COMPREHENSIVE QSAR ANALYSIS AND COMPUTER ASSISTED MECHANISM STUDY OF CINNAMIC ACIDS AS POTENT ANTITUBERCULAR AGENTS

Jainendra Kumar B., Suresh K., Umarani W. A., Sony Priya K., Purna Nagasree K. and Murali Krishna Kumar M.*

ABSTRACT

Cinnamic acids are one of the oldest class of natural products known to mankind. Along with varied bioactivities, these compounds are also known to possess antimicrobial activity. As these compounds possess αβ unsaturated carboxylic acid system similar to intermediates formed in fatty acid biosynthesis, it is hypothesized to interfere with enzymes involved in fatty acid biosynthesis. But there is no report of cinnamic acids interfering with the enzyme complex involved in human fatty acid biosynthesis (FAS-I), probably due to steric hindrance offered by the phenyl unit. But in case of Mycobacterium tuberculosis, very long chain fatty acids (mycolic acids) are biosynthesized by enzymes of FAS-II pathway. These enzymes are dissociated and relatively liberal in allowing larger substrates to participate in enzyme activity. Hence, we made an attempt to prepare and screen cinnamic acids for anti TB activity using MABA method and cell viability assays. Further we did a thorough docking simulation study on enzymes involve in FAS-II pathway with cinnamic acids. We found surprisingly high potency for the synthesized cinnamic acids (MIC 1.6 μg/mL). We also found the docking scores completely in agreement with our hypothesis of FAS-II enzyme inhibition as main mechanism of action. The bioactivity and SAR are discussed in detail.

Keywords: Cinnamic acids, FAS-II inhibition, anti TB, Mycobacterium tuberculosis.