ANTIBACTERIAL INDOLYL QUINOLINES

SYNTHESIS, SAR, & MOA
R N 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, vancomycinresistant 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

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.

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 Inhibition 80 60 40 20 0 2 4 6 Time 8 12 22 Ciprofloxacin 155342 118843

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

SRN 23rd Oct 02

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

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

SRN 23rd Oct 02

MOA results

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

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 Calculated log P quite high (>4) High plasma protein binding Poor solubility

R

N N

Since compds are basic to start with Increase basicity Reduction of logP / logD should lead to Lower protein binding Better solubility?

R

N N

SRN 23rd Oct 02

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

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 / trans (2:1). SRN 23 Oct 02
rd

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

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