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

Phenotypic whole cell high-throughput screening of a ∼150,000 diverse set of compounds against (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide 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 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 and drug metabolism and pharmacokinetics profiles of several active compounds from the series were established leading to the identification of a compound for efficacy proof-of-concept studies.