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In vivo potent BM635 analogue with improved drug-like properties
Giovanna Poce1, Martina Cocozza1, Salvatore Alfonso2
1Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy.
Abstract:
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)morpholine (17), that shows excellent activity (MIC = 0.15 μM; SI = 133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection.
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