Quinolyl Indoles: A viable antimycobacterial lead

8/14/2019 Quinolyl Indoles: A viable antimycobacterial lead

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2/19

SRN 23 rd Oct 02

Initial SPOS route to Indolyl Quinolines


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SRN 23 rd Oct 02

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)quinolinederivatives with significant zones of inhibition (>15 mm) versusMRSA and VRE. Upon deconvolution, compound 2 proved to

be the most potent with activity against the two Gram-positiveorganisms, MRSA (MIC=12.5 mg/mL) and VRE (MIC=25 mg/mL).

A Hit from the SPOS Library


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SRN 23 rd Oct 02

Doebner Route to Indolyl Quinolines


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SRN 23 rd Oct 02

The C-4 substituent is not required for optimal activity


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SRN 23 rd 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.


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SRN 23 rd Oct 02

The indole ring is quite sensitive to changes but tolerates halogens atthe 5 posn


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SRN 23 rd Oct 02

DNA synthesi

0

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2 4 6 8 12 22

Time

I n h i b i t i o n Ciprofloxacin

155342

118843

Protein synthesi

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40

60

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120

2 4 6 8 12 22

Time

I n h i b i t i o n Chloramphenicol

155342

118843

MOA results


9/19

SRN 23 rd Oct 02

MOA results

RNA Synthesi

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2 4 6 8 12 22

Time

I n h i b i t i o n Rifampicin

155342

118843

Peptidoglycan synthesi

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4060

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100

120

2 4 6 8 12 22

Time

I n h i b i t i o n Vancomycin

155342118843


10/19

SRN 23 rd Oct 02

MOA results

Lipid Synthesis

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2 4 6 8 12 22

Time

I n h i b i t i o n Cerulenin

155342

118843

AS IS USUAL WITH ALL ICAAC POSTERS,STRUCTURES OF INTERESTING MOLECULES ARE RARELY DISCLOSED.


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12/19

SRN 23 rd Oct 02

Concerns with the indolyl quinolinesCalculated log P quite high (>4)High plasma protein bindingPoor solubility

Since compds are basic to start withIncrease basicity Reduction of logP / logD should lead toLower protein binding Better solubility?

Easy to postulate; strategy adopted is to reduce the quinolinering (stereo & regio isomers).

Now all they had to do was solve the synthetic problem

N

N

R

N

N

R


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SRN 23 rd Oct 02

Use of the Kobayashi 3CC reaction to solve the synthetic problem

Mixture of regioisomers and stereoisomers. In principle 16compds were obtained. Relative stereochemical ratio cis /trans (2:1).


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SRN 23 rd Oct 02

Establishing the structure unequivocally


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SRN 23 rd Oct 02

Reducing the no of isomers

Make use of earlier SARUse a 4-subst aniline insteadof 3-subst aniline toeliminate the regioisomer


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SRN 23 rd Oct 02

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


17/19

SRN 23 rd Oct 02

The best substitution

pattern is a singlehalogen at 6.

It can also tolerate larger basic substituents at thispositions.


18/19

SRN 23 rd Oct 02

The NH of thequinoline is essential

for activity.

There is considerablescope for variation atposns 3 & 4 of the

tetrahydroquinoline.


19/19

SRN 23 rd Oct 02

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?)

Conclusions and Unanswered Questions

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 thisseries?

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Quinolyl Indoles: A viable antimycobacterial lead