In vivo potent BM635 analogue with improved drug-like properties
01 Pubblicazione su rivista
Poce Giovanna, Cocozza Martina, Alfonso Salvatore, Consalvi Sara, Venditti Giulia, Fernandez-Menendez Raquel, Bates Robert H., Barros Aguirre David, Ballell Lluis, De Logu Alessandro, Vistoli Giulio, Biava Mariangela
ISSN: 0223-5234
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 ¼ 0.15 mM; SI ¼ 133) against drug-sensitive Mycobacterium
tuberculosis strains, as well as efficacy in a murine model of TB infection