S

Supporting Information
A Comparison of Methods for Modeling Quantitative Structure-Activity
Relationships
Jeffrey J. Sutherland, Lee A. OBrien and Donald F. Weaver.

Contents
A.1. Datasets and literature references ........................................................................................... 2
ACE............................................................................................................................................. 2
AchE ........................................................................................................................................... 3
BZR............................................................................................................................................. 7
COX2 ........................................................................................................................................ 13
DHFR........................................................................................................................................ 22
GPB, THER, THR .................................................................................................................... 34
A.2. Values of q2L20%O and q2L33%O, and thresholds for defining outliers..................................... 35
A.3. Alignment procedures for CoMFA, CoMSIA ...................................................................... 40
A.4. Description of grids used for CoMFA, CoMSIA.................................................................. 42
A.5. 2.5D descriptors used as inputs for neural network models ................................................. 43
A.6. Notes on electronic files........................................................................................................ 43

A.1. Datasets and literature references

ACE
The following compounds are drawn incorrectly in the original publication;1 they are corrected
in the electronic files: mol_35, mol_53, mol_54, mol_55, mol_56, thiol_2, thiol_4, thiol_27,
thiol_28.
Table A.1.1. ACE inhibitor sets
Training set
MOL_07, MOL_08, MOL_09, MOL_12, MOL_14, MOL_15, MOL_16, MOL_18, MOL_19,
MOL_20, MOL_21, MOL_22, MOL_24, MOL_25, MOL_26, MOL_29, MOL_30, MOL_31,
MOL_33, MOL_34, MOL_37, MOL_38, MOL_41, MOL_42, MOL_43, MOL_45, MOL_46,
MOL_47, MOL_49, MOL_50, MOL_51, MOL_52, MOL_53, MOL_56, MOL_57, MOL_59,
MOL_63, MOL_65, MOL_66, MOL_68, COO_23A, COO_23J, COO_24C, COO_25A,
COO_25E, COO_26A, COO_26C, COO_26H, SQ29852, SQ29852_2B, SQ29852_2Q,
SQ29852_2R, SQ29852_2T, SQ29852_2U, SQ29852_2V, SQ29852_2W, SQ29852_2Y,
SQ29852_2Z, SQ29852_2X, SQ29852_2E, SQ29852_2K, SQ29852_2I, THIOL_2, THIOL_4,
THIOL_5, THIOL_7A, THIOL_7B, THIOL_9, THIOL_10, THIOL_14, THIOL_18,
THIOL_20A, THIOL_20B, THIOL_27, THIOL_30A, THIOL_30B
Test set
MOL_01, MOL_02, MOL_03, MOL_04, MOL_05, MOL_06, MOL_10, MOL_11, MOL_13,
MOL_17, MOL_23, MOL_27, MOL_28, MOL_32, MOL_35, MOL_36, MOL_39, MOL_40,
MOL_44, MOL_48, MOL_54, MOL_55, MOL_58, MOL_60, MOL_61, MOL_62, MOL_64,
MOL_67, COO_23E, COO_24A, SQ29852_2A, SQ29852_2P, SQ29852_2S, SQ29852_2G,
SQ29852_2H, THIOL_12, THIOL_22, THIOL_28
ACE references
(1) Depriest, S. A.; Mayer, D.; Naylor, C. B.; Marshall, G. R. 3D-QSAR of angiotensin-converting enzyme and
thermolysin inhibitors - a comparison of CoMFA models based on deduced and experimentally determined
active-site geometries. J. Am. Chem. Soc. 1993, 115, 5372-5384.

S
AchE
Table A.1.2. Structures (families) of AchE inhibitors
A.2

A.1
N
R1

R3

R1

N
R2

B.2

B.1

N
R2

3
4

1
N

R1

R2

4
R1

1
R1
3

D.3

O
N

R2

1
2

R1

R2

R1

R2

R1

R2

D.1

D.2

1
N

R3

Table A.1.3. AchE inhibitors

a

Name
1-1
1-2
1-3a
1-3b
1-3c
1-3d
1-3e
1-3f
1-3g
1-3h
1-3i
1-3j
1-3k
1-3l
1-3m
1-3n
1-3o

R1
PhCOPhCOPhCOp-OCH3PhCOp-FPhCOp-NO2PhCOp-pyridineCOcyclohexylCOCH3COCH3CH2COCH3COCH3COCH3COCH3COCH3CH2CH3COCH3CO-

R2
HMePhPhPhPhPhPhPhPhm-OCH3Php-OCH3Phm-FPhp-FPhPhp-pyridineMe-

R3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H

Family
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1

IC50
(nM)
560
170
35
590
18
5.4
64
9400
52
830
46
700
65
205
12000
108
660

Set
b

1
1
1
1
1
1
2
1
1
1
1
2
2
1
1
1
2

S
2-3b
2-3c
2-3d
2-3e
2-3f
2-3g
2-3h
2-3i
2-3j
2-3k
2-3l
2-3m
2-3n
2-3o
2-3p
2-3r
2-12
2-14
2-15
2-21
2-22
2-23
2-25
2-26
2-27
2-28
2-29
2-30
2-24
2-31
2-32
2-33
2-34
2-35
2-36
1-10
1-13
1-14
1-15
1-17
1-18
1-19
1-20
1-21
1-22
1-23
1-24
1-25
1-16

o-MePhCOm-MePhCOp-MePhCOo-NO2PhCOm-NO2PhCOp-NO2PhCOp-OMePhCOp-CHOPhCOp-ClPhCOp-FPhCOp-MeCOPhCOp-(PhCH2SO2)PhCOo-pyridineCOm-pyridineCOp-pyridineCOcyclohexylCOPhCH2PhCOPhCOp-(PhCH2SO2)PhCOp-(PhCH2SO2)PhCOp-(PhCH2SO2)PhCOPhCOPhCOPhCOPhCOPhCOPhCOPhCOPhCOPhCOPhCOPhCOPhCOPhCOH
4-NO2
4-NO2
4-NO2
4-NH2
4-NHCOMe
4-NHCOPh
4-OMe
4-CONHCH2Ph
4-COPh
6-NO2
6-NH2
6-NHCOPh
4-NO2

HHHHHHHHHHHHHHHHHEtPhCH2MeEtPhMeMeMeMeMe
MeMeMeMeMeMeMeMeH
H
4-OMe
4-Cl
H
H
H
H
H
H
H
H
H
Me-

H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2-Me
3-Me
4-Me
2-NO2
3-NO2
4-NO2
H
PhCH2CH2PhCH=CHCH2-

PhCOcyclopropyl-CH2cyclohexyl-CH2-

adamantylCH2-

A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.2
A.2
A.2
A.2
A.2
A.2
A.2
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.2

1000
470
180
880
230
55
88
120
180
85
51
29
800
69
39
1600
46000
130
940
0.6
0.3
0.6
770
145
41000
14000
370
3300
26000
13000
54000
52000
38000
410
24000
30
12.5
440
240
8.8
2.8
1.2
8
2.2
2.4
9
11
340
6800

2
1
1
2
1
1
2
1
1
1
1
1
1
2
1
1
1
1
1
1
1
2
1
1
1
1
2
1
1
2
2
1
1
1
2
1
1
1
1
2
1
1
1
2
2
2
1
2
1

98

1-9

S
O

O2N

1-11

27000

3000

13

1100

13

1000

17

1600

23

1200

800

4.2

13

4.5

270

N
O
O

O2N

1-12

N
O

1-26

N
N
O

1-29

3-12a

MeO
MeO
O

1-31a

1-31b

O
N

1-31c
O

1-31d

N
O

1-34
N
O

1-35
N
H
O

1-37
N
H

O
N

1-38

N
H

O
O
N

1-39
N
H

Cl

1-40

N
O

S
2-9

PhCO(CH2)3-

530

150

3300

30

2100

15000

300

4400

3-9
O

3-13n

MeO
MeO
O

3-13o

MeO
MeO

3-13c
O

3-13d
OH

3-17

MeO
MeO
MeO

3-18
MeO

3-13e
5,6-diOMe
H
D.1
5.7
1
3-13f
6-OMe
H
D.1
81
2
3-13g
5-OMe
H
D.1
6.4
1
3-13h
4-OMe
H
D.1
12
1
3-13i
6.7-diOMe
H
D.1
85
1
3-13j
5,7-diOMe
H
D.1
25
1
3-13k
4,7-diOMe
H
D.1
36
1
3-13l
4,5-diOMe
H
D.1
20
1
3-13m
5,6,7-triOMe
H
D.1
13
2
3-16a
5,6-diOMe
2-Me
D.1
10
1
3-16b
5,6-diOMe
3-Me
D.1
2
1
3-16c
5,6-diOMe
4-Me
D.1
40
1
3-16d
5,6-diOMe
2-NO2
D.1
160
1
3-16e
5,6-diOMe
3-NO2
D.1
4
2
3-16f
5,6-diOMe
4-NO2
D.1
100
1
3-13a
5,6-diOMe
PhCOD.2
>10000
2
3-13b
5,6-diOMe
HD.2
5400
2
3-16g
5,6-diOMe
cyclohexylCH2D.2
8.9
1
3-16h
5,6-diOMe
PhCH2CH2D.2
180
2
3-15a
5,6-diOMe
C
D.3
480
1
3-15b
5,6-diOMe
N
D.3
94
2
a
names are formed by hyphenating the reference number and the label given to the compound in the reference; e.g.
1-2 is compound 2 in reference 1.
b
training set and test set compounds are indicated as 1 and 2.

AchE references
(1) Sugimoto, H.; Tsuchiya, Y.; Sugumi, H.; Higurashi, K.; Karibe, N. et al. Synthesis and structure-activity
relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine and related
derivatives. J. Med. Chem. 1992, 35, 4542-4548.
(2) Sugimoto, H.; Tsuchiya, Y.; Sugumi, H.; Higurashi, K.; Karibe, N. et al. Novel piperidine derivatives.
Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives.
J. Med. Chem. 1990, 33, 1880-1887.
(3) Sugimoto, H.; Iimura, Y.; Yamanishi, Y.; Yamatsu, K. Synthesis and structure-activity relationships of
acetylcholinesterase inhibitors: 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2- Yl)methyl]piperidine hydrochloride
and related compounds. J. Med. Chem. 1995, 38, 4821-4829.

BZR
Table A.1.4. Structures (families) of BZR ligands
A.1
9

R4

R2

R4

R3
R1

NHCH3

R3

A.12

R1

R2

O-

R4
R3

A.13
O

A.14

R1

A.15
R1

R4

N
O

R2

R3

R3

R4

A.8

N+

R4

O-

R3

H
N

N+

R4

R3

A.7

N
R4

R3

A.6

H
N
N

R3

A.5

H
N
R4

A.4

H
N

8
7

A.3

A.2

R1

S
R4

N
R2

R4

R1
N

R3

R3

7
R4

R5

A.17

H
N

A.18

A.19

R1

A.20

R1

N
R4

R4

R4

R4

R3

R3

R3

R3

A.21

A.22

R4

A.23

R1

A.24

H
N

COR1

R4

N
N

R3
N

R4

R4

R3

R3

A.25

A.26

N
COR1

R4 10
9
8
7

H
N

COOC2H5
N

COR1

R4

A.27

Table A.1.5. BZR ligands

a

Name

Ro05-3061
Ro05-4865
Ro05-6820
Ro05-6822
Nordazepam
Diazepam
Ro07-3953
Ro07-4065
Delorazepam
Ro05-2904
Ro14-3074
Nitrazepam
Ro05-4435
Flunitrazepam
Clonazepam

R1
-H
-Me
-H
-Me
-H
-Me
-H
-Me
-H
-H
-H
-H
-H
-Me
-H

R2
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H

R3
-Ph
-Ph
-C6H4-2-F
-C6H4-2-F
-Ph
-Ph
-C6H3-2,6-F
-C6H3-2,6-F
-C6H4-2-Cl
-Ph
-C6H4-2-F
-Ph
-C6H4-2-F
-C6H4-2-F
-C6H4-2-Cl

R4
-7-F
-7-F
-7-F
-7-F
-7-Cl
-7-Cl
-7-Cl
-7-Cl
-7-Cl
-7-CF3
-7-N3
-7-NO2
-7-NO2
-7-NO2
-7-NO2

R5

Family
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1

IC50
(
M)

Set

0.04
0.017
0.0074
0.0051
0.0094
0.0081
0.0016
0.0041
0.0018
0.013
0.0053
0.01
0.0015
0.0038
0.0018

1
1
1
1
1
1
1
1
1
1
2
2
1
1
1

S
Ro05-3590
Ro20-7736
Ro05-3072
Ro05-4318
Ro20-1815
Ro05-4619
Ro05-3308

-H
-Me
-H
-Me
-Me
-H
-H

-H
-H
-H
-H
-H
-H
-H

-C6H4-2-CF3
-C6H4-2-F
-Ph
-Ph
-C6H4-2-F
-C6H4-2-Cl
-Ph

Ro12-6377

-Me

-H

-C6H4-2-F

Ro05-9090
Ro05-4528
Ro20-2541
Ro20-2533
Ro20-5747
Ro20-5397
Ro20-3053
Ro05-3343
Ro05-2921
Ro05-4336
Ro07-4419
Ro05-4520
Ro05-3546
Ro13-0699
Ro07-6198
Ro20-8895
Ro13-0593
Ro13-0882
Ro22-6762
Ro20-8065
Ro20-8552
Ro05-2750
Ro14-2312
Ro17-2221
Halazepam
Pinazepam

-Me
-Me
-Me
-H
-H
-H
-H
-H
-H
-H
-H
-Me
-H
-Me
-H
-H
-Me
-Me
-Me
-H
-H
-H
-Me

-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H

-Ph
-Ph
-C6H4-2-F
-Ph
-Ph
-Ph
-C6H4-2-F
-Ph
-Ph
-C6H4-2-F
-C6H3-2,6-F
-C6H4-2-F
-Ph
-C6H4-2-F
-C6H3-2,6-F
-C6H4-2-F
-C6H4-2-F
-C6H4-2-F
-Ph
-C6H4-2-F
-C6H4-2-F
-Ph
-C6H4-2-F
-Ph
-Ph
-Ph

-H

Prazepam
Ro06-9098
Ro20-1310
Ro05-7094
Ro07-1986
Ro07-2750

-CH2CH2NH2

-CH2CF3
-CH2CCH
-CH2cycloPr
-CH2OCH3
-t-Bu
-CH(CH3)
CONHCH3
-CH2CH2NH2
-CH2CH2OH

-7-NO2
-7-NHOH
-7-NH2
-7-NH2
-7-NH2
-7-NH2
-7-NHCOCH3
-7NHCONHCH3
-7-CH2NH2
-7-CN
-7-CN
-7-Et
-7-CH=CH2
-7-CHO
-7-COCH3

A.1
A.1
A.1
A.1
A.1
A.1
A.1

0.0035
0.096
0.386
0.46
0.065
0.075
>1

1
1
1
1
1
1
3

A.1

0.455

-7-Cl
-7-Cl

A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1

>1
0.38
0.03
0.036
0.024
0.043
0.018
>1
0.35
0.021
0.019
0.014
0.32
0.15
0.028
0.019
0.072
0.3
0.04
0.0036
0.014
0.037
>1
0.26
0.092
0.0925

