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

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.