of R221239 against the
HIV-1 strains carrying the V106A, Y188L, and F227C mutations (Fig. 45).171
Compared with benzimidazole 34a, its analog 34b is apparently able to make signicant
interactions with the RT backbone via additional hydrogen bonds (Fig. 46), which are unlikely
to be disrupted by side chain mutations and contribute signicantly to the compacted binding
for the inhibitor, and eventually, signicantly improve the resistance prole of this inhibitor.47ac
HIV-1 NNRTIs K E43
F F
F F F F
N N
N N
F F
Me
O
O
34a 34b
IC50 = 0.2 M,EC50 = 0.44 M(WT) EC50 (M) = 0.062 (WT); 0.068 (L100I);
SI > 100 0.025 (K101E); 0.027 (K103N); 0.013 (V108I);
2.32 (Y181C); 0.033 (Y188C); 4.5 (V106A)
Figure 46. Benzimidazole-based NNRTIs.47a--c [Color figures can be viewed in the online issue, which is available at
O Me
HN Me
O
O N
H 2N
N
Me CN
F
39f, KRV- 2110
Figure 47. Compound 39f bound in the NNRTI binding pocket of HIV-1RT (PDB code 3LAK, 2.3 resolution).218b [Color
figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
As mentioned above, one difference in the binding manner of different NNRTIs are the
hydrogen bond interactions with the protein backbone. For instance, diarylpyrimidine (DAPY)
NNRTIs could make a hydrogen bond from the imino (connected to pyrimidine) to the
backbone carbonyl of K101, while the benzophenone family has a hydrogen bond interaction
between its amide carbonyl and the imino of the K103 amide. Interestingly, some promising
NNRTIs are capable to make double hydrogen bond interactions with K101 and K103.
Antiviral proles revealed that HEPT derivative 39f exhibited potent activity against
Y181C and K103N mutant strains. Detailed crystallographic analysis of 39f/HIV RT complex
structure indicated that an additional hydrogen bond was formed between the amino of the
aminouoropyridyl moiety and the backbone carbonyl of the K103 besides the hydrogen bond
between the imino of the pyrimidinedione and the backbone carbonyl of K101 (Fig. 47).226b
Compared with etravirine, piperidine-linked aminopyrimidine derivatives 128a and 128b
possess favorable potency against WT RT as well as several important mutant strains
(including the K103N/Y181C and Y188L mutants) (Table VI). Crystal structure analysis of
this series compounds showed that, besides a hydrogen bond from the aminopyrimidine
imino to the backbone carbonyl of K101, the piperidine nitrogen could probably make an
additional hydrogen bond with the K103 backbone (via a bridging water molecule).237a,b
E44 K ZHAN ETAL.
Table VI. Activity of 128a, 128b, and Etravirine Against WT RT as well as Several Important Mutant
Strains
SO2CH3 CONH2
N N
Cl
Me Me F Me
O N NH O N NH
N N
Br Br
128a 128b
WT K103N/Y181C K103N/L100I Y188L G190A V106A

Compds (nM) (nM) (nM) (nM) (nM) (nM)
128a237a 6.1 7.3 5.9 2.8 1.8 2.0

128b237b 6 5 ND 29 ND ND
Etravirine237a 2.1 9.2 9.5 3.1 1.1 2.0
O Me
N
O HN Me
N O
Cl
N
129
238
238
Figure 48. Cocrystal structure of 129 inthe NNIBP (3FFI). [Color figures can be viewed inthe online issue, which is available at
Similarly, pyridone inhibitor 129, which was found to strongly inhibit the WT and
NNRTI-resistant K103N and Y181C mutant HIV RT, could not only interact with the
carbonyl group of K101 through a strong traditional hydrogen bond but also engage in
additional hydrogen bond interaction with the backbone amide of K103 (Fig. 48).238
In comparison with that of compound 33b, the improved potency of compounds 33a and
101 might be owing to the electronic characteristics of the sulfonyl moiety and the phenyl
group carrying a cyano group, respectively (Fig. 49). Molecular modeling indicated that the
sulfonyl linker in compound 33a was able to form tight interactions with residues Y181,
Y188, V179, and V106, while the methylene linker of compound 33b forms contacts only
with residues Y188 and V179.46
HIV-1 NNRTIs K E45
Cl
Me NC Br
F Me O
O
F S F
Cl Cl O
N N N
O O O
N N N
H H H
33b 33a 101

