Optimization of Indolecarboxamides Inhibiting MmpL3 in Mycobacterium Tuberculosis
Authors: Sauvik Samanta (a), Candice Soares de Melo (a), Sandeep R. Ghorpade (a), Vinayak Singh (b), Chandramohan Bathula (a), Lebu Taleli (a), Sanjit Das (a), Stephen Fienberg (a), Nina Lawrence (c), Mathew Njoroge (c), Natalie Hawryluk (d), Stacie Canan (d), Dale Robinson (d), Geraldine Hernandez (d), Yixing Shen (d), Joseph Camardo (e), Vikram Khetani (e), Ben Gold (f), Carl Nathan (f), Dirk Schnappinger (f), Tanya Parish (g), Gregory S. Basarab (a,c), Leslie Street (a), Charles J. Eyermann (a), and Kelly Chibale (a,h)*
Affiliations: (a) Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; (b) Drug Discovery and Development Centre (H3D), Institute of Infectious Disease and Molecular Medicine University of Cape Town, Rondebosch 7701, South Africa; (c) Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa; (d) Celgene Global Health, San Diego, California, United States of America; (e) Celgene Global Health, Summit, New Jersey, United States of America; (f) Department of Microbiology and Immunology, Weill Cornell Medicine, New York, United States of America; (g) Infectious Disease Research Institute, Seattle, United States; (h) South African Medical Research Council Centre for Tuberculosis Research / DST/NRF
Abstract body: With the growing incidence of multi- and extensively drug resistant tuberculosis (TB), there is a continuous need to identify multiple novel and mechanistically distinct anti-TB drugs possessing reduced liabilities for investigation in new TB drug regimens.1 The mycobacterial membrane protein large 3 (MmpL3) is an inner membrane protein that transports mycolic acids, in the form of their precursors trehalose monomycolates, from the cytoplasm to the periplasmic space, where mycolic acids can then be used in assembly of the mycobacterial outer membrane. Inactivation of MmpL3 weakens the bacterial cell wall and impacts the viability and virulence of M. tuberculosis (Mtb), making it an attractive target for anti-TB drugs. The phenotypic screening of a diversity library from Celgene Global Health against replicating Mtb led to the identification of the indole-2-carboxamide hits with potent antimycobacterial activity, a favorable selectivity index over mammalian cytotoxicity, good permeability and an improved lipophilicity and structural diversity over literature indolecarboxamides. MmpL3 was confirmed as a target of indolecarboxamides by generating spontaneous-resistant mutants followed by whole-genome sequencing, and the observed hypersusceptibility of tested compounds to M. tuberculosis upon mmpL3 silencing. Encouraged by this, we initiated structure-activity relationship (SAR) investigations and optimization of series issues such as poor solubility and hERG inhibition, to establish scope of progression of indolecarboxamides towards a preclinical candidate nomination.
1. Zumla, A. I.; Gillespie, S. H.; Hoelscher, M.; Philips, P. P. J.; Cole, S. T.; Abubakar, I.;McHugh, T. D.; Schito, M.; Maeurer, M.; Nunn, A. J. The Lancet Infectious Diseases 2014, 14, 327-340.
2. Hett, E.C.; Rubin, E.J. Microbiol. Mol. Biol. Rev. 2008, 72, 126–156.