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Title: Improved BM212 MmpL3 Inhibitor Analogue ShowsEfficacy in Acute Murine Model of Tuberculosis Infection
Authors: Giovanna, Poce
Robert H., Bates
Salvatore, Alfonso
Martina, Cocozza
Giulio Cesare, Porretta
Lluı´s, Ballell
Joaquin, Rullas
Fa´tima, Ortega
Alessandro De, Logu
Emanuela, Agus
Valentina La, Rosa
Maria Rosalia, Pasca
Edda De, Rossi
Baojie, Wae
Scott G., Franzblau
Manetti, Fabrizio 
Botta, Maurizio 
Mariangela, Biava
Issue Date: 2013
Project: None 
Journal: PLOS ONE
1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M.tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinalchemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and byreplacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement ofthe sulfur with oxygen gave compounds with lower lipophilicity and improved in vitro microsomal stability. Moreover, sincethe parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compoundshave been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene.The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. Theresulting ED99 of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential ofthis chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as adruggable target of interest for anti-tubercular drug discovery.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0056980
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