EC50 = 240 nM, SI > 1766 IC50 = 5 nM, EC 50 = 2 nM IC50 (WT) = 13 nM, IC 50 (K103N/Y181C) = 8 nM
SI = 17,846 EC50 (WT) = 5 nM, EC 50 (K103N/Y181C) = 46 nM
Figure 49. Benzimidazolone-based NNRTIs.46,197d [Color figures can be viewed in the online issue, which is available at
K101
V179
C
O O K103
B
V106 Me
HN
Y318 R P95
D Me
S 2 N
F227 R R Y181
F F
P225 MeO Y188
A
P236 40d W229
F227
L100 L234
EC50: 0.07 nM (WT); 36 nM (K103N); 13 nM (Y181C); 1.5 nM (Y188L);

CC50: 14640 nM
Figure 50. Interactions of a C2-arylalkyl S-DABO (40d) within the NNIBP.239b [Color figures can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
It seems likely that extended phenyl ring in compound 101 (Fig. 49) could (i) occupy an
hydrophobic space near the top of the NNIBP, thus creating additional intermolecular contacts
with the adjoining residues and (ii) increase the hydrophobic interaction with the highly conserved
W229 at the roof of NNIBP, thereby decreasing the dependence on binding with Y181.197d
The structural modications of S-DABO NNRTIs were aimed at exploring the SAR of
the C2-functionalization in pyrimidine core,239a,b leading to the discovery of a potent in-
hibitor 40d having picomolar activity against WT RT and nanomolar activity against many
key mutant strains. The introduction of an arylalkyl group in C2 signicantly increased the
antiviral activity due to protable hydrophobic interaction with a large pocket (zone D) of
the allosteric pocket. Especially, the cyclopropyl group, as a bulky lipophilic substituent,
probably formed additional interactions with the hydrophobic residues of zone D, giving an
additional contribution to the afnity with the allosteric site (Fig. 50).239b
When introducing modications in the indolylarylsulfone (IAS) type of NNRTIs,240,241
new potent candidates 25cg were obtained by coupling several kinds of amino acids to the
2-carboxamide of the indole core (Fig. 51). In human T-lymphocyte (CEM) cell assay, the
E46 K ZHAN ETAL.
Me Me
NH O
Me Me 25c: R = 25f: R =
S
Me O NH
O
O O NH
S S
O O 25d: R =
Cl NH Cl HN R O
O 25g: R =
S
NH NH
N O N O Me O
H H 25e: R =
25b 25c-g O
Figure 51. The structures of novel indolylarylsulfones bearing natural and unnatural amino acids.241
IASs could inhibit the HIV-1 replication at low/subnanomolar concentrations and with weak
cytotoxicity. The antiviral potency against the K103N, Y181C, and L100I mutant strains in
CEM cells was comparable to that of EFV. With the aim to investigate the conceivable
binding mode of the new IASs, the highly potent compound 25e (IC50 5 26 nM; EC50 5
0.70 nM) was selected for docking studies into the NNIBP of WT RT (PDB code 2RF2) and
L100I RT (PDB codes 1S1T, 2OPQ). From docking 25e into the NNIBP were the newly
formed interactions of the N-(3-amino-3-oxopropyl)carboxamide moiety with the residues
K101 and E138 at the bottom of the NNIBP, which seemed to be particularly important for
the anti-HIV activity. Mutation of leucine to isoleucine did not affect the binding mode.241
In addition, the highly potent pyrazolo[3,4-c]pyridazine derivatives discovered by
structure-based optimization of diaryl ether NNRTIs could bind RT in an expanded volume
relative to most other analogs in the diaryl ether family, and probably engage in additional
interactions with RT.197a
Besides the above described NNRTIs, several series of divalent RT inhibitors by
tethering one molecule of NRTI to an NNRTI structure via a exible linker were designed
and synthesized to occupy the distinct but proximal catalytic site and NNIBP simulta-
neously. However, the results of their anti-HIV assay were not satisfactory.242
5. The Usefulness of Stereochemistry in Overcoming Drug Resistance

