Discovery of novel N-phenyl 1, 4-dihydropyridines with a dual mode of antimycobacterial activity. Issue 24 (15th December 2016)

• Record Type: Journal Article
• Authors: Lentz, Fabian; Hemmer, Marc; Reiling, Norbert; Hilgeroth, Andreas
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 24(2016)
• Page Start: 5896
• Page End: 5898
• Publication Date: 2016-12-15
• Subjects: 1, 4-Dihydropyridines -- ABCB1 inhibitor -- Biological activity data -- Antituberculotic drugs; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.11.010
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.