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  4. Whole cell screen based identification of spiropiperidines with potent antitubercular properties
 
research article

Whole cell screen based identification of spiropiperidines with potent antitubercular properties

Tantry, Subramanyam J.
•
Degiacomi, Giulia
•
Sharma, Sreevalli
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2015
Bioorganic & Medicinal Chemistry Letters

Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[indene-1,4'-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1'-alkylspiro[chromene-2,4'-piperidine] (abbr. spirochromenes) and 1'-benzylspiro[indole-1,4'-piperidin]-2(1H)-one (abbr. spiroindolones). Spiroindenes showed >= 4 log(10) kill (at 2-12 mu M) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives. (C) 2015 Elsevier Ltd. All rights reserved.

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Type
research article
DOI
10.1016/j.bmcl.2015.05.087
Web of Science ID

WOS:000357572000033

Author(s)
Tantry, Subramanyam J.
Degiacomi, Giulia
Sharma, Sreevalli
Jena, Lalit Kumar
Narayan, Ashwini
Guptha, Supreeth
Shanbhag, Gajanan
Menasinakai, Sreenivasaiah
Mallya, Meenakshi
Awasthy, Disha
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Date Issued

2015

Publisher

Elsevier

Published in
Bioorganic & Medicinal Chemistry Letters
Volume

25

Issue

16

Start page

3234

End page

3245

Subjects

Whole cell screen

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ss18b

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Antimycobacterial

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Non-replicating phase

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Hypoxic conditions

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MmpL3

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
UPCOL  
Available on Infoscience
September 28, 2015
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/118782
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