Molecular modeling studies pointed to the asymmetric geometry of the NNIBP, and
experimental data proved that the regiochemistry and stereochemistry of NNRTIs can in-
uence their anti-HIV activity substantially.243ad
The introduction of different stereocenters in important pharmacophoric sites of pro-
mising NNRTIs scaffold could allow the emerge of a collection of enantiopure drugs with
improved efcacy and potential usefulness in managing drug-induced mutations. Typically,
the chiral cyclopropane ring-containing oxindole 29,44 quinolones 30,45a S-DABO 40d,239
urea-PETT analogs 56c, 56d,74a,b 56e,74c,d and tetrahydroquinoline 120220 exhibited nano-
molar activity against several clinically relevant mutants (Fig. 52).
C. Computational Chemistry Approaches for NNRTIs Optimization

In the past 15 years, with the signicantly increased computer speed and program efciency,
the role of computational chemistry in drug design has expanded exponentially. Recently, the
applicability of computational chemistry and the computer-aided drug design (CADD)
techniques on NNRTIs has been intensively reviewed by Hannongbua244,245 and Jorgensen
et al.246 Pharmacophore modeling, database searching, and de novo methodologies have been
described in the above sections. Thus, the aim of this section is to summarize the applications
of computational chemistry to the structural modication of HIV-1 NNRTIs. The following
applications are emphasized, including quantitative structure-activity relationship (QSAR),
HIV-1 NNRTIs K E47
OEt
O
O
R Me
Br Cl CO R HN
O Me
S N
N N O
H H F F
MeO
29a R = (CH ) CHCH , nPent
40d
R = Et, Me, Allyl
30
Me Me
O O
F
OH
O O Cl
H
F N
N cis
F F Cl O
Br NC SO Me
HN HN O HN
N N N
O O O
N O 120
N N
H H H Cl
NH
HN
56c, MSC-204 56d, MSC-372 56e
Figure 52. NNRTIs containing a chiral cyclopropane ring. [Color figures can be viewed in the online issue, which is available
molecular docking, free energy perturbation (FEP)-guided lead optimization, and sub-
structural molecular fragments (SMF) method.
Many applications have been reported on the use of two- and three-dimensional QSAR
(2D/3D-QSAR) studies to understand the NNRTI-RT interactions and help in the design of
more effective analogs.247256 The 3D-QSAR model based on the docked conformation
reveals an excellent capability to predict the activity and provides valuable information on
possible improvement in the ligand structure for increasing potency of the inhibitors.
Combination of structure-based docking simulation with ligand-based QSAR will enhance
the likelihood for nding novel lead compounds. Moreover, the particular interaction energy
trend calculated from quantum chemical calculations (QCC) of the NNRTIs and individual
residues in the NNIBP and QM/MM methodology (such as ONIOM method our own
N-layered integrated molecular orbital and molecular mechanics) should increase the un-
derstanding of NNRTI-RT interaction mechanism as well as providing some insights into
drug resistance, which can be used as a promising descriptor identifying a key structural
element for QSAR study.244,245
To rationalize the most relevant SARs of potent NNRTIs and to investigate the
orientation and estimated binding energy of NNRTIs in the NNIBP, molecular docking
simulations were usually performed. The docking results gave an insight into the pharma-
cophoric structural requirements for efcient RT inhibition of related NNRTIs, providing an
informative guideline in designing new derivatives. To manage the conformational exibility
of RT, the inclusion of structural variability in a docking study and the concept of ligand-
induced t by cross-docking approach (the process of docking each ligand into the binding
site of a number of different ligandreceptor complexes) have been taken into account.96,257
Dock molecular mechanics-generalized born/surface area (MM-GB/SA-ADME) is a useful
tool to predict the afnity of NNRTIs with the RT and further screen for promising
candidate drugs though CADD.258,259
FEP-guided lead optimization is regarded as a valuable approach for molecular design
including drug discovery.260 Efcient optimization of an inactive 2-anilinyl-5-benzyloxadiazole
48
E48 KK ZHAN
ZHANETAL.
ETAL.
A
Me Me CN
Me
FEP-Guided
Optimization
X X
X
O NH O
Y NH
N N N
Cl
46a, inactive Cl 46e, X= Cl, Y = H, EC 50= 22 nM
O NH 46f, X= F, Y = H, EC 50= 13 nM
46g, X= F,Y = Cl, EC 50= 6 nM
N N
46b, X= Cl, Y= H. EC 50= 820 nM
46c, X= Y= Cl. EC 50= 310 nM
46d, X= CN, Y= H. EC 50= 130 nM
B
Me Me Me
Me Me Me
O FEP-Guided O FEP-Guided O
Optimization Cl Optimization R2
S N N
N N N N R1 N N
H H H
77: EC50 = 10,000 nM 43a: EC50 = 200 nM 43b: R1 = MeO, R 2 = Cl. EC 50 = 10 nM
FEP-Guided 43c: R1 = MeO, R 2 = CN. EC 50 = 2 nM
Optimization 43d: R1 = MeNH, R 2 = CN. EC 50 = 5 nM
Me Me Me
Me Me Me
O O O Y O
Cl N Cl CN
X N N
N N N N X N N
H H H
130a: X = CH, EC 50 = 6 nM, SI = 4167 131: EC50 = 19 nM, SI = 1053 43e: X = MeS, Y = H. EC 50 = 5 nM
130b: X = N, EC 50 = 5 nM, SI = 3400 43f: X = MeO, Y = NH 2. EC50 = 9 nM
Figure 53. The application of free energy perturbation (FEP)-guided lead optimization.
46 (false-positive molecule in virtual screening) and the less potent thiazole 77 (generated by
