BM635 is a small molecule endowed with outstanding anti-mycobacterial activity (minimum inhibitory concentration of 0.12 ?M against M. tuberculosis H37Rv) identified during a hit-to-lead campaign. Its poor aqueous solubility together with its high lipophilicity led to low exposure in vivo. Indeed, the half-life in vivo of BM635 was 1 h, allowing a reasonable maximum concentration (Cmax = 1.62 ?M) and a moderate bioavailability (46%).
BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations
around the central pyrrole core of BM635 and we describe the design, synthesis, biological
evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues
that show improved physicochemical properties. This hit-to-lead campaign led to the identification
of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)
In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against Mycobacterium tuberculosis. Among them, only the 1,3,5-trisubstituted pyrazoles 5−49 exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile without cytotoxic effects.
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