Synthesis of various 3-nitropropionamides as Mycobacterium tuberculosis isocitrate lyase inhibitor

  • Bioorg Med Chem Lett. 2011 Sep 15;21(18):5149-54. doi: 10.1016/j.bmcl.2011.07.062.
Dharmarajan Sriram  1 ,  Perumal Yogeeswari ,  Swetha Methuku ,  Devambatla Ravi Kumar Vyas ,  Palaniappan Senthilkumar ,  Mallika Alvala ,  Variam Ullas Jeankumar
Affiliations
  • 1. Antitubercular Drug Discovery Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, India. [email protected]
PMID: 21840711 DOI: 10.1016/j.bmcl.2011.07.062
Abstract

Various 3-nitropropionamides were synthesized and evaluated for in vitro activities against log and starved phase culture of two mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among 22 compounds, 1-cyclopropyl-7-(3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (22) was found to be the most active compound in vitro with MICs of 0.16 and 0.04 μM against log- and starved-phase culture of MTB. Compound 22 also showed good enzyme inhibition of MTB ICL with IC(50) of 0.10 ± 0.01 μM. The docking studies also confirmed the binding potential of the compounds at the ICL active site.