Life Sciences & Biotechnology
Title : | Discovery and Biological Evaluation of Novel Dual Inhibitors of DprE1 and InhA as Potential Anti-Tubercular Agents |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Molecular Biology, Medicinal Chemistry |
Principal Investigator : | Dr. KVG Chandrasekhar, Birla Institute Of Technology & Science Pilani (BITS), Hyderabad Campus, Telangana |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | kvgcs@yahoo.com |
Details
Executive Summary : | Tuberculosis (TB) is one of the most common infectious diseases known to mankind. About 32% of the world’s population (1.7 billion) is infected with TB. Drugs for treating TB have been available for over half a century, and yet the incidence of disease worldwide is not under control. Every year, approximately 8 million of these infected people develop active TB, and almost 2 million of these would die from the disease, a life lost to TB every 15 seconds. Co-infection with human immunodeficiency virus is driving the increase in incidence, and the cause of death in 31% of AIDS cases can be attributed to TB. Increasing emergence of resistance, and longer treatment period along with the increased cost of TB drugs, compel the researchers in search of newer strategies to combat this lethal disorder. Our group is working in the area of anti-TB drug discovery for past ten years and we have identified some potential hits for Mycobacterium tuberculosis (MTB) enzymes viz., pantothenate synthetase, DNA gyrase and InhA. The present study would involve, for the first time, the design of newer leads based on dual inhibition of mycobacterial enzymes DprE1 and InhA, a NADH-dependent enoyl-acyl carrier protein reductase. The compounds are designed based on thorough structure activity relationship studies of the existing DprE1 and InhA inhibitors. The present study would involve design of novel compounds employing structure-based drug design and molecular hybridization approach using available leads and evaluating the derivatives for the biological activity. Several compounds are designed hybridizing various scaffolds and docking studies were also performed to the DprE1 and InhA active site to identify the correct combination of heterocycles giving dual inhibition. Three synthetic schemes are proposed to synthesize the identified compounds exhibiting dual inhibition. In the first scheme, N-terminal of various alkylidene thiazolidine-2,4-diones / imidazolidine-2,4-diones will be coupled with substituted α-bromo acetophenones to get the final compounds. In the second scheme, N-terminal of substituted 2,4-dioxo-thiazolidin-5-ylidene-N-phenylacetamides will be coupled with substituted α-bromo acetophenones to get the final compounds while in the third scheme spiro compounds of indene and imidazolidine-2,4-diones will be coupled with substituted α-bromo acetophenones to get the final compounds. Once the compounds are well characterized through various spectroscopic techniques, the novel compounds will be evaluated for anti-TB activity and their InhA and DprE1 inhibition. Cytotoxicity studies of the most active compounds will be performed and selectivity index will also be determined. Structure activity relationship studies will be carried out and one lead compound will be identified from the studies for further development. |
Co-PI: | Prof. Murugesan Sankaranarayanan, Birla Institute Of Technology And Science (BITS), Pilani, Rajasthan-333031 |
Total Budget (INR): | 34,52,180 |
Organizations involved