Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c

Kawaljit Singh; Malkeet Kumar; Elumalai Pavadai; Krupa Naran; Digby F Warner; Peter G Ruminski; Kelly Chibale

doi:10.1016/j.bmcl.2014.05.022

Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c

Bioorg Med Chem Lett. 2014 Jul 15;24(14):2985-90. doi: 10.1016/j.bmcl.2014.05.022. Epub 2014 May 16.

Authors

Kawaljit Singh¹, Malkeet Kumar¹, Elumalai Pavadai¹, Krupa Naran², Digby F Warner³, Peter G Ruminski⁴, Kelly Chibale⁵

Affiliations

¹ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa.
² MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Division of Medical Microbiology, University of Cape Town, Rondebosch 7701, South Africa.
³ MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, Division of Medical Microbiology, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
⁴ Centre for World Health and Medicine, Saint Louis University, USA.
⁵ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: Kelly.Chibale@uct.ac.za.

PMID: 24894561
DOI: 10.1016/j.bmcl.2014.05.022

Abstract

New verapamil analogues were synthesized and their inhibitory activities against Mycobacterium tuberculosis H37Rv determined in vitro alone and in combination with rifampicin (RIF). Some analogues showed comparable activity to verapamil and exhibited better synergies with RIF. Molecular docking studies of the binding sites of Rv1258c, a M. tuberculosis efflux protein previously implicated in intrinsic resistance to RIF, suggested a potential rationale for the superior synergistic interactions observed with some analogues.

Keywords: Efflux pump; Rifampicin; Rv1258c; Tuberculosis; Verapamil.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP-Binding Cassette Transporters / chemistry*
ATP-Binding Cassette Transporters / metabolism
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry*
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / chemistry*
Bacterial Proteins / metabolism
Binding Sites / drug effects
Dose-Response Relationship, Drug
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Rifampin / chemistry
Rifampin / pharmacology*
Structure-Activity Relationship
Verapamil / analogs & derivatives*
Verapamil / chemical synthesis
Verapamil / chemistry
Verapamil / pharmacology*

Substances

ATP-Binding Cassette Transporters
Anti-Bacterial Agents
Bacterial Proteins
Rv1258c protein, Mycobacterium tuberculosis
Verapamil
Rifampin