1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in Mycobacterium tuberculosis

J Med Chem. 2021 Sep 9;64(17):12790-12807. doi: 10.1021/acs.jmedchem.1c00837.

Lutete Peguy Khonde ¹, Rudolf Müller ¹, Grant A Boyle ¹, Virsinha Reddy ¹, Aloysius T Nchinda ¹, Charles J Eyermann ¹, Stephen Fienberg ¹, Vinayak Singh ² ³, Alissa Myrick ², Efrem Abay ⁴, Mathew Njoroge ⁴, Nina Lawrence ⁴, Qin Su ⁵, Timothy G Myers ⁵, Helena I M Boshoff ⁶, Clifton E Barry 3rd ⁶, Frederick A Sirgel ⁷, Paul D van Helden ⁷, Lisa M Massoudi ⁸, Gregory T Robertson ⁸, Anne J Lenaerts ⁸, Gregory S Basarab ¹ ⁴, Sandeep R Ghorpade ¹, Kelly Chibale ¹ ³

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), Institute of Infectious Disease and Molecular Medicine, 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, Cape Town 7925, South Africa.
5 Genomic Technologies Section, Research Technologies Branch, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, United States.
6 Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, United States.
7 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, Cape Town 7505, South Africa.
8 Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523, United States.

PMID: 34414766 DOI: 10.1021/acs.jmedchem.1c00837

Abstract

Phenotypic whole cell high-throughput screening of a ∼150,000 diverse set of compounds against Mycobacterium tuberculosis (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide 1 as a moderately active hit. Structure-activity relationship (SAR) studies demonstrated a clear scope to improve whole cell potency to MIC values of <0.5 μM, and a plausible pharmacophore model was developed to describe the chemical space of active compounds. Compounds are bactericidal in vitro against replicating Mtb and retained activity against multidrug-resistant clinical isolates. Initial biology triage assays indicated cell wall biosynthesis as a plausible mode-of-action for the series. However, no cross-resistance with known cell wall targets such as MmpL3, DprE1, InhA, and EthA was detected, suggesting a potentially novel mode-of-action or inhibition. The in vitro and in vivo drug metabolism and pharmacokinetics profiles of several active compounds from the series were established leading to the identification of a compound for in vivo efficacy proof-of-concept studies.

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