3
1
2
1
1
1
2
3
1
1
1
1
1
1
1
1
1
2
1
1
1
2
3
1
1
1

-Ph

-7-Cl

A.1

0.11

-H
-H

-Ph
-Ph

-7-NO2
-7-Cl

A.1
A.1

0.43
0.62

2
2

-H

-Ph

-7-Cl

A.1

>1

-H
-H

-C6H4-2-F
-C6H4-2-F

-7-Cl
-7-Cl

A.1
A.1

0.0083
0.0245

1
1

-7-SO2N(CH3)2

-6-Cl
-6-Cl
-8-Cl
-8-CH3
-9-Cl
-6,8-Cl
-6,7-Cl
-6,7-Cl
-6-Me,7-Cl
-6,8-Cl
-6-NH2,8-Cl

-CH2CH
(OH)CH2OH
-t-Bu
-CH2CO2H
-H

-H

-C6H4-2-F

-7-Cl

A.1

0.14

-H
-H
-H

-C6H4-2-Cl
-C6H4-2-F
-Me

-7-NO2
-7-Cl

A.1
A.1
A.1

0.3
>1
>1

2
3
3

-H

-H

-7-Cl

A.1

0.034

Tetrazepam

-Me

-H

-7-Cl

A.1

0.034

Ro05-3328

-H

-H

-7-Cl

A.1

0.087

Ro10-3580
Ro22-4683
Ro07-5096
Ro05-3663
Desmethyltetrazepam

-1cyclohexene
-1cyclohexene

cyclohexane

S 10
Bromazepam
Ro11-4878
Meclonazepam
Ro11-6896
Ro07-4532
Ro06-7263
Oxazepam
Temazepam
Lorazepam
Ro20-7078
Clorazepate
Ro11-8125
Ro08-6739
Ro08-9212
Ro10-2643
Premazepam
Ro05-3395
Ro05-2181
Ro05-2881
Ro05-3636
Ro15-8852
Chlordiazepoxide
Demoxepam
Medazepam
Clobazam
Desmethylclobazam
U-35005
Estazolam
Alprazolam
Triazolam
alpha-hydroxytriazolam
Adinazolam
Ro11-5073
Ro11-6679
Ro17-4582
Etizolam
Ro11-1465
Ro11-7800
Midazolam
alpha-hydroxymidazolam
Ro15-8670
Ro16-0529
Ro21-5205

-H
-H
-H
-Me
-Me
-Cl
-H
-Me
-H
-Me
-H

-H
--Me
--Me
--Me
-(CH3)2
-Me
-OH
-OH
-OH
-Cl
-CO2H

-H
-H
-Me
-Me
-H

-H
-H
-H
-Me
-Me

Ro22-1892

-H

Ro22-0992
Ro21-8137
Ro21-8482
Ro14-1359

-H
-H

-2-pyridyl
-C6H4-2-F
-C6H4-2-Cl
-C6H4-2-F
-Ph
-Ph
-Ph
-Ph
-C6H4-2-Cl
-C6H4-2-F
-Ph
-C6H4-2-Cl
-Ph
-C6H4-2-Cl
-C6H4-2-Cl
-Ph
-Ph
-Ph
-Ph
-C6H4-2-F
-C6H4-2-Cl

-7-Br
-7-Cl
-7-NO2
-7-NO2
-7-Cl
-7-Cl
-7-Cl
-7-Cl
-7-Cl
-7-Cl
-7-Cl
-H
-Cl
-Cl
-Cl
-H
-Cl
-Cl
-Cl
-NO2

A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.2
A.2
A.2
A.3
A.4
A.5
A.5
A.5
A.5
A.5

0.018
0.0035
0.0012
0.007
>1
0.049
0.018
0.016
0.0035
0.0053
0.059
0.037
0.07
0.0039
0.0094
0.17
>1
>5
>1
>1
0.726

2
1
1
2
3
1
1
1
2
1
2
1
1
2
2
2
3
3
3
3
2

-Ph

-Cl

A.6

0.352

-Me

-Ph
-Ph
-Ph

-Cl
-Cl
-Cl

A.7
A.8
A.12

0.31
0.87
0.13

2
2
2

-H

-Ph

-Cl

A.12

0.21

-Me
-H
-Me
-Me

-H
-H
-H
-H

-C6H4-2-Cl
-Ph
-Ph
-C6H4-2-Cl

-H
-Cl
-Cl
-Cl

A.13
A.13
A.13
A.13

0.0043
0.0085
0.02
0.004

1
1
1
1

-CH2OH

-H

-Ph

-Cl

A.13

0.0042

-CH2N(CH3)2

-H
--Me
--Me

-H

-Ph
-C6H4-2-F
-C6H4-2-F
-C6H4-2-Cl
-C6H4-2-Cl
-C6H4-2-Cl
-C6H4-2-Cl
-C6H4-2-F

-Cl
-Cl
-NO2
-H
-Et
-Cl
-Cl
-8-Cl

A.13
A.13
A.13
A.14
A.14
A.14
A.14
A.15

0.135
0.0033
0.004
0.0035
0.0031
0.0014
0.0029
0.0048

1
2
1
1
1
2
1
1

-CH2OH

-H

-C6H4-2-F

-8-Cl

A.15

0.0045

-H
-H
-H

-CO2Et
-CO2C(CH3)3
-CO2CH3

-Ph
-Ph
-C6H4-2-F

-8-Cl
-7-Cl
-8-Cl

A.15
A.15
A.15

0.015
0.014
0.0074

1
2
1

-C6H4-2-F

-8-Cl

A.15

0.012

-C6H4-2-Cl
-C6H4-2-F
-C6H4-2-Cl
-C6H4-2-F

-8-Cl
-8-Cl
-8-Cl
-Cl

A.15
A.15
A.15
A.17

0.013
0.0035
0.026
0.07

1
1
2
2

-Me
-Me
-Me
-Me
-Me
-CH2NH2
-Me

-CH2N(CH3)2

CO2CH(CH3)2
-CO2H
-CONH2
-CONH2

S 11
Ro15-8867
Ro14-7187
Ro13-9868
Ro14-5921
Ro14-0304
Ro14-2652
Ro15-9270
Ro14-0609
Ro15-2201
Ro15-0791
Ro15-2200
Ro15-3929
Ro14-3930
Ro14-5568
Ro22-1274
Ro22-1251
Ro22-1366
Ro22-2038
Ro22-3245
Ro22-3148
Ro22-3147
Ro22-0780
Ro22-2466
Ro14-7181
Ro16-4234
Ro14-5974
Ro15-4941
Ro14-5975
Ro16-3607
Ro16-6624
Ro16-3774
Ro16-0071
Ro16-5824
Ro16-8912
Ro16-4261
Ro16-6127
Ro16-6048
Ro16-6950
Ro16-4019
Ro16-3031

-Me
-Me
-H
-Me
-CH2NH2
-Me
-CO2CH3
-CO2Et
-CO2Et
-CO2Et
-CONH2
-H
-Me
-Me
-NH2
-H

-NH2
-NH2
-OEt
-OEt
-OEt
-O-t-Bu
-O-t-Bu
-O-t-Bu
-O-t-Bu
-O-t-Bu
-O-t-Bu
-O-t-Bu
-O-t-Bu
-O-t-Bu
-O-t-Bu
-O-n-Pr
-O-i-Pr

-C6H4-2-Cl
-Ph
-Ph
-C6H4-2-F
-C6H4-2-F
-C6H4-2-F
-C6H4-2-Cl
-C6H4-2-F
-Ph
-Ph
-C6H4-2-F
-C6H4-2-F
-C6H4-2-F
-C6H4-2-F
-C6H4-2-F
-Ph
-C6H4-2-F
-C6H4-2-F
-C6H4-2-Cl
-Ph
-C6H4-2-Cl
-Ph
-C6H4-2-F

-NO2
-H
-Cl
-Cl
-Cl
-Cl
-NO2
-Cl
-H
-H
-H
-Cl
-Cl
-Cl
-Cl
-Cl
-Cl
-Cl
-Cl
-H
-H
-Cl
-Cl

-8-SMe
-8-F
-9-F
-8-Cl,9-F
-8-CF3
-8-NO2
-8-Cl
-8-Cl

A.17
A.18
A.18
A.18
A.18
A.18
A.18
A.19
A.20
A.20
A.20
A.20
A.20
A.20
A.21
A.22
A.22
A.22
A.22
A.23
A.23
A.23
A.23
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24
A.24

0.025
0.41
0.042
0.019
0.0065
0.0056
0.005
0.0244
0.0015
0.0025
0.0042
0.016
0.015
0.23
0.075
0.011
0.004
0.0028
0.0028
0.42
0.0052
0.011
0.0019
>1
3
0.0064
0.0017
0.062
0.046
0.01
0.0032
0.0032
0.0034
0.0062
0.0077
0.0031
0.0033
0.0028
0.0014
0.0025

1
2
1
1
1
2
2
2
2
1
1
1
2
2
2
1
1
2
1
1
1
1
2
3
2
1
2
1
1
1
1
1
1
1
1
1
1
2
1
1

-8-Cl
-8-Cl
-9-Cl
-8-OMe
-8-Et
-8-Me

Ro16-9906

-OCH2CH=CH2

-8-Cl

A.24

0.0017

Ro16-7082
Ro16-7083

-O-i-Bu
-O-sec-Bu

-8-Cl
-8-Cl

A.24
A.24

0.0063
0.0029

1
1

Ro16-9918

-O-CH2cycloPr

-8-Cl

A.24

0.0023

-8-Cl

A.24

0.004

-8-Cl

A.24
A.25
A.25
A.25
A.25
A.25

0.0053
>1
0.003
0.0027
0.0068
>1

1
3
1
1
2
3

Ro16-6654
Ro17-1302
Ro15-2427
Ro14-7437
Ro15-3505
Ro15-1310
Ro15-1746

-Ocyclohexyl
-O-Ph
-NH2
-OEt
-OEt
-OEt
-OEt

-7-Cl
-8-Cl
-9-Cl

S 12
Ro15-3237
-OEt
-10-Cl
Ro17-9741
-OMe
-7-Cl
a
names are those given in the original reference.
b
training set, test set and inactive compounds are indicated as 1, 2 and 3.

A.25
A.26

>1
0.0024

3
1

BZR references
(1) Haefely, W.; Kyburz, E.; Gerecke, M.; Mohler, H. Recent advances in the molecular pharmacology of
benzodiazepine receptors and in the structure-activity relationships of their agonists and antagonists. Adv. Drug
Res. 1985, 14, 165-322.

S 13
COX2
Table A.1.6. Structures (families) of COX-2 inhibitors
A.1

A.2

R1

R2

B.1

R1

R2

B.2

R1

R2

R4

R3

C
R1

R2

R3

B.4

R1

R2

R3

B.3

R3
R4

R1

D.1

R1

R2

R1

R2

N
R3
N

R3

R2

R3

D.2

E.1

R3

R3

E.2

R1

R1
R2

R1

R2

R1

R3
N

N
N

R4

n=R3

R2

R3

R3

R2

(CH2)n

G
R1

R2

R1

R1

J.2

R2

R3

R3

K
R2

R1

N
R2

J.1
R2

R1

R2

R1

R2

R1

R2

R1

N
N

R3

R4

R3

R3

S 14
Table A.1.7. COX-2 inhibitors
a

Name
1-1
1-3
1-4
1-5
1-6
1-8
1-9
1-10
1-16
1-17
1-19
1-20
1-21
1-22
1-27
1-28
1-29
1-31
1-32
1-33
1-34
1-37
1-38
1-41
1-42
2-20
3-5
3-6
3-10
3-12
3-13
3-14
3-15
3-16
3-17
3-18
3-20
3-22
3-27
3-28
3-29
3-30
3-31
3-32
3-33
3-38
3-40
3-41
3-42

R1
-4-SO2Me
-4-F
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-F
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2

R2
-4-F
-4-SO2Me
-4-F
-H
-4-CF3
-4COMe
-3,4-F
-4-F
-3-SO2Me
-4SO2Et
-3-Cl-4-SO2Me
-4-SO2NH2
-4-SO2NHMe
-4-SO2NMe2
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-4-Cl
-4-Cl
-H
-4-OMe
-4-NHMe
-4-NMe2
-4-SMe
-4-SOMe
-4-SO2Me
-4-Cl
-H
-3-Cl
-3-OMe
-3-SMe
-3-CH2OMe
-3-NMe2
-3-NHMe
-3-NH2
-3-NO2
-2-Cl
-2-Me
-2-OMe
-2-F

R3
-Me
-H
-H
-Me
-Me
-Me
-Me
-Et
-H
-H
-H
-H
-H
-H
-CF3
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3

R4

Family

-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-COCF3
-COMe
-SO2CF3
-CHO
-CN
-Br
-CH2OAc
-CH2OH
-CH(OH)CF3
-CH2CF3
-H

A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.1
A.2
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1

IC50
(
M)
0.06
0.51
10.2
0.06
0.08
2.87
0.25
>100
>100
>100
>100
0.014
>100
>100
>100
0.12
1.61
0.06
3.23
0.75
0.02
0.47
3.88
1.44
0.14
0.52
0.24
0.11
0.12
0.57
1.47
0.7
0.16
>100
5.7
0.01
0.04
0.06
0.35
0.35
68.1
3.2
0.92
5.89
0.58
0.9
0.8
>100
0.1

Set
1
1
2
1
1
2
1
3
3
3
3
2
3
3
3
1
1
2
2
2
2
2
1
1
2
2
1
1
1
1
1
1
1
3
1
1
1
1
1
1
2
1
1
1
2
1
1
3
1

S 15
3-43
3-44
3-46
3-47
3-49
3-50
3-52
3-54
3-55
3-56
3-57
3-58
3-61
3-64
3-65
3-66
3-69
3-70
3-71
3-72
3-73
3-75

-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2

3-79

-4-SO2Me

3-80

-4-SO2Me

3-83
3-87
3-88
3-89
3-90
3-91
3-92
3-96
3-99
3-100
3-101
3-103
4-25
4-36
4-40
4-41
4-42
4-43
4-44
4-48
4-49
4-58
4-59
4-60
4-62
4-63
4-50
4-51