de novo design) has been guided by FEP calculations to provide potent anilinylbenzyloxa-
(dia)zole-based NNRTIs62ad and diarylamine-based NNRTIs,59ac,261,262 respectively
(Fig. 53). More importantly, achieving simultaneous efcacy for the WT RT and a panel of
commonly observed mutants can be highly automated by running FEP calculations in parallel
for a given designed NNRTI with all known, common mutant forms of the RT.
The SMF method was also applied for computer-aided design of new NNRTIs poten-
tially possessing high anti-HIV activities, such as TIBO and HEPT derivatives.263
The innovative computational approach GRID-Based Pharmacophore Model
(GBPM) was believed to have great value in the identication of conserved regions of the
HIV-1 RT, to be targeted for the development of novel therapeutic agents.264
HIV-1NNRTIs
HIV-1 NNRTIs KK 49
E49
Totally, as more structural information has become available and a wide range of
computational approaches have proven to have reasonable predictive value, CADD should
play increasingly important roles in designing novel NNRTIs to defeat the nagging resistance
issue and handling the exibility of the target site (NNIBP).
6. SUMMARY AND PERSPECTIVES
In recent years, in spite of the rapid growth of HIV-1 RT 3D-structural information, the
difculty in structure-based de novo design of NNRTI scaffolds and docking-based virtual
screening lies in the following two aspects: (i) The exibility of NNIBP, formed by con-
formational changes in the RT on binding of the NNRTI ligand; (ii) The NNRTI-resistant
mutations situated in and around the NNIBP. Therefore, as reviewed above, structure-based
and ligand-based combined drug design methodology was carried out to facilitate both drug
lead generation and lead optimization. Quite a few cases illustrated the benets for NNRTIs
design of closely coupled traditional medicinal chemistry, structural biology, computational
chemistry methodology, and several other disciplines.265,266
In the NNRTI lead discovery process, compared to the structure-based de novo design
and computer-aided in silico screening, large chemical libraries, combinatorial chemistry,
HTS, and naturally occurring products still serve as approaches or sources of new active
NNRTI leads to be further developed as anti-AIDS drug candidates. Yet, such screenings
and the subsequent optimization of the inhibitors by systematic chemical modications are
highly time- and resource consuming.
In the NNRTIs modication process, the crystallographic studies, providing a basis for
understanding the interactions or tolerant region between the bound NNRTIs and the sur-
rounding amino acid residues, contributed to the improved resilience or afnity of the opti-
mized compounds. Great progress has been made in the development and application of
medicinal chemistry strategies, such as bioisosterism, molecular hybridization, scaffold hop-
ping, and multiple/multivalent ligand design strategy. The coordination of computational
chemistry and crystallography is playing an increasingly important role in attempting to
understand and defeat virusdrug resistance and the target site exibility problem.246 For
instance, cross-docking experiments on the WT and mutated RTs were conducted to consider the
enzyme exibility as an inevitable problem for structure-based drug design studies and to gain
insight into the mode of action of new NNRTIs active against both WT and resistant strains.
The fundamental goal of medicinal chemists is to make drug discovery more efcient by
reducing the number of compounds that need to be synthesized and assayed; the ultimate
goal is to obtain novel anti-HIV drugs with high levels of potency against WT and key
mutant HIV strains without allowing breakthrough, excellent oral bioavailability, and
overall pharmacokinetics. It is clear that only multidisciplinary coordination could help to
achieve these goals.
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reverse transcriptase. J Med Chem 2005;48:16891696.
Dr. Peng Zhan was born in 1983 in Jinan, Shandong province, China. He obtained his B.S.
degree from Shandong University, China, in 2005. Then, he earned his M.S. degree and Ph.D. in
medicinal chemistry from Shandong University under the supervision of Prof. Xinyong Liu in
2008 and 2010, respectively. He is now working as a young researcher in the lab of Prof.
Xinyong Liu. His research area involves design and synthesis of novel HIV-1 non-nucleoside
reverse transcriptase inhibitors.
Xuwang Chen was born in 1987 in Zoucheng, Shandong province, China. He graduated from
Shandong University and obtained his B.S. degree in 2009. At the same year he was
recommended without examination to study for his Ph.D. in the Institute of Medicinal
Chemistry, School of Pharmaceutical Sciences, Shandong University.
Dongyue Li was born in 1984 in Guyuan, Ningxia province, China. In 2007, he graduated from
the School of Pharmaceutical Sciences in Shandong University. He is currently studying for
master degree in the Department of Medicinal Chemistry of the School of Pharmaceutical
Sciences in Shandong University.

