In vivo potent BM635 analogue with improved drug-like properties.

European journal of medicinal chemistry, Volume: 145
February 10, 2018
Giovanna Poce G, Martina Cocozza M, Salvatore Alfonso S, Sara Consalvi S, Giulia Venditti G, Raquel Fernandez-Menendez R, Robert H Bates RH, David Barros Aguirre D, Lluis Ballell L, Alessandro De Logu A, Giulio Vistoli G, Mariangela Biava M

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.