Open Access1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in Mycobacterium tuberculosis
Author(s) -
Lutete Peguy Khonde,
Rudolf Müller,
Grant A. Boyle,
Virsinha Reddy,
Aloysius T. Nchinda,
Charles J. Eyermann,
Stephen Fienberg,
Vinayak Singh,
Alissa Myrick,
Efrem Abay,
Mathew Njoroge,
Nina Lawrence,
Qin Su,
Timothy G. Myers,
Helena I. Boshoff,
Clifton E. Barry,
Frederick A. Sirgel,
Paul D. van Helden,
Lisa M. Massoudi,
Gregory T. Robertson,
Anne J. Lenaerts,
Gregory S. Basarab,
Sandeep R. Ghorpade,
Kelly Chibale
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c00837
Subject(s) - mycobacterium tuberculosis , inha , pharmacophore , in vivo , chemistry , tuberculosis , in vitro , mode of action , isoniazid , biochemistry , microbiology and biotechnology , biology , medicine , pathology
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.