Arista, Luca, Renier , van der Westhuyzena, Susan, Winks, Colin, Wilson, Grant, Boyle, Richard, Gessner, Candice, Soares de Melo, Dale, Taylor, Carmen, de Kock, Mathew, Njoroge, Christel, Brunschwig, Nina, Lawrence, Frik, Sirgel, Paul, van Helden, Ronnett, Seldon, Atica, Moose, Digby, Warner, Ujjini , Manjunatha, Paul, Smith, Leslie, Street and Kelly, Chibale (2015) Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A new anti-mycobacterial class that targets mycobacterial energy metabolism. Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A new anti-mycobacterial class that targets mycobacterial energy metabolism, 58 (23). pp. 9371-9381. ISSN 0022-26231520-4804

Abstract

Phenotypic whole-cell high throughput screening of a library of small polar molecules led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure activity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity against Mycobacterium tuberculosis. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (∆cydKO) was hyper-susceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase (bc1 complex), was resistant to compounds in this series. In combination, these observations indicate that this novel class of anti-mycobacterial compounds inhibits the cytochrome bc1 complex, a validated drug target in M. tuberculosis.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/27132