Dually acting nonclassical 1,4-dihydropyridines promote the anti-tuberculosis (Tb) activities of clofazimine

Fabian Lentz, Norbert Reiling, Gabriella Spengler, Annamária Kincses, Andrea Csonka, Joseph Molnár, Andreas Hilgeroth

Research output: Contribution to journalArticle

Abstract

The number of effective antituberculotic drugs is strongly limited to four first-line drugs in standard therapy. In case of resistances second-line antibiotics are used with a poor efficacy and tolerability. Therefore, novel antituberculotic drugs are urgently needed. We synthesized novel nonclassical 1,4-dihydropyridines and evaluated their antituberculotic properties depending on substituent effects. Preferred substituents could be identified. As related classical 1,4-dihydropyridines are known as inhibitors of the transmembrane efflux pump ABCB1 in cancer cells, we wondered whether a use of our compounds may be of favour to enhance the antituberculotic drug efficacy of the second-line antituberculotic drug clofazimine, which is a known substrate of ABCB1 by a suggested inhibition of a corresponding efflux pump in Mycobacterium tuberculosis (Mtb). For this, we determined the ABCB1 inhibiting properties of our compounds in a mouse T-lymphoma cell line model and then evaluated the drug-enhancing properties of selected compounds in a co-application with clofazimine in our Mtb strain. We identified novel enhancers of clofazimine toxicity which could prevent clofazimine resistance development mediated by an efflux pump activity.

Original languageEnglish
Article number2873
JournalMolecules
Volume24
Issue number16
DOIs
Publication statusPublished - Aug 8 2019

Keywords

  • Antibacterial activity
  • Inhibition
  • Structure-activity
  • Substituent
  • Synthesis

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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