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J Med Chem. 2015 Dec 10;58(23):9371-81. doi: 10.1021/acs.jmedchem.5b01542. Epub 2015 Nov 20.

Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration.

Author information

1
Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
2
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory 7925, South Africa.
3
South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry, University of Cape Town , Rondebosch 7701, South Africa.
4
Novartis Institute for Tropical Diseases (NITD) , 10 Biopolis Road, Chromos no. 05-01, Singapore 138670, Singapore.
5
DST/NRF Centre of Excellence in Biomedical TB Research, SA MRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Health Sciences, Stellenbosch University , Tygerberg 7505, South Africa.
6
MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Department of Pathology, University of Cape Town , Rondebosch 7701, South Africa.
7
Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Rondebosch 7701, South Africa.
8
Global Discovery Chemistry, Novartis Institutes for BioMedical Research , Novartis Campus, CH-4056 Basel, Switzerland.

Abstract

High-throughput screening of a library of small polar molecules against Mycobacterium tuberculosis 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. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (ΔcydKO) 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, was resistant to compounds in this series. In combination, these observations indicate that this novel class of antimycobacterial compounds inhibits the cytochrome bc1 complex, a validated drug target in M. tuberculosis.

PMID:
26551248
DOI:
10.1021/acs.jmedchem.5b01542
[Indexed for MEDLINE]

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