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.