title: Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection.
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.
authors: Istituto Pasteur Fondazione Cenci-Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, Italy. giovanna.poce@uniroma1.it
authors: Giovanna
authors: G
authors: Poce
authors: Robert H
authors: RH
authors: Bates
authors: Salvatore
authors: S
authors: Alfonso
authors: Martina
authors: M
authors: Cocozza
authors: Giulio Cesare
authors: GC
authors: Porretta
authors: Lluís
authors: L
authors: Ballell
authors: Joaquin
authors: J
authors: Rullas
authors: Fátima
authors: F
authors: Ortega
authors: Alessandro
authors: A
authors: De Logu
authors: Emanuela
authors: E
authors: Agus
authors: Valentina
authors: V
authors: La Rosa
authors: Maria Rosalia
authors: MR
authors: Pasca
authors: Edda
authors: E
authors: De Rossi
authors: Baojie
authors: B
authors: Wae
authors: Scott G
authors: SG
authors: Franzblau
authors: Fabrizio
authors: F
authors: Manetti
authors: Maurizio
authors: M
authors: Botta
authors: Mariangela
authors: M
authors: Biava
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005260:Female; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008861:Microsomes / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014376:Tuberculosis / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000904:Antibiotics, Antitubercular; D001426:Bacterial Proteins; D010879:Piperazines; D011758:Pyrroles; C115651:BM 212