Data di Pubblicazione:
2018
Citazione:
In vivo potent BM635 analogue with improved drug-like properties / G. Poce, M. Cocozza, S. Alfonso, S. Consalvi, G. Venditti, R. Fernandez-Menendez, R.H. Bates, D. Barros Aguirre, L. Ballell, A. De Logu, G. Vistoli, M. Biava. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 145(2018 Feb 10), pp. 539-550. [10.1016/j.ejmech.2017.12.075]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Anti-mycobacterials; Drug discovery; MmpL3; Pyrroles; Tuberculosis; Animals; Antitubercular Agents; Cell Proliferation; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Hep G2 Cells; Humans; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Pyrroles; Structure-Activity Relationship; Tuberculosis; Pharmacology; Drug Discovery3003 Pharmaceutical Science; Organic Chemistry
Elenco autori:
G. Poce, M. Cocozza, S. Alfonso, S. Consalvi, G. Venditti, R. Fernandez-Menendez, R.H. Bates, D. Barros Aguirre, L. Ballell, A. De Logu, G. Vistoli, M. Biava
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