Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies

J Med Chem. 2021 Jan 14;64(1):719-740. doi: 10.1021/acs.jmedchem.0c01727.

Candice Soares de Melo ¹, Vinayak Singh ² ³, Alissa Myrick ², Sandile B Simelane ¹, Dale Taylor ⁴, Christel Brunschwig ⁴, Nina Lawrence ⁴, Dirk Schnappinger ⁵, Curtis A Engelhart ⁵, Anuradha Kumar ⁶, Tanya Parish ⁶, Qin Su ⁷, Timothy G Myers ⁷, Helena I M Boshoff ⁸, Clifton E Barry 3rd ⁸, Frederick A Sirgel ⁹, Paul D van Helden ⁹, Kirsteen I Buchanan ¹⁰, Tracy Bayliss ¹⁰, Simon R Green ¹⁰, Peter C Ray ¹⁰, Paul G Wyatt ¹⁰, Gregory S Basarab ¹ ⁴, Charles J Eyermann ¹, Kelly Chibale ¹ ³, Sandeep R Ghorpade ¹

Affiliations

1 Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
2 Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa.
3 South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
4 Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory 7925, South Africa.
5 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States.
6 Infectious Disease Research Institute, 1616 Eastlake Ave E, Suite 400, Seattle, Washington 98102, United States.
7 Genomic Technologies Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
8 Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
9 South African Medical Research Council Centre for Tuberculosis Research/DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Science, Stellenbosch University, Tygerberg 7505, South Africa.
10 Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K.

PMID: 33395287 DOI: 10.1021/acs.jmedchem.0c01727

Abstract

Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.

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