title: Discovery of novel N-phenyl 1,4-dihydropyridines with a dual mode of antimycobacterial activity.
abstract: There is an urgent need for novel drugs for the treatment of tuberculosis (TB) due to the increasing prevalence of antibiotic resistance among Mycobacterium tuberculosis (Mtb) strains against first-line and second-line therapeutics. We developed novel N-phenyl 1,4-dihydropyridines as potential antituberculotic agents. The observed activity depends on the substitution patterns of the aromatic residues. N-unsubstituted 1,4-dihydropyridines are known inhibitors of the cancer-relevant transmembrane efflux pump ABCB1. Based on the similarity of ABCB1 amino acids sequences relevant to 1,4-dihydropyridine binding and the MTb efflux pump Rv0194, we determined ABCB1-inhibitory properties of our compounds in a cell line model. We identified one compound, which substantially increased the activity of two antituberculotic drugs which are substrates of ABCB1. The data indicate that our N-phenyl 1,4-dihydropyridines represent a novel compound class which improves the efficacy of anti-TB drugs by interfering with transmembrane efflux pumps in Mtb.
authors.affiliation: Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Lentz
authors.affiliation: Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Hemmer
authors.affiliation: Research Center Borstel, Leibniz Center for Medicine and Biosciences, Parkallee 22, 23845 Borstel, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
authors.affiliation: Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany. Electronic address: andreas.hilgeroth@pharmazie.uni-halle.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hilgeroth
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009525:Niacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D009525:Niacin
keywords: 1,4-Dihydropyridines; ABCB1 inhibitor; Antituberculotic drugs; Biological activity data