-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2Me
-4-SO2Me

-2-Me
-4-OMe-3-F
-4-SMe-3-Cl
-4-NMe2-3-Cl
-4-NHMe-3-Cl
-4-Me-3-Cl
-3-Me-4-F
-3-OMe-4-Cl
-3-NMe2-4-Cl
-3,4-OCH2O-3,4-F
-3,4-Me
-3-OMe-5-F
-2-Me-5-F
-2-Me-6-Cl
-4-OMe-3-F
-4-SMe-3-Cl
-4-Me-3-Cl
-3-OMe-4-Cl
-3,4-F
-3-Me-5-Cl
-3-OMe-5-Cl
-4-OMe-3,5Me
-4-OMe-2,5Me
-4-Cl
4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-H
-2-Me
-6-OMe
-5-OMe
-5-Br
-H
-2-Me
-5-OMe
-5-Br
-H
-H
-H
-H
-H
-6-Me
-5-Me

-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
R2
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3

B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1

0.2
0.15
0.04
0.32
0.66
0.03
0.17
0.25
1.04
0.17
0.12
0.33
0.96
>100
>100
0.03
0.01
0.003
0.02
0.03
0.04
0.46

1
1
1
1
2
1
1
1
1
1
1
1
1
3
3
1
1
1
1
1
1
2

-CF3

B.1

0.72

-CF3

B.1

12.2

-H
-CHF2
-CH2F
-CHO
-CN
-CO2Et
-CO2H
-Ph
-CH2OMe
-CH2OH
-CH2SMe
-CH2CN
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CHF2
-CN
-Me
-CH2OH
-CHF2
-CF3
-CF3

B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.1
B.2
B.2
B.2
B.2
B.2
B.2
B.2
B.2
B.2
B.2
B.2
B.2
B.2
B.2
B.3
B.3

>100
0.61
0.41
1.6
0.23
5.7
>100
0.24
3.72
8.35
0.32
1.54
1.69
9.6
1.2
37.6
0.95
0.44
2.8
>100
0.34
20.7
24.4
79
93.4
1.83
2.9
1.3

3
1
1
1
1
2
3
1
1
1
2
2
1
1
1
1
1
1
1
3
1
1
2
2
1
2
1
1

S 16
4-52
4-53
4-54
4-55
4-56
4-57

-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2

-4-Me
-3-Me
-6-Me
-5-Me
-4-Me
-3-Me

4-64

-4-SO2Me

-CF3

-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
N

B.3
B.3
B.3
B.3
B.3
B.3

0.53
5.8
0.42
0.73
0.44
1.54

1
1
1
1
1
1

B.4

1.2

B.4

0.63

B.4

1.1

B.4

0.47

B.4
B.4
B.4
B.4
B.4

51
0.47
0.07
0.026
1.1

2
1
1
1
2

B.4

0.94

B.4

0.52

B.4

0.43

B.4

0.11

B.4

4.15

B.4

0.41

C
C
C
C
C
C
C
C
C
C
C
C

0.026
0.005
0.003
0.865
0.053
77.9
3.2
6.6
0.221
0.075
0.015
0.067

1
1
1
1
2
2
1
2
1
1
1
1

4-66

-4-SO2Me

-CF3
H3C
N

4-67

-4-SO2Me

-CF3
O

4-69

-4-SO2Me

-CF3

4-70
4-71
4-72
4-73
4-74

-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2Me
-4-SO2Me

-CF3
-CF3
-CF3
-CF3
-CF3

4-75

-4-SO2Me

-3-thienyl
-2-thienyl
-2-thienyl
-4-Br-2-thienyl
-3-Me-2-thienyl
S

-CF3

CH3
N

4-76

-4-SO2NH2

-CF3

CH3
N
S

4-77

-4-SO2NH2

4-78

-4-SO2NH2
-4-SO2Me

N
CH3

-CF3
S

4-79

CH3

-CF3

-CF3
N

4-80

-4-SO2NH2

-CF3

5-1a
5-1b
5-1d
5-1f
5-1g
5-1h
5-1i
5-1j
5-1k
5-1l
5-7a
5-7c

-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me

-4-F
-4-OMe
-4-Me
-4-CF3
-2,4-Cl
-4-CN
-4-CH2OH
-4-CH2OCH3
-4-SMe
-4-F-2-Me
-4-F
-4-F

CH3

O
CH3

-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-Me
-CF3

S 17
5-7e
6-7b
6-7d
6-7i
6-7l
6-7m
6-7p
6-8a
6-8b
6-8h
6-8i
6-8l
6-8m
6-8o
6-8p
7-16a
7-16d
7-17a
7-17b
7-17d
7-20c
7-20f
7-20g
7-20h
7-20i
7-20j
7-20k
7-20o
7-21c
7-21d
7-21g
7-21h
7-21i
7-21j
7-21l
7-21m
7-21o
7-32
7-34
7-36
7-20q
7-21q
7-20p
7-21p
8-1b
8-1c
8-1d
8-1g
8-1i
8-1j
8-1l
8-1m
8-1n

-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2

-4-F
-3,4-F
-3-CF3-4-F
-4-OMe-3-F
-3,4-OCH2O-4-NMe2-3-Cl
-4-CF3-3-F
-4-F
-3,4-F
-4-OMe
-4-OMe-3-F
-3,4-OCH2O-4-NMe2-3-Cl
-4-CF3
-4-CF3-3-F
-4-F
-4-OMe-3-F
-4-F
-4-F-3-Cl
-4-OMe-3-F
-4-F-3-Me
-4-OMe-3,5-Cl
-4-OMe-3-Me
-3,4-OMe
-3,4-OEtO-3,4-OMeO-4-Me
-4-NMe2-3-Cl
-4-F-3-Me
-4-OMe-3-F
-4-OMe-3-Me
-3,4-OMe
-3,4-OEtO-3,4-OMeO-4-Me-3-Cl
-3,4-Me
-4-NMe2-3-Cl
-4-F
-4-F
-4-F
-6-Me-3-pyridyl
-6-Me-3-pyridyl
-5-Me-2-pyridyl
-5-Me-2-pyridyl

-2-F
-3-F
-4-F
-2-Me
-4-Me
-4-Et
-4-NO2
-4-OH
-2-OMe

-CH2F
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-F
-3,4-OMeO-2,3,4,5-F
-3,4-(CH)4-3,4-F
-3,4-F
-3,4-F
-3,4-F
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3

-H
-H
-H
-H
-H
-H
-H
-H
-H

C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.1
D.2
D.2
D.2
D.2
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1

0.051
0.051
>100
0.12
0.021
0.005
0.76
0.007
0.018
0.002
0.016
0.002
0.002
0.15
0.17
0.26
>100
0.061
0.017
0.033
0.005
>100
0.013
0.34
0.34
0.012
0.007
0.008
0.002
0.013
0.005
0.065
0.032
0.004
0.003
0.005
0.006
0.083
>100
>100
0.17
0.051
52.3
0.33
0.058
7.73
0.041
0.069
0.04
0.86
2.63
>100
0.29

2
1
3
1
1
2
1
1
1
2
1
2
1
1
2
2
3
1
1
2
1
3
2
1
1
1
1
1
1
1
1
2
2
1
1
2
2
2
3
3
2
1
2
1
1
1
1
1
1
1
1
3
1

S 18
8-1o
8-1p
8-1q
8-1r
8-1s
8-1t
8-1u
8-1v
8-1w
8-1x
8-1y
8-1z
8-1aa
8-1ab
8-1ac

-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2

8-1ad

-4-SO2NH2

8-1ae
8-1af
8-1ag
8-2a
8-29
8-2c
8-2d
8-2e
8-2f
8-2g
8-2h
8-2l
8-2o
8-3a
8-8a
8-9b
8-10a
8-11a
8-13a
8-14a
8-16a
8-17a
8-19
8-20b
8-20c
8-20d
8-20e
8-20f
8-20g
8-21b
8-22a
8-22c
8-22d
8-22e
8-22f
8-23
8-24

-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NHCH3

-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2

-4-OMe
-4-OEt
-4-SMe
-4-NH2
-2-NMe2
-4-NHMe
-4-NMe2
-4-CH2OH
-4-CO2H
-4-OMe-3-Me
-4-OMe-3-Et
-3,4-OMe
-3-Me-4-SMe
-3-F-4-NMe2
-4NHMe-3-Cl
-5-Me-4-OMe3-Cl
-3,4-Cl
-2,4-Cl
-2,5-Cl
-4-Cl
-4-Cl
-4-CN
-4-SO2Me
-4-CONH2
-4-CO2H
-4-OMe
-4-OMe-3-F
-2,5-Me
-H
-4-F
-H
-4-Cl
-4-F
-4-F
-4-F
-4-Cl
-H
-4-Cl
-H
-H
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-Cl
-4-F
-H
-4-Me
-H
-4-Cl
-H
-H

-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3

-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H

E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1

0.008
0.64
0.009
0.34
14.3
0.016
0.0047
93.3
11.2
0.0093
0.43
0.6
0.0037
0.0057
0.027

1
2
1
1
2
1
1
2
1
1
1
1
1
1
2

-CF3

-H

E.1

0.066

-CF3
-CF3
-CF3
-CHF2
-CF3
-CHF2
-CHF2
-CHF2
-CHF2
-CHF2
-CHF2
-CHF2
-CHF2
-CO2Me
-Me
-5-Cl-2-thienyl
-CO2H
-CO2NH2
-CN
-CH2OH
-CH2F
-CH2CN
-OMe
-Me
-CH2OH
-CN
-CO2H
-CO2Me
-CONH2
-H
-H
-H
-H
-H
-H
-H
-CF3

-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-Cl
-Cl
-Cl
-Cl
-Cl
-Cl
-Br
-H
-Me
-CN
-NO2
-SO2Me
-NH2
-F

E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1

0.015
0.056
>100
0.01
>100
29.7
>100
>100
46.8
0.015
0.05
>100
0.13
100
62.8
0.052
>100
>100
0.34
0.83
0.2
0.12
>100
0.028
0.34
0.01
70
0.16
1.09
0.031
>100
47.1
0.076
0.29
19.8
29.7
0.0017

1
1
3
1
3
2
3
3
2
1
1
3
1
3
2
2
3
3
2
2
1
2
3
1
1
1
2
2
2
2
3
2
2
2
2
2
1

S 19
8-25a
8-25b
8-25d
8-26
8-28a
8-30
8-31

-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-F
-4SO2N(CH3)2
-4NHSO2CH3
-4-NO2
-4-COCF3
-H
-4-Cl
-4-OMe
-4-Cl
-4-OMe
-4-SO2Me

-4-Cl
-4-Cl
-H
-H
-4-SO2NH2

-CF3
-CF3
-CF3
-CF3
-CF3

-Me
-Et
-OMe
-OH
-H

E.1
E.1
E.1
E.1
E.1

0.022
0.028
0.08
3.58
0.01

1
2
2
1
1

-4-Cl

-CF3

-H

E.1

>100

-4-Cl

-CF3

-H

E.1

>100

-4-Cl
-4-Cl
-H
-4-Cl
-4-OMe
-4-OMe
-4-Cl
-4-F

-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3
-CF3

-H
-H
-H
-H
-H
-H
-H
-H

E.1
E.1
E.1
E.1
E.1
E.1
E.1
E.1

>100
>100
>100
4.79
0.75
0.75
74.9
0.1

3
3
3
1
1
2
2
2

-H

E.1

0.04

E.2
E.2
E.2
E.2

45.6
45
64.7
0.012

2
2
2
1

E.2

0.35

E.2

0.89

E.2

0.084

E.2

0.031

E.2

0.23

E.2

0.021

E.2

0.052

E.2

3.29

E.2

0.024

F
F
F
F
F
F
F

0.0075
0.017
0.002
0.003
0.0015
0.005
0.001

1
2
1
2
1
1
1

8-32
8-33
8-34
8-35
8-36
8-37
8-38
8-39
8celecoxib
8-1ai
8-1aj
8-1ak
8-1al

-4-SO2NH2

-4-Me

-CF3

-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2

-CF3
-CF3
-CF3
-CF3

-2-pyridyl
-3-pyridyl
-4-pyridyl
-thienyl-5-Br

8-1an

-4-SO2NH2

-CF3
S

8-1ao

-4-SO2NH2

-CF3
O

8-1ap

-4-SO2NH2

-CF3

8-1aq

-4-SO2NH2

-CF3

8-1ar

-4-SO2NH2

-CF3

-1-cyclohexene

8-1as

-4-SO2NH2

-CF3
O

8-1at

-4-SO2NH2

-CF3

8-2m

-4-SO2NH2

-CHF2

O
CH3

-furyl-5-Me
O

8-2n

-4-SO2NH2

-CHF2
O

9-3
9-20
9-24
9-32
9-35
9-36
9-37

-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-SO2NH2

-4-F
-4-OMe-3-Cl
-4-OMe-3-Cl
-4-F
-4-Me
-4-OMe
-4-OMe

0
0
0
0
0
0
0

S 20
9-38
9-39
9-40
9-41
9-46
9-47
9-48
9-53
9-19
9-29
10-2
10-3
6-Dup697
11-8
11-10
11-13
11-14
11-16
11-21
11-24
11-25
11-26
11-29
11-30
11-31
11-32
12-3a
12-5a
12-5b
12-10b
12-10c
11-33
11-34
13-4
13-5

-4-SO2Me
-4-SO2NH2
-4-SO2Me
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-4-F
-2-F
-3-F
-2,5-F
-2,4-F
-4-F
-H
-4-Cl
-4-OMe-3-F
-4-OMe-3-F
-2-thienyl
-3-thienyl
-4-SO2Me
-4-SO2Me

-4-OCF3
-4-OCF3
-4-CF3
-4-CF3
-3,4-OCH2O-3,4-F
-3,4-F
-2,4-F
-4-F
-4-OCH3-3-Cl
-Me
-CH2OH
-4-F
-4-F
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2Me
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2NH2
-4-SO2Me
-4-SO2Me
-4-F
-4-F

0
0
0
0
0
0
0
0

-Br
-Me
-CF3
-Et
-t-Bu
-CH2CN
-C6H4-2-Cl
-2-thienyl
-3-pyridyl
-4-pyridyl
-C6H4-2-Cl
-C6H4-2-Cl
-C6H4-2-Cl
-C6H4-2-Cl
-C6H4-2-Cl
-CH3
-CH3
-C6H4-2-Cl
-Me
-C6H4-2-Cl
-C6H4-2-Cl
-H
-CF3

13-6a

-4-SO2Me

-4-F

-H

13-7a

-4-SO2Me

-4-F

-CF3

-H
-H
CH2CH=CH2
CH2CH=CH2
-Et
-Et

F
F
F
F
F
F
F
F
G
G
H
H
I
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.2
J.2
K
K

0.135
0.13
0.002
0.001
0.0025
0.0033
0.003
0.022
0.026
0.027
0.005
0.18
0.01
0.12
0.023
0.023
0.11
0.35
0.05
0.021
0.43
1.6
0.01
0.016
>100
0.021
0.013
0.038
0.005
2.48
0.028
0.057
0.079
>100
>100

1
1
2
1
1
1
1
1
2
1
1
2
2
1
1
1
1
2
1
1
1
1
2
1
3
1
1
1
1
2
2
1
2
3
3

>100

0.075

13-7c
-4-SO2Me
-4-F
-CF3
K
0.13
13-10
-4-SO2NH2
-4-F
-CF3
K
0.033
14-3
-4-SO2Me
-4-F
C
L
0.011
14-7
-4-SO2Me
-4-F
O
L
0.02
14-13
-4-SO2NH2
-4-F
C
L
0.005
14-12
-4-SO2NH2
-4-F
O
L
0.007
14-14
-4-SO2Me
-3-F-4-OMe
O
L
0.093
14-15
-4-SO2NH2
-3-F-4-OMe
O
L
0.005
7-39
-4-SO2Me
-4-F
M
>100
a
names are formed by hyphenating the reference number and the label given to the compound in the reference.
b
training set, test set and inactive compounds are indicated as 1, 2 and 3.

