Background: Tuberculosis (TB) is the most devastating infectious disease caused by the Mycobacterium tuberculosis (MTB) bacillus existed for millennia and remains a global health problem. Poor compliance is partly to blame for the evolution of drug-resistant MTB strains that are difficult and expensive to treat. The treatment for RIF-resistant TB, multidrug-resistant TB, and extensively drug-resistant TB is even longer (18-24 months), and requires more expensive and more toxic drugs. The emerging problem of antimicrobial resistance is proving to be a bigger challenge in the post-antibiotic era and the search for new drugs has become one of the great challenges for medicinal chemistry. An improvement in the outcomes of TB chemotherapy can be achieved by the development of new, shorter, cheap, safe and effective anti-TB regimens. In this context, we have explored chalcones as potential anti-tubercular compounds. Chalcones, being natural or synthetic compounds are known to display a remarkable spectrum of biological activities such as antibacterial, anti-malarial, anti-inflammatory, analgesic and as antioxidants. They are also well known as valuable intermediates in organic synthesis of many heterocyclic compounds that exhibit a multitude of biological activities. Abstract: Chalcones (1a-1o) were synthesized by reacting aromatic-aldehydes with various acetophenones by the Claisen-Schimidt condensation in the presence of sodium hydroxide in ethanol. The synthesized products were recrystallized from appropriate solvents and were characterized by spectral analysis, melting point, infrared spectroscopy, 1H and 13C NMR and mass spectrometry. Minimum inhibitory concentration (MIC) were determined for these synthesized compounds by broth micro-dilution according to CLSI guidelines. Based on the Selectivity Index (SI) values obtained from cytotoxic studies performed on mouse macrophage J774 cell line, compound 1a (SI=8.4) was selected for mode of action elucidation. To investigate whether 1a affects the synthesis of mycobacterial lipids, mycolic acid methyl esters (MAMEs) and fatty acid methyl esters (FAMEs) were extracted and analyzed by TLC. A dose dependent reduction of MAMEs with the overall abundance of FAMEs suggests that 1a targets mycolic acid biosynthesis (fatty acid synthase (FAS)-II inhibitors). To further corroborate 1a inhibits mycolic acid biosynthesis, the impact on the MIC was investigated using strains of M. bovis BCG overexpressing components of FAS-II. The ample growth of InhA overexpressor strain was observed, indicating an increase in resistance and the MIC shift of > 4X providing further evidence to support InhA as the cellular target for 1a.
|Title of host publication||Identification and Validation of Mode of Action of Chalcones as Anti-Tubercular Compounds|
|Publication status||Published - 25 Apr 2017|
|Event||27th European Congrss on Clinical Microbiology and Infectious Diseases - Vienna, Austria|
Duration: 22 Apr 2017 → 25 Apr 2017
|Conference||27th European Congrss on Clinical Microbiology and Infectious Diseases|
|Abbreviated title||27th ECCMID|
|Period||22/04/17 → 25/04/17|