Please use this identifier to cite or link to this item:
|Title:||Improved BM212 MmpL3 Inhibitor Analogue ShowsEfficacy in Acute Murine Model of Tuberculosis Infection||Authors:||Giovanna, Poce
Robert H., Bates
Giulio Cesare, Porretta
Alessandro De, Logu
Valentina La, Rosa
Maria Rosalia, Pasca
Edda De, Rossi
Scott G., Franzblau
|Issue Date:||2013||Project:||None||Journal:||PLOS ONE||Abstract:||
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.
|Appears in Collections:||Publications|
Show full item record
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.