1
1
2
1
1
2
2
1
3

S 21
COX-2 references
(1) Khanna, I. K.; Weier, R. M.; Yu, Y.; Collins, P. W.; Miyashiro, J. M. et al. 1,2-diarylpyrroles as potent and
selective inhibitors of cyclooxygenase-2. J. Med. Chem. 1997, 40, 1619-1633.
(2) Chavatte, P.; Yous, S.; Marot, C.; Baurin, N.; Lesieur, D. Three-dimensional quantitative structure-activity
relationships of cyclo-oxygenase-2 (cox-2) inhibitors: A comparative molecular field analysis. J. Med. Chem.
2001, 44, 3223-3230.
(3) Khanna, I. K.; Weier, R. M.; Yu, Y.; Xu, X. D.; Koszyk, F. J. et al. 1,2-diarylimidazoles as potent,
cyclooxygenase-2 selective, and orally active antiinflammatory agents. J. Med. Chem. 1997, 40, 1634-1647.
(4) Khanna, I. K.; Yu, Y.; Huff, R. M.; Weier, R. M.; Xu, X. D. et al. Selective cyclooxygenase-2 inhibitors:
Heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents. J. Med. Chem.
2000, 43, 3168-3185.
(5) Reitz, D. B.; Li, J. J.; Norton, M. B.; Reinhard, E. J.; Collins, J. T. et al. Selective cyclooxygenase inhibitors novel 1,2-diarylcyclopentenes are potent and orally-active COX-2 inhibitors. J. Med. Chem. 1994, 37, 38783881.
(6) Li, J. J.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Collins, J. T. et al. 1,2-diarylcyclopentenes as selective
cyclooxygenase-2 inhibitors and orally-active antiinflammatory agents. J. Med. Chem. 1995, 38, 4570-4578.
(7) Li, J. J.; Norton, M. B.; Reinhard, E. J.; Anderson, G. D.; Gregory, S. A. et al. Novel terphenyls as selective
cyclooxygenase-2 inhibitors and orally active anti-inflammatory agents. J. Med. Chem. 1996, 39, 1846-1856.
(8) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W. et al. Synthesis and biological
evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4methylphenyl)-3-(trifluoromethyl)-1h-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib). J. Med. Chem.
1997, 40, 1347-1365.
(9) Huang, H. C.; Li, J. J.; Garland, D. J.; Chamberlain, T. S.; Reinhard, E. J. et al. Diarylspiro[2,4]heptenes as
orally active, highly selective cyclooxygenase-2 inhibitors: Synthesis and structure-activity relationships. J.
Med. Chem. 1996, 39, 253-266.
(10) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M. et al. 4-[5-methyl-3-phenylisoxazol-4yl]-benzenesulfonamide, Valdecoxib: A potent and selective inhibitor of COX-2. J. Med. Chem. 2000, 43, 775777.
(11) Carter, J. S.; Rogier, D. J.; Graneto, M. J.; Seibert, K.; Koboldt, C. M. et al. Design and synthesis of sulfonylsubstituted 4,5-diarylthiazoles as selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett. 1999, 9,
1167-1170.
(12) Carter, J. S.; Kramer, S.; Talley, J. J.; Penning, T.; Collins, P. et al. Synthesis and activity of sulfonamidesubstituted 4,5-diaryl thiazoles as selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett. 1999, 9,
1171-1174.
(13) Penning, T. D.; Kramer, S. W.; Lee, L. F.; Collins, P. W.; Koboldt, C. M. et al. 3,4-diarylpyrazoles: Potent and
selective inhibitors of cyclooxygenase-2. Bioorg. Med. Chem. Lett. 1997, 7, 2121-2124.
(14) Huang, H. C.; Chamberlain, T. S.; Seibert, K.; Koboldt, C. M.; Isakson, P. C. et al. Diaryl indenes and
benzofurans - novel classes of potent and selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett.
1995, 5, 2377-2380.

S 22
DHFR
Table A.1.8. Structures (families) of DHFR inhibitors
E

F.1
N

G.1

NH2

R1

H2N

I.1

NH2
R1

N
H2 N
NH2

R1
N

NH2

R3
R2

N
H2N

H2N

N
H

N.1

NH2
N

N
H 2N

R1
N

N
H

NH2
N

R2
R1

N.3
O

R1

R2
N

R2
N

R1

N
N

H2N

N
H
H2N

H2N

R3

H2N

R1
N

R1

NH2

R2

R1

R2

J.3

R3

R2

N
H2N

NH2

N.2
NH2

NH2

R1

R1

R1

H2N

H2 N

R2

R2

R2

H2N

R3

NH2

R1

R1

R2

N
H2N

NH2

I.2

J.2

R3

R2

NH2

H2N

H.1

R1

N
H2N

R1

H.2

R2

N
NH2

R2

J.1

H2N

NH2

R1

G.2

R3

N
H2N

N
N

H2N

F.2

NH2

NH2

R3

H 2N

N
H

R1

S 23
Table A.1.9. DHFR inhibitors

7-1
7-2
7-3
7-4
7-5
7-6
1-98535
1-107146
1-117356
1-127977
1-131463
1-137545
1-144698
1-152737
1-233903
1-233904
1-233910
1-235791
1-236642
1-241522
9-12c
9-12d
9-12e
9-12g
9-12h
9-12i
9-12j
9-12k
9-12l
9-12m
9-12n
9-12o
9-12p
9-12q
9-12r
9-12s
9-12t
9-12u
10-2d
9-12f
1-232965
1-235776
1-233912
1-235777
6-48
11-GR92754

R1
-H
-3,4,5-OMe
-3,5-OMe
-2,4-Cl
-3,4-Cl
-2,6-Cl
-4-CO-L-Glu
-2-F,-4-D-Glu
-4-D-Glu
-4-CO-D-Lys
-4-CO2H
-2-Me,-4-CO2H,-6Me
-2-CF3,-4-D-Glu
-2-OMe,-4-D-Glu
-4-CONH2
-H
-4-NHCOMe
-4-COMe
-4-CON(Me)2
-4-CONH-Pr
-2,3-(CH)4-3-Me
-4-Me
-4-OMe
-3,4-OMe
-3-Cl
-4-Cl
-4-Cl
-2-Me,-5-OMe
-2-Me,-6-OMe
-2,5-OMe
-2,5-OMe
-3,5-OMe
-3,4,5-OMe
-2-OMe,-5-CF3
-3-OMe,-5-CF3
-2,3-(CH)4-2,5-OMe
-H
-3-OMe
-CH2-S-Ph
-CH2-NH-Ph
-CH2-O-Ph
-CH2NH-1-naphthyl
1,2-naphthyl
-i-Butyl

>9
>35
>22.8
22.6
24.1
40.5
0.028
0.00072
0.00088
>8
0.94

1.4
>35
>20.4
13.1
22.3
31.7

-CH2NH-CH2N(Me)-CH2N(Me)-CH2N(Me)-CH2N(Me)-

E
E
E
E
E
E
F.1
F.1
F.1
F.1
F.1

-CH2N(Me)-

F.1

-CH2N(Me)-CH2N(Me)-CH2NH-CH2N(Me)-CH2NH-CH2NH-CH2NH-CH2NH-CH2S-CH2S-CH2S-CH2S-CH2S-CH2S-CH2S-CH2NH-CH2NH-CH2NH-CH2NH-CH2N(Me)-CH2NH-CH2NH-CH2NH-CH2NH-CH2CH2-CH2CH2-CH2CO2-CH2S-H
-H
-H
-H
R1
-R1

F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.1
F.2
F.2
F.2
F.2
F.2
F.2

R3

TG

PC

R2

RL

Set

Name

IC50 (
M)

Family

>8
2.27

15
>35
22.8
50.9
20.6
81.2
0.017
0.00036
0.0062
>8
0.11

2
3
2
1
1
2
1
1
1
3
1

0.19

0.28

0.038

0.00031
0.00049
>1000
10
7.1
0.72
>5
3.1
4.2
21.2
30
17.2
58.2
42.2
42.1
1.5
>3
15.8
6.2
3.9
0.96
7
21
0.68
97
11.1
9.8
9.9
9.5
>1.9
136
0.13
18.4
0.082

0.0067

0.00155
0.0011
220
0.83
0.17
0.075
>10
0.48
8.2
8.48
26
10.2
36.3
26.6
14.3
0.3
>3
5.7
22.9
0.47
0.88
1.9
21
1.9
60
23.2
7
7.7
246
>1.9
13
1.26
1.3
0.32

1
2
1
1
2
1
3
2
1
1
1
1
2
1
1
1
3
1
1
2
1
1
1
2
2
2
2
1
1
3
2
1
2
1

0.0119

16.9

7
1.8
15
14
23.2
5.7
16.8
0.59
0.44
1.85
6.9
0.21
0.11
1
10.6
0.89
0.82
5.4
5.8
1.6
0.77
2.7
2.7
0.076
4.9
0.028

S 24
11-AH2503
11-AH2504
12-4b

12-4d

-Et
-C6H4-2-OMe
N

-R1
-Et

F.2
F.2

0.62
2

1
0.018

2.2
0.41

2
2

-H

F.2

1.4

0.91

5.1

-H

F.2

3.4

2.2

13

-H

F.2

4.9

1.3

-H

F.2

0.042

0.029

0.027

-H

F.2

0.12

0.11

0.2

-H

F.2

0.21

0.043

4.4

12-4g
12-4c

12-4e

-CH2N(Ph)2
N

12-4a
10-18d
1-122870
1Trimetrexate
1-184692
1-351521
13-10
13-11
13-14
13-17
14-28
14-29
9-16b
9-16c
15-3
15-4
15-5
15-6
15-7
15-10
10-1a
10-3a
10-4a
10-5a
10-6a
16-9a
16-11
15-11
15-12
15-13
15-14
15-15
10-11a

-CH2OH
-4-CO-L-Asp

-H
-CH2NH-

-Me

F.2
G.1

>51
0.00042

>51
0.00133

>51
0.000156

3
1

-3,4,5-OMe

-CH2NH-

-Me

G.1

0.042

10

0.003

-4-CO-L-Asp
-3,5-OMe
-3,4,5-OMe
-2,5-OMe
-3,4,5-OMe
-3,4,5-OMe
-2,5-OMe
-3,4,5-OMe
-4-Cl
-2-Me,-4-Cl
-2,5-OMe
-3,5-OMe
-2,4-OMe
-3,4,5-OMe
-2,3,4-OMe
-2,3-(CH)4-H
-3,4,5-OMe
-2,5-OMe
-2,3,4-OMe
-3,5-OMe
-2-Br,-3,4,5-OMe
-2-Br,-3,4,5-OMe
-2,5-OMe
-3,5-OMe
-2,4-OMe
-2,3,4-OMe
-2,3-(CH)4-H

-CH2NH-CH2-CH2N(Me)-NHCH2-NHCH2-N(Me)CH2-CH2NH-CH2NH-CH2NH-CH2NH-NHCH2-NHCH2-NHCH2-NHCH2-NHCH2-NHCH2-CO2CH2-CH2CO2-CH2CO2-CH2CO2-CH2CO2-CH2NH-CH2NH-N(Me)CH2-N(Me)CH2-N(Me)CH2-N(Me)CH2-N(Me)CH2-CH2NH-

-Et
-Me
-Cl
-Cl
-Cl
-Cl
-Cl
-Cl
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-Cl
-H
-H
-H
-H
-H
-H
-H

G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1
G.1

0.010
0.031
0.012
0.053
0.033
0.17
0.051
0.033
0.6
0.33
4.6
2.2
4.4
6.8
4.9
0.72
2.5
0.56
2.4
1.4
0.46
0.028
0.55
0.087
0.024
0.1
0.052
0.017
0.98

0.001

0.004
0.002
0.012
0.028
0.006
0.038
0.044
0.006
0.073
0.023
1.1
0.84
1.2
0.9
1.3
0.19
0.42
0.026
0.42
0.5
0.35
0.010
0.33
0.026
0.008
0.043
0.019
0.017
0.44

2
2
1
2
1
1
1
1
1
2
1
1
1
1
1
1
2
2
1
1
1
2
1
1
2
1
1
1
1

0.006
0.017
0.007
0.016
0.03
0.005
0.075
0.033
0.16
0.12
0.17
0.084
0.19
0.099
0.36
0.05
0.22
0.14
0.15
0.008
0.039
0.03
0.009
0.039
0.017
0.021
0.1

S 25
10-12a
6-1
6-2
6-3
6-7
6-13
6-14
6-15
6-16
6-20
6-21
6-22
6-23
6-26
6-28

-H
-Me
-CF3
-F
-OMe
-SMe
-H
-H
-H
-H
-H
-H
-H
-Cl
-H

-CH2N(Me)-H
-H
-H
-H
-H
-Me
-CF3
-F
-OMe
-H
-H
-H
-Cl
-Me

7.7

0.069
7.4
215
5
1.2
0.54
55
4.1
452
46
42
63
189
3.5
7.9

2
1
2
2
1
2
1
1
1
2
1
1
1
1
2

13

5.8

1.5

G.2

0.51

0.13

0.019

G.2
G.2
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1
H.1

>32
51.7
4.6
0.095
0.119
1.67
0.3
0.114
1.57
0.319
6.8
0.246
0.41
0.502
0.94
0.171
0.33
0.517
0.1
0.29
0.25
0.34
0.45
0.27
0.44
0.4
0.1
0.58
0.057
0.1

>32
44.9
0.054
0.007
0.012
0.181
0.015
0.017
0.14
0.017
0.11
0.021
0.097
0.010
0.078
0.022
0.03
0.036
0.023
0.032
0.023
0.036
0.014
0.021
0.05
0.14
0.014
0.073
0.021
0.023

>32
40.3
0.29
0.038
0.074
0.56
0.26
0.071
1.47
0.116
0.15
0.034
0.24
0.109
0.128
0.067
0.227
0.139
0.047
0.18
0.11
0.11
0.12
0.11
0.077
0.19
0.079
0.17
0.034
0.063

