ANTIBACTERIAL

INDOLYL QUINOLINES

SYNTHESIS, SAR, & MOA

R

N
SRN 23rd Oct 02
 Initial SPOS route to Indolyl Quinolines

SRN 23rd Oct 02

 A Hit from the SPOS Library
Initial screening of the library, containing three compounds per
well, against a panel of micro-organisms (MRSA, vancomycin-
resistant Enterococcus faecium (VRE), Escherichia coli,
Pseudomonas aeruginosa, and Saccharomyces cerevisiae)
identified a subclass of 2-(5-bromo-1H-indol-3-yl)quinoline
derivatives with significant zones of inhibition (>15 mm) versus
MRSA and VRE. Upon deconvolution, compound 2 proved to
be the most potent with activity against the two Gram-positive
organisms, MRSA (MIC=12.5 mg/mL) and VRE (MIC=25 mg/mL).

SRN 23rd Oct 02

 Doebner Route to Indolyl Quinolines

SRN 23rd Oct 02

 The C-4 substituent is not required for optimal activity

SRN 23rd Oct 02

 The best substitution pattern is a single halogen at 5,6,7, 8.
It can also tolerate larger basic substituents at these positions.
SRN 23rd Oct 02
 The indole ring is quite sensitive to changes but tolerates halogens at
the 5 posn
SRN 23rd Oct 02
 MOA results
DNA synthesis

120
100
80 Ciprofloxacin

Inhibition
60 155342
40 118843
20
0
2 4 6 8 12 22
Time

Protein synthesis

120
100
80 Chloramphenicol
Inhibition

60 155342
40 118843
20
0
2 4 6 8 12 22
Time

SRN 23rd Oct 02

 MOA results
RNA Synthesis

120
100
80 Rifampicin
Inhibition
60 155342
40 118843
20
0
2 4 6 8 12 22
Time

Peptidoglycan synthesis

120
100
80 Vancomycin
Inhibition

60 155342
40 118843
20
0
2 4 6 8 12 22
Time

SRN 23rd Oct 02

 MOA results

Lipid Synthesis

120
100
80

Inhibition
Cerulenin
60 155342
40 118843
20
0
2 4 6 8 12 22
Time

AS IS USUAL WITH ALL ICAAC POSTERS,

STRUCTURES OF INTERESTING MOLECULES ARE
RARELY DISCLOSED.

SRN 23rd Oct 02

 Mode of Action studies (S.aureus)
No specific inhibition of PG synthesis.
Prevents the synthesis of all macromolecules (5-8 min
post addition).

Conclusions:
This class of molecules may de-energize the
cytoplasmic membrane thus leading to relA
independent cell lysis. (resembles sodium azide)

One of the molecules (118843) may inhibit RNA

synthesis earlier than other MOA’s. Possibility of
having a non lytic MOA.

SRN 23rd Oct 02

Concerns with the indolyl quinolines
R
Calculated log P quite high (>4)
High plasma protein binding
N
Poor solubility
N

Since compds are basic to start with

Increase basicity R

Reduction of logP / logD should lead to

N
Lower protein binding
Better solubility? N

Easy to postulate; strategy adopted is to reduce the quinoline

ring (stereo & regio isomers).
Now all they had to do was solve the synthetic problem
SRN 23rd Oct 02
Use of the Kobayashi 3CC reaction to solve the synthetic problem

Mixture of regioisomers and stereoisomers. In principle 16

compds were obtained. Relative stereochemical ratio cis /
SRNtrans (2:1).
23 Oct
rd
02
 Establishing the structure unequivocally

SRN 23rd Oct 02

 Reducing the no of isomers

Make use of earlier SAR

Use a 4-subst aniline instead
of 3-subst aniline to
eliminate the regioisomer

SRN 23rd Oct 02

 The indole ring is quite sensitive to changes but tolerates halogens at
the 5 posn. The cis geometry seems to be the preferred one.

SRN 23rd Oct 02

 The best substitution
pattern is a single
halogen at 6.
It can also tolerate larger
basic substituents at this
positions.

SRN 23rd Oct 02

 The NH of the
quinoline is essential
for activity.

There is considerable
scope for variation at
posns 3 & 4 of the
tetrahydroquinoline.

SRN 23rd Oct 02

 Conclusions and Unanswered Questions

No data provided on solubility or protein binding for tetrahydro series.

No information available on MOA for tetrahydro series.

SAR parallels that of of the quinoline series (common MOA?)

Will the SAR be similar?

Do we have to be aware of such a lytic mech of action for

our projects / compounds?

Can Microarray / MOA studies help us fast follow this

series?

SRN 23rd Oct 02