Structure−Activity relationship and optimization of drug-like properties of antituberculosis 3-(4,4-dimethyl-1,4-azasilinane)methylpyrazole MmpL3 inhibitors

Structure-activity relationship studies of previously reported 3-(4,4-dimethyl-1,4-azasilinane) methylpyrazoles with potent anti-tuberculosis activity were conducted to identify leads with drug-like properties by optimizing the lipophilicity of the compounds. Removal of phenyl substituents at 1 or 5 positions of the pyrazole ring or introducing polar substituents on the 5-phenyl ring identified potent compounds with lower logD and improved solubility. Compounds with a C5-cyclopentyl substituent showed improved stability in human microsomes. In vitro and in vivo metabolite identification studies were conducted to facilitate further compound optimization. Compounds are bactericidal in vitro against replicating Mycobacterium tuberculosis (Mtb) and retain activity against drug-resistant Mtb. Profiling against the MmpL3 TetON and tet-inducible over-expression (OE) mutants confirmed direct inhibition of the MtbMmpL3 transporter as a mode-of-action of the compounds.