3
1
1
1
2
2
1
1
1
1
1
2
1
1
1
1
1
1
1
1
2
1
1
1
1
1
2
1
1
1

-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-Me
-CF3
-F
-H
-Me

G.1
G.2
G.2
G.2
G.2
G.2
G.2
G.2
G.2
G.2
G.2
G.2
G.2
G.2
G.2

0.096
1.5
82
0.41
4.5
1.1
20
2.7
119
58
65
31
41
9.7
5.3

-H

G.2

-H
-H
-H

0.011
4.98

0.48

3.1
104
22
81

NH

18-5

-H
NH

18-6

-H

10-17a
10-18a
19-1
19-2
19-3
19-4
19-5
19-6
19-7
19-8
19-9
19-10
19-11
19-12
19-13
19-14
19-15
19-19
19-20
20-5a
20-5b
20-5c
20-5d
20-5e
20-5f
20-5g
20-5h
20-5i
20-5j
20-5k

-H
-H
-3,4,5-OMe
-3,4,5-OMe
-3,4,5-OMe
-2,5-OMe
-2,5-OMe
-2,5-OMe
-2,5-OEt
-2,5-OEt
-3,4-Cl
-3,4-Cl
-2,5-Cl
-2,6-Cl
-4-Cl
-4-Cl
-3-Br
-2,3-(CH)4-2,3-(CH)4-H
-2-Me
-3-Me
-2-OMe
-3-OMe
-4-OMe
-3-CF3
-3-OCF3
-4-OCF3
-2,5-OMe
-3,4-OMe

-CO2H
-CH2OH
-CH2NH-CH2N(Me)-CH2N(CH2CCH)-CH2NH-CH2N(Me)-CH2N(Et)-CH2NH-CH2N(Me)-CH2NH-CH2N(Me)-CH2NH-CH2NH-CH2NH-CH2N(Me)-CH2NH-CH2NH-CH2N(Me)-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-

S 26
20-5m
20-9a
20-9b
20-9c
14-5
14-8
14-9
14-10
21-3
21-4
21-5
21-6
21-7
21-8
21-9
21-10
21-11
21-12
21-13
21-14
21-15
21-16
21-18
21-19
21-20
21-21
21-22
21-23
21-24
21-27
21-34
21-36
21-38
21-40
21-41
21-42
21-43
21-44
22-4
22-5
22-6
22-7
22-8
22-9
22-11
22-12
22-15
22-19
22-21
22-14
22-20
22-16
22-22

-3,4-Cl
-Et
-t-Bu
-Ph
-2,5-OMe
-4-Cl
-3-Cl
-3,4-Cl
-H
-H
-H
-2-OMe
-2-OMe
-3-OMe
-3-OMe
-4-OMe
-4-OMe
-2-Cl
-2-Cl
-3-Cl
-2,4-OMe
-2,4-OMe
-2,5-OMe
-3,4-OMe
-3,4-OMe
-2,4-Cl
-2,4-Cl
-2,5-Cl
-2,5-Cl
-3,4-Cl
-2,3-(CH)4-2,3-(CH)4-2,3-(CH)4-4-COMe
-4-COMe
-4-COMe
-4-COCF3
-4-COCF3
-2-OMe
-4-OMe
-3,4-OMe
-2-OMe
-4-OMe
-3,4-OMe
-2-OMe
-4-OMe
-3,4-OMe
-4-OMe
-3,4-OMe
-2,5-OMe
-2,5-OMe
-3,4,5-OMe
-3,4,5-OMe

-CH2-

-CH2NH-CH2N(Me)-CH2N(Me)-CH2N(Me)-CH2S-CH2NH-CH2N(Me)-CH2NH-CH2N(Me)-CH2NH-CH2N(Me)-CH2NH-CH2N(Me)-CH2NH-CH2N(Me)-CH2NH-CH2NH-CH2N(Me)-CH2N(Me)-CH2NH-CH2N(Me)-CH2NH-CH2N(Me)-CH2NH-CH2N(Me)-CH2NH-CH2S-CH2NH-CH2N(Me)-CH2NH-CH2N(Me)-CH2N(CCH)-CH2N(Me)-CH2N(CCH)-S-S-S-SO2-SO2-SO2-NH-NH-NH-N(Me)-N(Me)-NH-N(Me)-NH-N(Me)-

H.1
H.2
H.2
H.2
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1
I.1

15
6.9
0.18
2.2
1.4
0.062
2.1
0.022
2
1.7
0.29
2.7
0.51
1.7
0.097
0.85
0.25
0.53
0.21
2
5.5
0.16
0.21
0.9
0.091
0.73
0.5
1.6
0.15
0.41
0.47
0.23
0.04
0.41
0.13
0.22
0.25
0.12
2.2
0.7
0.086
3.2
10.5
2.7
8.7
90.4
40.4
0.22
0.0023
16.1
0.034
25.9
0.021

2.6
1.1
0.018
1.3
0.1
0.015
0.02
0.098
0.13
0.085
0.008
0.12
0.026
0.1
0.015
0.054
0.016
0.11
0.015
0.13
0.14
0.014
0.025
0.09
0.010
0.05
0.05
0.091
0.025
0.057
0.049
0.026
0.018
0.027
0.015
0.02
0.046
0.054
0.058
0.045
0.019
0.21
1
0.94
0.46
2.8
0.68
0.009
0.00088
0.73
0.041
2.4
0.007

7.3
3
0.065
1.9
0.43
0.022
0.067
0.032
0.52
0.26
0.024
0.42
0.12
0.2
0.035
0.073
0.018
0.14
0.12
0.14
0.32
0.016
0.05
0.06
0.003
0.088
0.058
0.2
0.047
0.054
0.16
0.04
0.007
0.003
0.005
0.015
0.032
0.008
0.23
0.075
0.018
1.4
2
0.88
0.26
3.8
1.1
0.007
0.0004
3.6
0.004
3.2
0.004

1
1
1
2
1
1
1
1
2
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
1
2
1
1
2
1
1
2
1
1
1
1
2
1
1
1
2
1
1
1
2
2
1
2
1
1

S 27
22-23
22-17
22-10
22-18
22-13
22-25
18-4
8-3
8-6
8-7
8-8
23-6a
23-4b
23-6b
24-2a
24-2b
24-2c
24-2d
24-2e
24-3a
24-3c
24-3e
24-4a
24-4c
24-5a
24-5b
14-22
9-13b
9-13d
9-13e
9-13f
9-13g
9-13h
9-13i
9-13j
9-13l
9-13m
9-13r
9-13s
9-13t
9-13u
9-14a
9-14b
9-14c
9-14h
9-14k
9-14m
9-15a
9-15b
9-15c
9-16d

-2,3-(CH)4-3,4-(CH)4-H
-H
-4-Cl
-3,4,5-OMe

-N(Me)-NH-NH-N(Me)-NH-NHCH2-

-H
-2,5-Cl
-3,5-Cl
-3,4-OMe
-3,4,5-OMe
-3,4-Cl
-3,4-Cl
-2,5-OMe
-3,5-OMe
-2,4-OMe
-3,4-OMe
-2,5-OEt
-2,5-OMe
-2,4-OMe
-2,5-OEt
-3,4,5-OMe
-3,4,5-OMe
-2,3-(CH)4-2,3-(CH)4-,-4-OMe
-3,4-Cl
-H
-3-Me
-4-Me
-3-OMe
-4-OMe
-3,4-OMe
-3-Cl
-4-Cl
-2-Me,5-OMe
-2-Me,-6-OMe
-2-OMe,-5-CF3
-3-OMe,-5-CF3
-2,3-(CH)4-2,5-OMe
-2,5-Me
-2-Me,-4-OMe
-2-OMe,-5-Me
-3,4-OMe
-2-OMe,-5-CF3
-2,3-(CH)4-2,3-(CH)4-4-Cl
-3,4,5-OMe
-2,5-OMe

-CH2S-CH2S-CH2S-CH2S-CH2N(CHO)-CH2NH-CH2N(CHO)-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2N(Me)-CH2N(Me)-CH2N(Me)-CH2N(CH2CCH)-CH2N(Et)-CH2NH-CH2NH-CH2N(Me)-CH2S-CH2S-CH2S-CH2S-CH2S-CH2S-CH2S-CH2S-CH2NH-CH2NH-CH2NH-CH2NH-CH2CH2-CH2CH2-CH2NH-CH2NH-CH2NH-CH2N(Me)-CH2N(Me)-CH2N(Me)-CH2NH-CH2NH-CH2NH-CH2NH-

-H
-H
-H
-H
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-H
-H
-H
-H

I.1
I.1
I.1
I.1
I.1
I.1

5.1
15
8.3
0.010
14.6
29.4

2.1
1.1
0.3
0.002
0.83
0.49

3.3
2
0.43
0.001
0.82
1.4

1
2
1
1
1
2

I.2

0.037

0.034

0.053

J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1

1.3
5.9
11
2.2
0.55
0.32
0.51
0.046
0.023
0.316
0.044
0.077
0.216
0.32
3.1
0.054
0.050
0.573
0.041
0.1
0.44
0.17
0.53
0.34
0.56
0.15
0.068
0.36
0.038
1
0.044
0.02
0.064
0.34
0.03
0.17
0.068
0.32
0.093
0.15
0.26
0.97
2
0.75

0.47
2
6.2
1.1
0.013
0.028
0.083
0.016
0.005
0.057
0.009
0.017
0.030
0.029
0.1
0.008
0.003
0.015
0.023
0.027
0.034
0.065
0.057
0.11
0.063
0.03
0.09
0.09
0.023
0.1
0.022
0.018
0.026
0.008
0.016
0.007
0.015
0.003
0.038
0.016
0.15
0.3
0.13
0.14

1.9
2.5
38
4
0.11
0.053
0.14
0.128
0.043
0.214
0.008
0.017
0.407
0.044
3.0
0.012
0.011
0.030
0.054
0.042
0.43
0.33
0.5
0.6
0.52
0.18
0.19
0.37
0.15
0.32
0.02
0.017
0.135
0.77
0.12
0.029
0.16
0.004
0.23
0.14
0.23
0.72
0.81
0.46

1
1
2
2
2
1
2
1
1
1
1
1
1
2
2
2
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
2
2
1
1
1
1
1
1
1
2
1
1
1

S 28
25-10
25-11
25-12
25-13
25-14
25-15
25-16
25-19
25-20
25-21
25-22
25-23
25-24
25-25
25-26
26-7
26-8
26-9
26-10
27-6
27-7
27-9
27-10
27-11
27-13
27-14
27-15
27-16
10-2b
10-2c
28-3
28-4
28-5
28-6
28-7
28-8
28-9
28-10
28-11
29-2-piritrexim
26-5

-H
-3,4,5-OMe
-3,4,5-OMe
-3,4,5-OMe
-2,3,4-OMe
-2,3,4-OMe
-2,4,6-OMe
-3,5-OMe
-3,5-OMe
-2,5-OMe
-2,5-OMe
-2,3-(CH)4-2,3-(CH)4-,-4-OMe
-2,3-(CH)4-,-6-OMe
-4-O-Ph
-2,5-OMe,-4pyrrolo
-2-pyrrolo,-4,5OMe
-2,3,5,6-OMe,-4pyrrolo
-2-OMe,-5-Ph
-2-OMe
-3-OMe
-2-Cl
-3-Cl
-4-Cl
-3-OMe
-4-OMe
-2-Cl
-4-Cl
-H
-H
-3,4,5-OMe
-3,4,5-OMe
-3,4,5-OMe
-3,4,5-OMe
-3,4-OMe
-4-OMe
-3,4,5-OMe
-3,4-OMe
-4-OMe
-2,5-OMe
N

-N(Me)CH2-NHCH2-N(Me)CH2-NHCH(Me)-NHCH2-N(Me)CH2-NHCH2-NHCH2-N(Me)CH2-NHCH2-N(Me)CH2-NHCH2-NHCH2-NHCH2-NHCH2-

-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H
-H

J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1

0.068
14.1
0.061
9.2
15.3
0.079
20.7
5.7
0.076
3.8
0.084
3.9
8.2
15.4
24.3

0.032
0.35
0.014
0.194
0.67
0.026
0.23
1.2
0.031
0.31
0.006
0.98
0.38
0.71
3.7

0.14
3.3
0.033
1.27
3.24
0.03
1.2
3.4
0.072
0.35
0.057
0.24
0.43
0.37
2.9

2
1
1
1
1
2
1
1
1
1
1
1
1
1
2

-CH2NH-

-Me

J.1

0.35

0.033

0.23

-CH2NH-

-Me

J.1

1.8

0.6

3.5

-CH2NH-

-Me

J.1

0.62

0.075

0.17

-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2(Me)-CH2(Me)-CH2(Me)-CH2(Me)-CH2CO2-CH2CO2-CH2N(Me)-CH2N(Et)-CH2N(CHO)-CH=CH-CH=CH-CH=CH-CH2CH2-CH2CH2-CH2CH2-CH2-

-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-Me
-H
-Me
-H
-H
-H
-H
-H
-H
-H
-H
-H
-Me

J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1
J.1

0.64
0.117
0.069
0.047
0.023
0.055
0.03
0.035
0.084
0.029
5.45
0.25
0.24
0.19
18.5
>5.0
2.6
5.3
5
1.4
0.29
0.031

0.068
0.023
0.007
0.007
0.011
0.019
0.006
0.007
0.018
0.005
1.9
0.056
0.009
0.049
1.1
1.4
1.4
1.5
0.2
0.2
0.25
0.017

0.44
0.169
0.080
0.088
0.037
0.051
0.018
0.013
0.1
0.026
3.9
0.23
0.28
0.12
7.4
12.9
2.1
11.8
1.14
0.61
0.26
0.002

1
1
1
1
1
1
1
1
2
1
1
2
1
1
1
2
2
1
1
1
2
2

-Me

J.2

0.57

0.077

0.47

-Me

J.2

0.25

0.057

0.17

OMe

30-3

OMe

S 29

30-2

-Me

J.2

0.29

0.048

0.15

-Me

J.2

0.41

0.049

0.23

-H

J.2

0.043

0.04

0.19

-H
-Me
-CH2CHO-CH2CHO-CH2NH-CH2CH2-CH2-CH2-CH2-CH2CH2-CH2NH-CH2N(Me)-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2N(Me)-CH2N(Me)-CH2N(Me)-CH2S-CH2S-CH2S-CH2N(Me)-CH2NH-CH2NH-CH2N(Me)-CH2N(Me)-

>104
10.5
>2.6
>1.2
>3700
61.7
3.3
6.9
0.51
30
0.9
0.035
>4
>35
>21
119
279
45.7
>21
35.3
307
0.038
>12
28.3
209
11.1
58.5
10.6
0.044
>10
>10
>10
>10

>104
3.2

O
O
O
O
O
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
S
S
S
S

J.2
J.2
K
L
L
L
M
M
M
M
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1
N.1

0.47
0.3
0.2
0.09
3.2
0.7
19.8
>4
89.3
>21
4.3
6
1.7
5.3
1.4
1.1
0.21
3.4
1
0.87
2.6
11.6
0.81
0.15
>10
>10
>10
>10

