1,3-Diarylpyrazolyl-acylsulfonamides as Potent Anti-tuberculosis Agents Targeting Cell Wall Biosynthesis in <i>Mycobacterium tuberculosis</i>.
Khonde LP, Müller R, Boyle GA, Reddy V, Nchinda AT, Eyermann CJ, Fienberg S, Singh V, Myrick A, Abay E, Njoroge M, Lawrence N, Su Q, Myers TG, Boshoff HIM, Barry CE, Sirgel FA, van Helden PD, Massoudi LM, Robertson GT, Lenaerts AJ, Basarab GS, Ghorpade SR, Chibale K.
Phenotypic whole cell high-throughput screening of a ∼150,000 diverse set of compounds against <i>Mycobacterium tuberculosis</i> (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide <b>1</b> 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 <i>in vitro</i> 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 <i>in vitro</i> and <i>in vivo</i> drug metabolism and pharmacokinetics profiles of several active compounds from the series were established leading to the identification of a compound for <i>in vivo</i> efficacy proof-of-concept studies.