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Lead selection and characterization of antitubercular compounds using the Nested Chemical Library

Sipos, Anna and Pato, Janos and Szekely, Rita and Hartkoorn, Ruben C and Kekesi, Laszlo and Orfi, Laszlo and Szantai-Kis, Csaba and Mikusova, Katarina and Svetlikova, Zuzana and Kordulakova, Jana and Nagaraja, Valakunja and Godbole, Adwait Anand and Bush, Natassja and Collin, Frederic and Maxwell, Anthony and Cole, ST and Keri, Gyoergy (2015) Lead selection and characterization of antitubercular compounds using the Nested Chemical Library. In: TUBERCULOSIS, 95 (1). S200-S206.

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Official URL: http://dx.doi.org/10.1016/j.tube.2015.02.028

Abstract

Discovering new drugs to treat tuberculosis more efficiently and to overcome multidrug resistance is a world health priority. To find novel antitubercular agents several approaches have been used in various institutions worldwide, including target-based approaches against several validated mycobacterial enzymes and phenotypic screens. We screened more than 17,000 compounds from Vichem's Nested Chemical Library(TM) using an integrated strategy involving whole cell-based assays with Corynebacterium glutamicum and Mycobacterium tuberculosis, and target-based assays with protein kinases PknA, PknB and PknG as well as other targets such as PimA and bacterial topoisomerases simultaneously. With the help of the target-based approach we have found very potent hits inhibiting the selected target enzymes, but good minimal inhibitory concentrations (MIC) against M. tuberculosis were not achieved. Focussing on the whole cell-based approach several potent hits were found which displayed minimal inhibitory concentrations (MIC) against M. tuberculosis below 10 mu M and were non-mutagenic, non-cytotoxic and the targets of some of the hits were also identified. The most active hits represented various scaffolds. Medicinal chemistry-based lead optimization was performed applying various strategies and, as a consequence, a series of novel potent compounds were synthesized. These efforts resulted in some effective potential antitubercular lead compounds which were confirmed in phenotypic assays. (C) 2015 Elsevier Ltd. All rights reserved.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the CHURCHILL LIVINGSTONE, JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND
Keywords: Tuberculosis; Enzyme inhibitor; Targeted therapy; Kinase inhibitor; Phenotypical screening
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Depositing User: Id for Latest eprints
Date Deposited: 11 Aug 2015 09:06
Last Modified: 05 Mar 2019 05:08
URI: http://eprints.iisc.ac.in/id/eprint/52080

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