>104
8.5
>2.6
>1.2
3700
6.1
1.4
2.2
0.35
9.5
1.3
0.43
>37.0
35.2
>21
116
63
156
70
14.4
59.3
0.044
>12
3
8.2
16.7
5.3
3
0.06
>10
>10
>10
>10

3
2
3
3
3
2
2
1
2
2
2
1
3
2
3
1
2
1
2
1
1
1
3
2
1
1
1
2
2
3
3
3
3

-CH2NH-

N.1

>10

>10

>10

-CH2-CH2S-CH2NH-CH2O-CH2NH-CH2NH-

NH
O
O
O
O
O

N.1
N.1
N.1
N.1
N.1
N.1

>189
>26
13.5
14
>12
8.1

>130
>26
37
>42
>12
32.4

270
252
12
60.3
>12
16.2

2
3
1
2
3
1

OMe

30-4

OMe

OMe

18-3
10-18b
10-18c
23-7
23-8b
23-8
28-12
32-8
32-9
32-10
32-11
33-1
33-2
33-3
33-5
33-6
34-2
34-3
34-4
34-5
34-6
34-7
34-9
35-2
35-3
35-4
35-5
35-6
35-7
35-10
36-7a
36-7b
36-7c
36-7d
36-7e
37-1e
38-3
38-6
38-8
38-9
38-10

-CH2OH
-CH2OH
-3,4,5-OMe
-3,4,5-OMe
-3,4,5-OMe
-3,4,5-OMe
-2,5-OMe
-3,4,5-OMe
-2-Br,-3,4,5-OMe
-3,4,5-OMe
-4-L-Glu
-4-L-Glu
-3,4,5-OMe
-3,4-Cl
-2,5-OMe
-3,4-OMe
-4-OMe
-2,5-OMe
-2,5-OEt
-3,4-Cl
-2,3-(CH)4-4-L-Glu
-2,5-OMe
-3,4-Cl
-2,3-(CH)4-3,4-OMe
-3,4-Cl
-2,3-(CH)4-4-L-Glu
-3,4,5-OMe
-2,5-OMe
-3,4,5-OMe
-2,5-OMe
-3,5-Cl,-4-(1pyrrolo)
-H
-H
-2,3-(CH)4-3,4-(CH)4-2-O-Ph
-4-O-Ph

-Me
-Me
-Me
-H

S 30
38-11
38-12
38-13
38-14
38-16
38-17
40-3
40-4

-2-Ph
-3,4-(CH)4-2,5-Cl
-3,4-Cl
-3-OMe
-2,5-OMe
-Me
-Me

40-5

-Me

40-6

-Me

40-7

-Me

40-8

-Me

40-table2-1
40-table2-2
40-table2-3
40-table-2-4
40-table-2-5
40-table-2-6

-CH2CH2C6H3-2,5OMe
-Me
-Me
-Me
-C6H4-4-Cl
-CH2Ph
-(CH2)4-

16-8a

-Me

40-9

16-12
16-10
36-6a
36-6b
36-6c
36-6d
36-6e
37-1a
37-1b
37-1c
37-1d
41-4c
41-4d
41-4e
41-4f
41-4g
41-4h
41-4i
41-5a

-CH2CH2C6H1-2-Br3,4,5-OMe
-CH2NHC6H1-2-Br3,4,5-OMe
-CH2NHC6H2-3,4,5OMe
-CH2NHC6H3-2,5OMe
-CH2N(Me)C6H23,4,5-OMe
-CH2N(Me)C6H32,5-OMe
-CH2NC6H3-3,5-Cl,4-(1-pyrrolo)
-Ph
-C6H4-4-Cl
-C6H3-3,4-Cl
-C6H2-3,4,5-OMe
-CH2NH-1-fluorene
-CH2NH-2-fluorene
-CH2NH-3-(2methoxydibenzofuran)
-CH2NH-3-(N-ethylcarbazole)
-CH2NH-2-(9hydroxy-fluorene)
-CH2NH-2-(9oxofluorene)
-CH2NH-4-(9oxofluorene)
-CH2N(Me)-3-(2methoxy-

-CH2NH-CH2N(Me)-CH2NH-CH2(Me)-CH2NH-CH2(Me)-C6H3-2,5-OMe
-CH2C6H3-2,5-OMe
-(CH2)2C6H3-2,5OMe
-C6H2-3,4,5-OMe
-CH2C6H2-3,4,5OMe
-(CH2)2C6H2-3,4,5OMe

O
O
O
O
O
O
S
S

N.1
N.1
N.1
N.1
N.1
N.1
N.2
N.2

7.7
14.8
50.9
44.8
>31.3
>27
4.8
14

45.4
23.6
>47
>27
>31.3
>27
0.13
0.07

137
14.6
71.9
>27
>31.3
>27
0.37
0.4

1
1
1
3
3
3
2
1

N.2

1.2

3.3

5.9

N.2

>8

0.32

1.8

N.2

>8

0.63

51

N.2

>8

18

25

-H

N.2

28

5.8

3.1

-Ph
-C6H3-3,4-Cl
-CH2Ph
-Me
-Me
R1
-CH2C6H1-2-Br,3,4,5-OMe

S
S
S
S
S
S

N.2
N.2
N.2
N.2
N.2
N.2

26
16
35
>100
>100
2.1

3.9
>28
6.2
>70
>100
2.8

57
4.6
14
>100
>37
3.9

1
2
1
3
3
2

N.2

>12

0.21

0.93

-H

N.2

49

2.5

2.8

-H

N.2

200

25

43

-Br

N.2

13

34

17

-Br

N.2

>100

>100

33

-Br

N.2

31

127

28

-Br

N.2

>10

>10

>10

-Br

N.2

7.5

26

10

-H
-H
-H
-H
-H
-H

NH
NH
NH
NH
O
O

N.2
N.2
N.2
N.2
N.2
N.2

>186
>161
33
8.3
>29
36.2

12
113
16
14
>29
27.7

9.1
62
23
27
>29
500

2
2
2
2
3
1

-H

N.2

10.3

>32

>32

-H

N.2

16.2

4.5

12.6

-H

N.2

>13

63

>13

-H

N.2

>63

>63

>63

-H

N.2

19.3

>38

>38

-H

N.2

>54

392

241

S 31

41-5b
41-7a
41-7b
41-7c
42-8
42-9
42-10
42-11
43-7
43-8
43-9
43-10
43-11
43-13
43-14
43-15
43-16
43-17
44-2
44-3
44-6
44-7
44-8
44-9
44-10
44-11
44-12
44-14
44-16
44-17
44-18
44-19
44-20
44-21
44-22
44-23
a

dibenzofuran)
-CH2N(Me)-3-(Nethyl-carbazole)
-CH2S-2-biphenyl
-CH2S-3-biphenyl
-CH2S-4-biphenyl
-4-Cl
-3,4-Cl
-4-NO2
-3,4-OMe
-2,5-OMe
-3,5-OMe
-2,4-OMe
-3,4,5-OMe
-2,5-Cl
-2,4-Cl
-3-Cl
-2,5-OMe
-3,5-OMe
-3,4,5-OMe
-Ph
-C6H2-3,-4,5-OMe
-C6H2-2,-4,5-OMe
-C6H3-2,-5-OMe
-C6H3-3,-5-OMe
-C6H3-3,-4-OMe
-C6H3-2,-4-OMe
-C6H3-3,-4-Cl
-C6H3-2,-6-Cl
-C6H2-2-NO2-4,5OMe
-4-pyridine
-2-naphthyl
-1-naphthyl-4-OMe
-9-fluorenyl
-CH2-Ph
-CH2NH-C6H23,4,5-OMe
-CH2NH-C6H3-2,5OMe
-CH2S-2-naphthyl

-H

N.2

18.7

22.6

24.7

-H
-H
-H
-S-S-S-S-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2NH-CH2N(Me)-CH2N(Me)-CH2N(Me)-

O
O
O

N.2
N.2
N.2
N.3
N.3
N.3
N.3
N.3
N.3
N.3
N.3
N.3
N.3
N.3
N.3
N.3
N.3
O
O
O
O
O
O
O
O
O

46
22
41
40
>20
>15
>21
47
20
16
22
25
15
26
56
87
45
153
59.4
22
37.4
9
12
14
19.5
11

105
23
79
3.1
11.7
244
20
2.2
2.6
7.1
9.3
0.66
2.2
3.5
10.3
4.2
37
28
2.2
1.5
1.7
3
14.2
2.4
6.7
11

49
31
351
24.6
>20
7470
>21
47
20
16
22
25
15
26
56
87
45
59.9
13
7
3.5
32.4
52.3
0.9
252
11

2
1
1
2
3
3
3
1
1
1
1
1
2
1
2
1
1
1
1
1
2
1
1
1
2
1

25

16.8

25

O
O
O
O
O

18
113
13
35
9.8

20
27
13
30.5
0.5

18
280
13
29.8
1.6

2
1
2
2
2

34

34

34

29

49

29

105

1.02

107

names are formed by hyphenating the reference number and the label given to the compound in the reference
b
IC50 values in M for P. carinii (PC), T. gondii (TG) and rat liver (RL). Only RL activities are used in this work.
c
training set, test set and inactive compounds are indicated as 1, 2 and 3, respectively.

DHFR references*
(1) Broughton, M. C.; Queener, S. F. Pneumocystis-carinii dihydrofolate-reductase used to screen potential
antiPneumocystis drugs. Antimicrob. Agents Chemother. 1991, 35, 1348-1355.
(6) Rosowsky, A.; Hynes, J. B.; Queener, S. F. Structure-activity and structure-selectivity studies on
diaminoquinazolines and other inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolatereductase. Antimicrob. Agents Chemother. 1995, 39, 79-86.

S 32
(7) Gangjee, A.; Elzein, E.; Queener, S. F.; McGuire, J. J. Synthesis and biological activities of tricyclic
conformationally restricted tetrahydropyrido annulated furo[2,3-d] pyrimidines as inhibitors of dihydrofolate
reductases. J. Med. Chem. 1998, 41, 1409-1416.
(8) Gangjee, A.; Adair, O.; Queener, S. F. Synthesis of 2,4-diamino-6-(thioarylmethyl)pyrido [2,3- d]pyrimidines
as dihydrofolate reductase inhibitors. Bioorg. Med. Chem. 2001, 9, 2929-2935.
(9) Piper, J. R.; Johnson, C. A.; Krauth, C. A.; Carter, R. L.; Hosmer, C. A. et al. Lipophilic antifolates as agents
against opportunistic infections .1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii
and Pneumocystis carinii in in vitro evaluations. J. Med. Chem. 1996, 39, 1271-1280.
(10) Graffner-Nordberg, M.; Kolmodin, K.; Aqvist, J.; Queener, S. F.; Hallberg, A. Design, synthesis, computational
prediction, and biological evaluation of ester soft drugs as inhibitors of dihydrofolate reductase from
Pneumocystis carinii. J. Med. Chem. 2001, 44, 2391-2402.
(11) Jackson, H. C.; Biggadike, K.; McKilligin, E.; Kinsman, O. S.; Queener, S. F. et al. 6,7-disubstituted 2,4diaminopteridines: Novel inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase.
Antimicrob. Agents Chemother. 1996, 40, 1371-1375.
(12) Rosowsky, A.; Cody, V.; Galitsky, N.; Fu, H. N.; Papoulis, A. T. et al. Structure-based design of selective
inhibitors of dihydrofolate reductase: Synthesis and antiparasitic activity of 2,4- diaminopteridine analogues
with a bridged diarylamine side chain. J. Med. Chem. 1999, 42, 4853-4860.
(13) Rosowsky, A.; Mota, C. E.; Wright, J. E.; Queener, S. F. 2,4-diamino-5-chloroquinazoline analogs of
trimetrexate and piritrexim - synthesis and antifolate activity. J. Med. Chem. 1994, 37, 4522-4528.
(14) Rosowsky, A.; Forsch, R. A.; Queener, S. F. 2,4-diaminopyrido[3,2-d]pyrimidine inhibitors of dihydrofolatereductase from Pneumocystis carinii and Toxoplasma gondii. J. Med. Chem. 1995, 38, 2615-2620.
(15) Gangjee, A.; Vidwans, A. P.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L. et al. Structure-based design and
synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate
reductases and potential antitumor agents. J. Med. Chem. 1998, 41, 3426-3434.
(16) Rosowsky, A.; Mota, C. E.; Queener, S. F. Brominated trimetrexate analogues as inhibitors of Pneumocystis
carinii and Toxoplasma gondii dihydrofolate reductase. J. Heterocycl. Chem. 1996, 33, 1959-1966.
(18) Rosowsky, A.; Fu, H. N.; Queener, S. F. Synthesis of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4diaminoquinazolines with bulky dibenz[b,f]azepine and dibenzo[a,d]-cycloheptene substituents at the 6-position
as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium
avium. J. Heterocycl. Chem. 2000, 37, 921-926.
(19) Gangjee, A.; Zaveri, N.; Kothare, M.; Queener, S. F. Nonclassical 2,4-diamino-6-(aminomethyl)-5,6,7,8tetrahydroquinazoline antifolates - synthesis and biological- activities. J. Med. Chem. 1995, 38, 3660-3668.
(20) Rosowsky, A.; Papoulis, A. T.; Forsch, R. A.; Queener, S. F. Synthesis and antiparasitic and antitumor activity
of 2,4- diamino-6-(arylmethyl)-5,6,7,8-tetrahydroquinazoline analogues of piritrexim. J. Med. Chem. 1999, 42,
1007-1017.
(21) Gangjee, A.; Zhu, Y. M.; Queener, S. F.; Francom, P.; Broom, A. D. Nonclassical 2,4-diamino-8-deazafolate
analogues as inhibitors of dihydrofolate reductases from rat liver, Pneumocystis carinii, and Toxoplasma
gondii. J. Med. Chem. 1996, 39, 1836-1845.
(22) Gangjee, A.; Zhu, Y. M.; Queener, S. F. 6-substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues of
piritrexim as inhibitors of dihydrofolate reductase from rat liver, Pneumocystis carinii, and Toxoplasma gondii
and as antitumor agents. J. Med. Chem. 1998, 41, 4533-4541.
(23) Gangjee, A.; Shi, J. F.; Queener, S. F.; Barrows, L. R.; Kisliuk, R. L. Synthesis of 5-methyl-5-deaza
nonclassical antifolates as inhibitors of dihydrofolate reductases and as potential antipneumocystis,
antitoxoplasma, and antitumor agents. J. Med. Chem. 1993, 36, 3437-3443.
(24) Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L. 6-substituted 2,4-diamino-5-methylpyrido[2,3d]pyrimidines as inhibitors of dihydrofolate reductases from Pneumocystis carinii and Toxoplasma gondii and
as antitumor agents. J. Med. Chem. 1995, 38, 1778-1785.
(25) Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L. 2,4-diamino-5-deaza-6-substituted pyrido[2,3d]pyrimidine antifolates as potent and selective nonclassical inhibitors of dihydrofolate reductases. J. Med.
Chem. 1996, 39, 1438-1446.
(26) Gangjee, A.; Vasudevan, A.; Queener, S. F. Synthesis and biological evaluation of nonclassical 2,4- diamino-5methylpyrido[2,3-d]pyrimidines with novel side chain substituents as potential inhibitors of dihydrofolate
reductases. J. Med. Chem. 1997, 40, 479-485.
(27) Gangjee, A.; Adair, O.; Queener, S. F. Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase
inhibitors and antitumor agents: Synthesis and biological activities of 2,4-diamino-5-methyl-6[(monosubstituted anilino)methyl]pyrido[2,3-d]pyrimidines. J. Med. Chem. 1999, 42, 2447-2455.