72
E72 KK ZHAN
ZHANETAL.
ETAL.
Zengjun Fang received his M.S. degree from Shandong University in 2007. His Ph.D. project,
which was under the supervision of Prof. Xinyong Liu, was on the design and synthesis of novel
HIV-1 non-nucleoside reverse transcriptase inhibitors as potential antiviral therapeutics.
Erik De Clercq, M.D., Ph.D. has been the Chairman of the Department of Microbiology and
Immunology of the Medical School at the Katholieke Universiteit Leuven (K.U.Leuven) as well
as Chairman of the Board of the Rega Institute for Medical Research (until September 2006).
He is currently the President of the Rega Foundation, a member of the Belgian (Flemish) Royal
Academy of Medicine, a member of the Academia Europaea, and Fellow of the American
Association for the Advancement of Science. He has also been the titular of the Prof. P. De
Somer Chair for Microbiology at the K.U.Leuven. Professor De Clercq received in 1996 the
Hoechst Marion Roussel (now called Aventis) award (American Society for Microbiology),
and in 2000 the Maisin Prize for Biomedical Sciences (National Science Foundation, Belgium)
for his pioneering efforts in the eld of antiviral research. He is an honorary doctor of several
Universities [i.e. Ghent (Belgium), Athens (Greece), Ferrara (Italy), Shandong (Jinan,
China), Charles University (Prague, Czech Republic), and Jihoceska University (Ceske
Budejovice, Czech Republic)]. In 2008 he was elected European Inventor of the Year (Life time
achievement award). His scientic interests are in the antiviral chemotherapy eld, and, in
particular, the development of new antiviral agents for various viral infections, including herpes
simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), human
immunodeciency virus (HIV), hepatitis B virus (HBV), human papilloma virus (HPV),
and hepatitis C virus (HCV). He has (co)-discovered a number of antiviral drugs, currently
used in the treatment of HSV infections (valaciclovir, Valtrexs, Zelitrexs), VZV infections
(brivudin, Zostexs, Briviracs, Zerpexs), CMV infections (cidofovir, Vistides), HBV
infections (adefovir dipivoxil, Hepseras), and HIV infections (AIDS) (tenofovir disoproxil
fumarate, marketed as Vireads, and, in combination with emtricitabine, as Truvadas, and, in
combination with both emtricitabine and efavirenz, as Atriplas). Vireads has also recently
been approved for the treatment of HBV infections (chronic hepatitis B).
Prof. Dr. Xinyong Liu was born in 1963 in Qingdao, Shandong province, China. He received his
B.S. and M.S. degrees from School of Pharmaceutical Sciences, Shandong University, in 1984
and in 1991, respectively. From 1997 to 1999 he worked at Instituto de Quimica Medica
(CSIC) in Spain as a senior visiting scholar. He obtained his Ph.D. from Shandong University
in 2004. He is currently a distinguished professor, a designated Ph.D. advisor, Director of the
Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University.
His research work is partly engaged in rational drug design, synthesis, and bio-evaluation of a
variety of molecules targeted at the specic enzymes and receptors. At present time, his research
interests are mainly focused on the design and synthesis of novel anti-HIV agents based on the
mechanism of drugs action and computer-assisted drug design, such as HIV-1 (non)nucleoside
reverse transcriptase inhibitors, HIV-1 transactivation inhibitors based on HIV-1 Tat-TAR
interaction, and Rev-RRE interaction in the viral transcription step. His second ongoing
program is total synthesis and structural modications of some natural products from Chinese
Traditional Medicine active in cerebro- and cardio-vascular biology. He has contributed to
about 150 scientic publications and patents as well as many monographs.

