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 medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have 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. The resulting ED(99) of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antitubercular / chemistry
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Antibiotics, Antitubercular / pharmacology*
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Antibiotics, Antitubercular / toxicity
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Cell Line
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Female
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Humans
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Mice
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Microbial Sensitivity Tests
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Microsomes / metabolism
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / genetics
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Mycobacterium tuberculosis / metabolism
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Piperazines / chemistry
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Piperazines / pharmacology*
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Piperazines / toxicity
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Pyrroles / toxicity
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Tuberculosis / drug therapy
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Tuberculosis / metabolism*
Substances
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Antibiotics, Antitubercular
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Bacterial Proteins
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Piperazines
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Pyrroles
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BM 212
Grants and funding
This work was supported by Istituto Pasteur Fondazione Cenci-Bolognetti (Italy), MIUR-PRIN 2008 (Italy), MIUR 2011 (Progetti di Ricerca di Ateneo) (Italy) and Tres Cantos Open Lab Foundation. The research leading to these results also received funding from the European Union's 7th framework programme (FP7- 2007–2013) under grant agreement no 261378. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.