S 33
(28) Gangjee, A.; Devraj, R.; Queener, S. F. Synthesis and dihydrofolate reductase inhibitory activities of 2,4diamino-5-deaza and 2,4-diamino-5,10-dideaza lipophilic antifolates. J. Med. Chem. 1997, 40, 470-478.
(29) Rosowsky, A.; Forsch, R. A.; Queener, S. F. Inhibition of Pneumocystis carinii, Toxoplasma gondii, and
Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-[omegacarboxyalkyloxy)benzyl]pyrimidines: Marked improvement in potency relative to trimethoprim and species
selectivity relative to piritrexim. J. Med. Chem. 2002, 45, 233-241.
(30) Gangjee, A.; Vasudevan, A.; Queener, S. F. Bicylic conformationally restricted analogs of nonclassical
pyrido[2,3-d] pyrimidines as potential inhibitors of dihydrofolate reductases. Chemistry and biology of
pteridines and folates; Plenum Press: New York, 1993; pp 449-453.
(31) Gangjee, A.; Zeng, Y. B.; McGuire, J. J.; Kisliuk, R. L. Synthesis of classical and nonclassical, partially
restricted, linear, tricyclic 5-deaza antifolates. J. Med. Chem. 2002, 45, 5173-5181.
(32) Rosowsky, A.; Mota, C. E.; Queener, S. F. Synthesis and antifolate activity of 2,4-diamino-5,6,7,8tetrahydropyrido[4,3-d]pyrimidine analogs of trimetrexate and piritrexim. J. Heterocycl. Chem. 1995, 32, 335340.
(33) Gangjee, A.; Devraj, R.; McGuire, J. J.; Kisliuk, R. L.; Queener, S. F. et al. Classical and nonclassical furo[2,3d]pyrimidines as novel antifolates - synthesis and biological-activities. J. Med. Chem. 1994, 37, 1169-1176.
(34) Gangjee, A.; Mavandadi, F.; Queener, S. F.; McGuire, J. J. Novel 2,4-diamino-5-substituted-pyrrolo[2,3d]pyrimidines as classical and nonclassical antifolate inhibitors of dihydrofolate reductases. J. Med. Chem.
1995, 38, 2158-2165.
(35) Gangjee, A.; Mavandadi, F.; Queener, S. F. Effect of n-9-methylation and bridge atom variation on the activity
of 5-substituted 2,4-diaminopyrrolo[2,3-d]pyrimidines against dihydrofolate reductases from Pneumocystis
carinii and Toxoplasma gondii. J. Med. Chem. 1997, 40, 1173-1177.
(36) Rosowsky, A.; Papoulis, A. T.; Queener, S. F. 2,4-diaminothieno [2,3-d]pyrimidine lipophilic antifolates as
inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. J. Med. Chem. 1997, 40,
3694-3699.
(37) Rosowsky, A.; Fu, H. N.; Queener, S. F. Synthesis of new 2,4-diamino-7h-pyrrolo[2,3-d]pyrimidines via the
taylor ring transformation/ring annulation strategy. J. Heterocycl. Chem. 2001, 38, 1197-1202.
(38) Gangjee, A.; Guo, X.; Queener, S. F.; Cody, V.; Galitsky, N. et al. Selective Pneumocystis carinii dihydrofolate
reductase inhibitors: Design, synthesis, and biological evaluation of new 2,4-diamino-5-substituted-furo[2,3d]pyrimidines. J. Med. Chem. 1998, 41, 1263-1271.
(39) Gangjee, A.; Yu, J. M.; McGuire, J. J.; Cody, V.; Galitsky, N. et al. Design, synthesis, and X-ray crystal
structure of a potent dual inhibitor of thymidylate synthase and dihydrofolate reductase as an antitumor agent. J.
Med. Chem. 2000, 43, 3837-3851.
(40) Rosowsky, A.; Mota, C. E.; Wright, J. E.; Freisheim, J. H.; Heusner, J. J. et al. 2,4-diaminothieno[2,3d]pyrimidine analogs of trimetrexate and piritrexim as potential inhibitors of Pneumocystis carinii and
Toxoplasma gondii dihydrofolate-reductase. J. Med. Chem. 1993, 36, 3103-3112.
(41) Gangjee, A.; Dubash, N. P.; Queener, S. F. The synthesis of new 2,4-diaminofuro[2,3-d]pyrimidines with 5biphenyl, phenoxyphenyl and tricyclic substitutions as dihydrofolate reductase inhibitors. J. Heterocycl. Chem.
2000, 37, 935-942.
(42) Gangjee, A.; Mavandadi, F.; Kisliuk, R. L.; McGuire, J. J.; Queener, S. F. 2-amino-4-oxo-5-substitutedpyrrolo[2,3-d]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase. J. Med. Chem. 1996, 39,
4563-4568.
(43) Gangjee, A.; Vidwans, A.; Elzein, E.; McGuire, J. J.; Queener, S. F. et al. Synthesis, antifolate, and antitumor
activities of classical and nonclassical 2-amino-4-oxo-5-substituted-pyrrolo[2,3- d]pyrimidines. J. Med. Chem.
2001, 44, 1993-2003.
(44) Gangjee, A.; Vasudevan, A.; Queener, S. F. Conformationally restricted analogues of trimethoprim: 2,6diamino-8-substituted purines as potential dihydrofolate reductase inhibitors from Pneumocystis carinii and
Toxoplasma gondii. J. Med. Chem. 1997, 40, 3032-3039.
(45) Rosowsky, A.; Papoulis, A. T.; Queener, S. F. 2,4-diamino-6,7-dihydro-5h-cyclopenta[d]pyrimidine analogues
of trimethoprim as inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. J. Med.
Chem. 1998, 41, 913-918.
(46) Then, R. L.; Hartman, P. G.; Kompis, I.; Santi, D. Selective inhibition of dihydrofolate reductase from problem
human pathogens. Chemistry and biology of pteridines and folates; Plenum Press: New York, 1993; pp 533536.
(47) Gangjee, A.; Shi, J. F.; Queener, S. F. Synthesis and biological activities of conformationally restricted,
tricyclic nonclassical antifolates as inhibitors of dihydrofolate reductases. J. Med. Chem. 1997, 40, 1930-1936.

S 34
(48) Gangjee, A.; Mavandadi, F.; Queener, S. F. Synthesis and biological activity of tricyclic, conformationally
restricted analogs of lipophilic pyrido[2,3-d]-pyrimidine antifolates. Chemistry and biology of pteridines and
folates; Plenum Press: New York, 1993; pp 441-449.
(49) Gangjee, A.; Mavandadi, F.; Queener, S. F. Conformationally restricted tricyclic analogues of lipophilic
pyrido[2,3-d]pyrimidine antifolates. J. Heterocycl. Chem. 2001, 38, 213-220.
(50) Rosowsky, A.; Papoulis, A. T.; Queener, S. E. One-step synthesis of novel 2,4-diaminopyrimidine antifolates
from bridged alicyclic ketones and cyanoguanidine. J. Heterocycl. Chem. 1999, 36, 723-728.
(51) Donkor, I. O.; Devraj, R.; Queener, S. F.; Barrows, L. R.; Gangjee, A. Synthesis of a series of diaminobenzo[f]and diaminobenzo[h]pyrimido[4,5-b]quinolines as 5-deaza tetracyclic nonclassical antifolates. J. Heterocycl.
Chem. 1996, 33, 1653-1661.
* Reference numbers are not sequential to keep them consistent with our previous classification
work

GPB, THER, THR

Table A.1.10. GPB inhibitor sets
Training set
1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 13, 14, 16, 18, 20, 21, 24, 25, 26, 27, 28, 30, 31, 32, 34, 35, 36, 37,
38, 39, 41, 43, 44, 45, 49, 50, 51, 53, 56, 58, 59, 60, 61, 64
Test set
8, 12, 15, 17, 19, 22, 23, 29, 33, 40, 42, 46, 47, 48, 52, 54, 55, 57, 62, 63, 65, 66
Table A.1.11. THER inhibitor sets
Training set
ACE_OHLEU_AGNH2, BZSAG, C6PLTNME, CH3COCH2CO_FAGNH2, CLTZNCRYS,
DAH51, DAH52, DAH53, NHOHBZMAGNH2, NHOHBZMAGOH, OHBZMAGNH2, ZALA,
ZAPOLA, ZFGNH2, ZFPOLA, ZGGLNHOH, ZGG_D_LNHOH, ZGLNH2, ZGLNHOH,
ZGLY, ZGPCLA, ZGPCLF, ZGPCLG, ZGPCLLZNCRYS, ZGPLA, ZGPLF, ZGPLG,
ZGPLLZNCRYS, ZGPOLA, ZGPOLF, ZGPOLLZNCRYS, ZGPOLNH2, ZG_D_LNHOH,
ZLGNH2, ZLPOLA, Z_D_APOLA, Z_D_FPLA, Z_D_FPOLA, Z_NH_GLNHOH,
C6POLTNME, CHO_OHLEU_AGNH2, DAH50, NHOHMALAGNH2, PAAOH, PPHEOH,
PPPHE, PO3_FAGNH2, P_OPHE_OME_LEUNH2, ZGLNMEOH, ZGPLNH2, ZGPOLG
Test set
C6PCLTNME, DAH55, HOCH2CO_FAGNH2, NHOHIBMAGNH2, PLFOH, PNHET,
P_ILE_AOH, R_THIORPHAN, SO3_FAGNH2, ZFPLAZNCRYS, ZGPCLNH2, Z_D_LPOLA,
CBZPHE, CH3O2S_FAGNH2, DAH54, NHOHBZMAGNA, NHOHBZMOET, NHOHLEU,
PHOSPHORAMIDON, PLEUNH2, S02P_FAGNH2, S_THIORPHAN, ZGGNHOH, ZYGNH2,
Z_NH_GLNH2

S 35

Table A.1.12. THR inhibitor sets

Training set
2, 3, 4, 6, 8, 9, 12, 13, 15, 17, 18, 19, 22, 23, 24, 25, 26, 27, 28, 32, 33, 34, 36, 37, 38, 40, 41, 42,
43, 45, 47, 48, 50, 52, 53, 55, 57, 59, 60, 62, 63, 64, 66, 68, 69, 73, 74, 75, 76, 77, 78, 79, 80, 83,
84, 85, 86, 87, 88
Test set
1, 5, 7, 10, 11, 14, 16, 20, 21, 29, 30, 31, 35, 39, 44, 46, 49, 51, 54, 56, 58, 61, 65, 67, 70, 71, 72,
81, 82

A.2. Values of q2L20%O and q2L33%O, and thresholds for defining outliers
Table A.2.1. Values of q2L20%O and q2L33%O, and thresholds used for defining q2LOO outliers
for PLS analyses
CoMFA

CoMSIA
basic

CoMSIA
extra

q2L20%O
q2L33%O
thresh

0.67
0.65
2.00

0.65
0.63
2.00

0.66
0.64
2.00

q2L20%O
q2L33%O
thresh

0.49
0.42
2.00

0.41
0.37
2.35

EVA

HQSAR

2D

2.5D

0.70
0.67
2.09

0.71
0.70
2.00

0.67
0.66
2.05

0.71
0.67
2.00

AchE
0.44
0.36
0.41
0.29
2.00
2.00

0.29
0.19
2.00

0.31
0.29
1.96

0.30
0.28
2.00

ACE

BZR

q L20%O
q2L33%O
thresh

0.31
0.28
2.00

0.38
0.37
2.18

0.44
0.41
2.00

0.39
0.38
2.00

0.38
0.36
2.00

0.36
0.33
2.06

0.33
0.30
2.00

q2L20%O
q2L33%O
thresh

0.46
0.43
2.00

0.38
0.39
2.00

COX2
0.55
0.43
0.55
0.40
2.02
2.00

0.47
0.45
2.00

0.47
0.43
1.97

0.51
0.49
2.00

q2L20%O
q2L33%O
thresh

0.63
0.62
2.00

0.62
0.61
2.00

DHFR
0.64
0.61
0.63
0.58
2.00
2.00

0.68
0.66
2.00

0.50
0.49
2.00

0.51
0.48
2.00

S 36
Table A.2.1. (continued)
CoMFA

CoMSIA
basic

CoMSIA
extra

0.37
0.33
2.00

0.24
0.09
2.00

0.58
0.54
2.00

0.44
0.42
2.00

EVA

HQSAR

2D

2.5D

0.51
0.42
2.00

0.66
0.65
2.00

0.26
0.22
1.96

0.39
0.31
2.04

THER
0.46
0.41
0.43
0.35
2.00
2.00

0.44
0.41
2.00

0.57
0.51
2.00

0.60
0.56
2.00

0.40
0.28
2.08

0.55
0.50
1.98

0.43
0.38
2.00

GPB

q2L20%O
q2L33%O
thresh
2

q L20%O
q2L33%O
thresh

0.45
0.42
2.00

THR

q L20%O
q2L33%O
thresh

0.47
0.40
2.00

0.49
0.42
2.00

0.65
0.58
2.00

0.44
0.34
2.00

Table A.2.2. Thresholds for defining r2test outliers for PLS analyses
CoMFA
ACE
AchE
BZR
COX2
DHFR
GPB
THER
THR

2.00
2.00
2.00
2.06
2.00
2.00
2.00
2.00

CoMSIA
basic
1.97
2.00
2.00
2.05
2.00
2.00
2.00
2.00

CoMSIA
extra
2.00
2.00
1.90
2.00
1.98
2.00
2.00
2.00

EVA

HQSAR

2D

2.5D

2.00
2.00
2.00
2.00
1.97
2.05
1.92
2.00

1.97
2.08
2.00
2.00
2.05
2.05
2.00
2.00

1.96
2.00
2.00
1.95
1.95
2.00
2.00
2.00

2.05
2.00
2.03
2.05
2.01
2.00
2.00
2.00

Table A.2.3. Thresholds for defining r2test outliers for 2.5D descriptors with various modelbuilding methods