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HIV-1 NNRTIs: Structural Diversity,

Pharmacophore Similarity, and

Published online 26 April 2011 in Wiley Online Library (wileyonlinelibrary.com).

Medicinal Research Reviews, 33, No. S1, E1E72, 2013

1, Nevirapine 2, Delavirdine 3, Efavirenz 4, Etravirine/TMC-125

Medicinal Research Reviews DOI 10.1002/med

Necessity Feasibility Inspiration

NNRTIs Leads Discovery and Optimization

Medicinal Chemistry Crystallography Computational Chemistry

Bioisosterism Principle The Explanation of QSAR Molecular Docking

2. STRUCTURAL DIVERSITY OF NNRTIS

Table I. Overview of the Structural Classes of NNRTIs

Chemical General Representative

Medicinal Research Reviews DOI 10.1002/med

Chemical General Representative

linker (a-APA, R89439)

30 -spiro-500 -(400 -amino-100 ,200 -

heterocyclic core scaffolds, ve-membered heterocyclic core scaffolds, (thio)amide linker

5a, Tivirapine (R 86183) 1, (Nevirapine, BI-RG-587) 6 7, NSC 625487

Figure 3. Chemical structures of NNRTIs with multicyclic scaffolds.

Figure 4. Chemical structures of NNRTIs with benzo-fused heterocyclic scaffolds.

3. COMMON FEATURES OF NNRTIs

A. Ubiquitous Fragments (Motifs) in NNRTI Scaffolds

Figure 5. Chemical structures of NNRTIs with six-membered heterocycles core scaffolds.

B. Molecular Modeling (From Buttery to Horseshoe)

44, RD4-2024 45a 45b

Figure 6. Chemical structures of NNRTIs with five-membered heterocycles core scaffolds.

Figure 7. Chemical structures of NNRTIs with (thio)amide linker containing scaffolds.

Medicinal Research Reviews DOI 10.1002/med

COOMe COOMe MeO Br NC CN

58 a 59a 60 61a: R = Me, RT IC = 50 nM

Figure 8. Chemical structures of NNRTIs with diphenyl scaffolds.

Figure 9. Chemical structures of NNRTIs with other scaffolds.

Medicinal Research Reviews DOI 10.1002/med

C. 3D Pharmacophore Model of NNRTIs

1, Nevirapine 2, Delavirdine 3, Ef avirenz 25, L-737,126

Molecular mechanics calculations

Uniform sampling of low energy conformers

Mapping the essential structural components

D. General Types of NNIBP

Medicinal Research Reviews DOI 10.1002/med

Hydrogen bond OH, SH, NH Donor to K103 (1EP4, 1KLM)

W229 Wing I Wing II

4. THE NNRTI LEAD DISCOVERY APPROACHES

Figure 15. Examples of representative NNRTIs discovered from HTS.

Figure 16. The discovery of hexahydroxybiphenyl NNRTIs.

MeO OMe OMe

Figure 17. Lignans-based NNRTIs.

Figure 19. The novel suksdorfin derivatives as potent NNRTIs.

4-methyl-DCK (20b), 3-hydroxymethyl-4-methyl-DCK (20c, HMDCK), and (30 R,40 R)-3-

1. Docking-Based Virtual Screening

Figure 20. The structures of NNRTIs obtained using virtual screening.

Medicinal Research Reviews DOI 10.1002/med

D. De Novo Design of NNRTIs

Four RT crystal structures: WT, Y181C, K103N, L100I + K103N

Identified fragments that appears in all structures

Build a molucule by linking cross reacting fragments

Minimize and dock final molecule to each structure separately

Synthesize and test various derivatives based on the designed pharmacophore

conformational exibility of RT has complicated the traditional structure-based de novo drug

31a 0.71 1.13 1.36 0.035 0.607

Medicinal Research Reviews DOI 10.1002/med

5. OPTIMIZATION STRATEGIES OF NNRTI LEADS

In the NNRTI modication process, the combination of traditional medicinal chemistry,