In vivo potent BM635 analogue with improved drug-like properties

Giovanna Poce; Martina Cocozza; Salvatore Alfonso; Sara Consalvi; Giulia Venditti; Raquel Fernandez-Menendez; Robert H Bates; David Barros Aguirre; Lluis Ballell; Alessandro De Logu; Giulio Vistoli; Mariangela Biava

doi:10.1016/j.ejmech.2017.12.075

In vivo potent BM635 analogue with improved drug-like properties

Eur J Med Chem. 2018 Feb 10:145:539-550. doi: 10.1016/j.ejmech.2017.12.075. Epub 2017 Dec 27.

Affiliations

¹ Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy. Electronic address: giovanna.poce@uniroma1.it.
² Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy.
³ Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy; Diseases of the Developing World, Tres Cantos Medicines Development Campus, GSK, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.
⁴ Diseases of the Developing World, Tres Cantos Medicines Development Campus, GSK, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.
⁵ Dipartimento di Scienze della Vita e dell'Ambiente, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
⁶ Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
⁷ Department of Chemistry and Technology of Drugs, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy. Electronic address: mariangela.biava@uniroma1.it.

PMID: 29335214
DOI: 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.

Keywords: Anti-mycobacterials; Drug discovery; MmpL3; Pyrroles; Tuberculosis.

MeSH terms

Animals
Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Design
Hep G2 Cells
Humans
Mice
Mice, Inbred C57BL
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship
Tuberculosis / drug therapy*

Substances

Antitubercular Agents
BM635 compound
Pyrroles