ACE
AchE
BZR
COX2
DHFR
GPB
THER
THR

PLS

GFA-l

2.05
2.00
2.03
2.05
2.01
2.00
2.00
1.80*

2.05
1.98
2.00
2.08
2.00
2.00
2.00
2.00

GFA-lens
2.00
2.00
2.00
2.00
2.01
2.00
2.02
2.08

GFAnl
1.92
2.00
2.00
2.00
2.00
2.00
2.02
2.00

GFAnl-ens
2.00
2.00
2.00
2.00
2.00
2.05
2.04
2.00

GPLS
2.00
2.00
2.00
2.05
2.01
2.00
2.00
2.00

GPLSens
1.98
2.00
2.00
1.99
2.06
2.00
2.00
2.00

NN
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.06

NNens
2.00
2.00
1.93
2.00
2.00
2.05
2.00
2.00

S 37
Table A.2.4. Test set outliers
ACE

COO_24A

MOL_10

AchE

COX2

DHFR

GPB

CoMFA
1-351521
5-1H
22-20
RO15-2201 8-1V
22-21
1-31C RO16-4234 8-2C
57
29-2
RO15-8852 8-1AK
28-12
11-29
40-3

2-36

2-36

COO_24A
THIOL_28

BZR

3-18

CoMSIA basic
9-12T
5-1H
22-21
RO15-2201 8-22F
29-2
RO16-4234 8-8A
32-11
RO15-8852 8-20E
40-7
8-1AK
40-8
CoMSIA extra
9-12T
5-1H
22-21
RO15-2201 8-8A
29-2
RO16-4234 8-20E
24-3E
RO15-8852 12-10B
36-6C
40-7
EVA
25-26
8-22F
24-3E
RO15-2201 8-2C
36-6C
RO16-4234 8-8A
36-6E
RO15-8852 8-22C
44-16
8-23
40-8

THER

THR

CH3O2S_FAGNH2 71

57

CH3O2S_FAGNH2 71

57

DAH55
71
CH3O2S_FAGNH2

57

67

HQSAR
1-137545
5-1H
1-184692
8-1V
22-21
MOL_32
2-36
RO16-4234
57
8-8A
29-2
SQ29852_2P 3-12A RO15-8852
8-20E
24-3E
8-22C
28-12

7
CH3O2S_FAGNH2 58
67

S 38

ACE

MOL_10

AchE

BZR

COX2

DHFR

GPB

2D
1-351521
8-22F
22-21
RO15-2201 8-8A
29-2
3-13A RO16-4234 8-20E
24-3E
RO15-8852 8-22C
40-T-2-6
8-23

MOL_10
1-3O
SQ29852_2P 2-36

2.5D-GFA-l-ens
6-2
5-1H
22-21
8-1V
29-2
RO14-3074
8-8A
36-6C
RO21-8482
8-20E
44-20
8-22C
28-6

SQ29852_2P
THIOL_28

MOL_10

2-32
2-36

THR

CH3O2S_FAGNH2 10

2.5D
1-351521
3-33
22-21
RO14-3074 5-1H
COO_24A
2-32
29-2
RO16-4234 7-20P
24-3E
SQ29852_2P 3-13A
RO15-8852 8-22E
28-6
8-8A
34-5
2.5D-GFA-l
6-2
1-31
6-13
3-33
RO14-3074
5-1H 22-21
RO21-8482
8-22E 29-2
RO16-4234
8-1V 44-20
8-8A 28-6

THER

CH3O2S_FAGNH2

10
67

57

DAH55

10
67

57

CH3O2S_FAGNH2

10
67

2.5D-GFA-nl
6-48
5-1H 1-351521
22-21
RO14-3074 8-2F
57
RO22-1274 8-8A 29-2
RO16-4234 8-20E 24-3E
8-22C 37-1E
34-5

10
CH3O2S_FAGNH2 67
71

S 39

ACE

AchE

COO_24A 2-32
THIOL_28 2-36

COO_23E
COO_24A

COO_24A
MOL_10

THIOL_28 2-36

MOL_10
2-32
THIOL_28 2-36

BZR

COX2

DHFR

GPB

2.5D-GFA-nl-ens
1-351521
5-1H
22-21
RO14-3074 8-2F
29-2
RO22-1274 8-8A
65
24-3E
RO16-4234 8-20E
28-6
8-22C
34-5

RO14-3074
RO15-2201
RO16-4234
RO15-8852

RO14-3074
RO15-2201
RO16-4234
RO15-8852

2.5D-GPLS
1-351521
3-33
22-21
5-1H
29-2
7-20P
24-3E
8-22E
28-6
8-20E
34-5
2.5D-GPLS-ens
1-351521
3-33
22-21
5-1H
29-2
7-20P
24-3E
8-22E
36-6C
8-20E
28-6

2.5D-NN
6-13
5-1H
22-21
7-20P
24-3E
RO16-4234
8-1V
40-T-2-6
RO15-8852
8-8A
28-6
8-22C
40-7

57

2.5D-NN-ens
1-152737
5-1H
6-2
RO14-3074 7-20P
6-13
57
RO16-4234 8-1V
22-21
RO15-8852 8-8A
24-3E
8-22C
28-6

THER

THR

10
CH3O2S_FAGNH2 67
71

CH3O2S_FAGNH2

10
67

CH3O2S_FAGNH2

10
67

DAH55

10
71

DAH55

10
67

S 40
A.3. Alignment procedures for CoMFA, CoMSIA
ACE: The alignment is described in ref. 1 [reference list below].
AchE: We use the 3 pharmacophore features described by Golbraikh et al.2 (i.e. the benzyl
group, the positively charged nitrogen atom of the piperidine group and the carbonyl acceptor in
E2020) for aligning compounds. The conformation of E2020 was determined using the MCMM
routine in Macromodel 7.2 (Schrodinger; Portland, OR) with the MMFF94S force field and
GBSA implicit solvation model (500 Monte Carlo steps, other parameters default), and rigidly
superposed on E2020 complexed with AchE (PDB 1eve). The lowest-energy conformation has a
heavy-atom root-mean-square deviation (RMSD) of 0.9 when compared to the conformation
extracted from the crystal structure. We did not use the ligand-bound conformation deduced
from the crystal structure, as the purpose of a project using this set was to develop receptor
surface models useful in the absence of such information. The same holds for the COX2 set.
Other compounds were minimised with MMFF94S in GBSA implicit solvent and flexibly fit
onto E2020 using the alignment module in Cerius2 (i.e. allowing rotation of free torsions).
BZR: All ligands have been aligned onto diazepam, which was subjected to the same MCMM
optimisation described for the AchE inhibitor E2020. As discussed in ref. 3, there are two lowenergy ring conformations for diazepam. Ring conformation a in Figure 10 of the above
reference was used, as it is the bioactive conformation. Other compounds were minimised with
MMFF94S in GBSA implicit solvent and flexibly fit onto diazepam using the shared fused ring
system and phenyl group. Substituents were placed in a consistent fashion. Substituents on the
rotatable phenyl ring of diazepam were placed on the edge nearest the fused ring structure (i.e.
the "left" edge when depicted in the orientation given for BZR family A.1 in Table A.1.4), as that
orientation has a lower energy compared to the alternate orientation having the phenyl ring
rotated by 180 about its torsion. We use the syn conformation for esters such as Ro14-5974 (as
depicted in Figure 1) instead of the anti conformation suggested by Cook et al.4,5 The syn
conformer gives better overlap with other classes of BZR ligands, and has a B3LYP/6311+G(d,p) // HF/6-31G* energy only 2.1 kcal/mol higher than that of the anti conformer.
COX2: The MCMM procedure discussed for the AchE inhibitor E2020 was applied to 8celecoxib. 8-celecoxib was superposed on the inhibitor SC558 in the PDB structure 1CX2. Note
however that the inhibitors were not docked into the protein, but merely placed in the active site.
In particular, the phenyl-SO2-X torsion determined by conformational searching is not the same
as that in the crystal structure 1CX2. The other inhibitors were minimised with MMFF94S in
GBSA implicit solvent and flexibly superposed on 8-celecoxib using three atoms on each of the
three rings. Substituents were placed in a consistent fashion. For example, substituents R2 on
the second vicinal ring (referring to the COX2 family A.1 in Table A.1.6) were always placed
away from the first vicinal ring. The energy difference is very small between that orientation,
and another in which the phenyl ring has been rotated by 180 about its torsion. As such, if one
were to have no protein structure to aid in the alignment, it is best to be consistent as opposed to
always choosing the global energy minimum.

S 41
DHFR: The crystal structures for several ligand - P. carinii (pc) DHFR complexes have been
used for aligning compounds. The pcDHFR-bound structures of 33-2 (PDB 1daj) and 12-4b
(PDB 1klk) were rigidly superposed onto folate (PDB 1cd2) using the atom mappings implied by
folate labels shown in Figure A.1; the root-mean-square deviations (RMSDs) with respect to
folate are 0.3 for 33-2 and 0.4 for 12-4b when calculated with the atoms used for the
superposition. All other compounds were flexibly fit onto the most similar of these three
templates. With the positions of the pyridine (having un-primed numbers in Figure A.1) and
phenyl rings (having primed numbers in Figure A.1) fixed, structures were relaxed using the
CFF97 force field in Cerius2 with no cut-off for van der Waals or electrostatic interactions (other
parameters default). Substituents on the phenyl ring were placed in a consistent fashion, with
preference for the solvent-exposed edge of the phenyl ring: the 2 position was occupied before
6 and the 3 position before 5, with the ortho position taking precedence over the meta position
when both are substituted. This placement of substituents is consistent with that observed for the
methoxy groups in 15-11 (PDB 1ly3) and the dibenzo[b,f]azepine ring in 12-4b. The active site
geometry of pc and human (for which rat liver is a surrogate) enzymes is very similar, and the
heavy-atom RMSDs for several inhibitors complexed to pc and human DHFR following rigid
superposition are small (15-11: 1ly3 vs. 1boz, 0.4 ; folate: 1cd2 vs 1drf, 0.7 ; 33-2: 1daj vs.
1hfp, 0.6 ; the latter two are reduced by half if the solvent-exposed glutamate side chain is
excluded).

Figure A.1. DHFR inhibitors. Numbers for MTX, TMQ, PTX, 33-2, 12-4b show mapping of
atoms to folate used for aligning compounds.
GPB, THERM, THR: Alignment procedures for GPB and THERM are described in reference
6. The alignment procedure for THR is described in reference 7.

S 42

References
(1) Depriest, S. A.; Mayer, D.; Naylor, C. B.; Marshall, G. R. 3D-QSAR of angiotensin-converting enzyme and
thermolysin inhibitors - a comparison of CoMFA models based on deduced and experimentally determined
active-site geometries. J. Am. Chem. Soc. 1993, 115, 5372-5384.
(2) Golbraikh, A.; Bernard, P.; Chretien, J. R. Validation of protein-based alignment in 3D quantitative structureactivity relationships with CoMFA models. Eur. J. Med. Chem. 2000, 35, 123-136.
(3) Haefely, W.; Kyburz, E.; Gerecke, M.; Mohler, H. Recent advances in the molecular pharmacology of
benzodiazepine receptors and in the structure-activity relationships of their agonists and antagonists. Adv. Drug
Res. 1985, 14, 165-322.
(4) Zhang, W.; Koehler, K. F.; Zhang, P.; Cook, J. M. Development of a comprehensive pharmacophore model for
the benzodiazepine receptor. Drug Des. Discov. 1995, 12, 193-248.
(5) Huang, Q.; He, X. H.; Ma, C. R.; Liu, R. Y.; Yu, S. et al. Pharmacophore/receptor models for GABA(A)/BZR
subtypes (alpha 1 beta 3 gamma 2, alpha 5 beta 3 gamma 2, and alpha 6 beta 3 gamma 2) via a comprehensive
ligand-mapping approach. J. Med. Chem. 2000, 43, 71-95.
(6) Gohlke, H.; Klebe, G. Drugscore meets CoMFA: Adaptation of fields for molecular comparison (AFMoC) or
how to tailor knowledge-based pair-potentials to a particular protein. J. Med. Chem. 2002, 45, 4153-4170.
(7) Bohm, M.; Sturzebecher, J.; Klebe, G. Three-dimensional quantitative structure-activity relationship analyses
using comparative molecular field analysis and comparative molecular similarity indices analysis to elucidate
selectivity differences of inhibitors binding to trypsin, thrombin, and factor Xa. J. Med. Chem. 1999, 42, 458477.

A.4. Description of grids used for CoMFA, CoMSIA

ACE
AchE
BZR
COX2
DHFR
x min
-12
-12
-12
12
4
x max
16
12
14
38
26
y min
-16
50
-10
14
-4
y max
12
76
12
32
18
z min
-10
54
-10
4
-4
z max
12
82
12
28
22
all grids use 2 step size, C.3 probe atom with charge +1

GPB THERM
-12
-10
12
16
-8
-18
10
12
-8
-12
14
10

THR
-6
20
-18
4
-2
24

S 43
A.5. 2.5D descriptors used as inputs for neural network models
ACE: SdO, chi-0, JX, FH20, FPSA-2, DPSA-1, shadow-YZfrac
AchE: SddsN, JX, dipole-mag, RPSA, shadow-XZfrac
BZR: SsssN, kappa-3, radius-of-gyration, FPSA-1, FPSA-3, PPSA-3, WPSA-3, RPSA
COX2: SdO, SaaN, SC-2, RNCG, RPCG
DHFR: SaaaC, SaasC, chi-v-1, chi-v-3_p, MW, MolRef, PPSA-1, PPSA-2, FPSA-3, TASA
GPB: SssNH, kappa-2, shadow-Xyfrac
THR: SsssCH, NaasC, NsssCH, Hbond_acceptors, chi-v-2, FH2O, PMI-mag, WPSA-3
THERM: SssO, IC, Rotlbonds, AlogP98, PPSA-1
A.6. Notes on electronic files
Files in MDL SD and Sybyl mol2 formats are provided. The files are tarred and gzipped
contents of the directories listed below (see UNIX commands tar and gzip), stored within a
Windows WinZip archive (only ZIP is supported by the ACS; use unzip for opening under
Linux). When .tar.gz files are opened in WinZip, the directory structure is not visible; use
extract in the action menu rather than drag-and-drop for preserving the directory structure.
3dqsar_mol2: Sybyl mol2 databases of aligned compounds, and tab-separated text files
containing spreadsheet data.
3dqsar_sd: MDL SD files of aligned compounds (the format does not allow specification of
charges; use the mol2 databases if you want our calculated charges).
corina_sd: MDL SD files of CORINA-generated structures.
25d_descriptors: contains tab-separated 2.5D descriptors for each set.
File contents:
Min_dist indicates the Tanimoto coefficient calculated between each test set compound
and the most similar training set compound; Avg_dist is the average value calculated
over all training set compounds. These may be viewed as measures for the degree of
extrapolation from the training set.
In the set column, 1, 2 and 3 indicate training, test and inactive compounds, respectively.
In the SD file of CORINA structures for the DHFR set, activities in M are given for P.
carinii (PC) and T. gondii (TG) in addition to rat liver (RL); only RL activities are used in
this work.