Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents

Oluseye K. Onajole, Shichun Lun, Young Ju Yun, Damkam Y. Langue, Michelle Jaskula-Dybka, Adrian Flores, Eriel Frazier, Ashle C. Scurry, Ambernice Zavala, Karen R. Arreola, Bryce Pierzchalski, A. Jean Luc Ayitou, William R. Bishai

Research output: Contribution to journalLetter

Abstract

Tuberculosis (TB) is a highly infectious disease that has been plaguing the human race for centuries. The emergence of multidrug-resistant strains of TB has been detrimental to the fight against tuberculosis with very few safe therapeutic options available. As part of an ongoing effort to identify potent anti-tuberculosis agents, we synthesized and screened a series of novel imidazo[1,2-a]pyridinecarboxamide derivatives for their anti-tuberculosis properties. These compounds were designed based on reported anti-tuberculosis properties of the indolecarboxamides (I2Cs) and imidazo[1,2-a]pyridinecarboxamides (IPAs). In this series, we identified compounds 15 and 16 with excellent anti-TB activity against H37Rv strain of tuberculosis (MIC = 0.10–0.19 μM); these compounds were further screened against selected clinical isolates of Mtb. Compounds 15 and 16 showed excellent activities against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB (MIC range: 0.05–1.5 μM) with excellent selectivity indices. In addition, preliminary ADME studies on compound 16 showed favorable pharmacokinetic properties.

Original languageEnglish (US)
JournalChemical Biology and Drug Design
DOIs
StateAccepted/In press - 2020

Keywords

  • antituberculosis activity
  • Imidazo[1,2-apyridine-3-carboxamide
  • Indole-2-carboxamide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Onajole, O. K., Lun, S., Yun, Y. J., Langue, D. Y., Jaskula-Dybka, M., Flores, A., Frazier, E., Scurry, A. C., Zavala, A., Arreola, K. R., Pierzchalski, B., Ayitou, A. J. L., & Bishai, W. R. (Accepted/In press). Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridinecarboxamides as potent anti-tuberculosis agents. Chemical Biology and Drug Design. https://doi.org/10.1111/cbdd.13739