Executive Summary : | Pro-inflammatory cytokines, particularly IL-6 and TNF-α, are involved in the pathogenesis and progression of complex multifactorial disorders like rheumatoid arthritis, asthma, cancer, psoriasis, and Alzheimer's disease. Monoclonal antibodies have been effective in treating these diseases, but they have poor oral bioavailability, high cost, and undesirable toxicities. small molecule biosimilars targeting TNF-α are under development, targeting either IL-6 or TNF-α. Combination drug therapy or dual inhibition of these cytokines by a single molecule has emerged as a promising strategy for treating complex disorders like RA, psoriasis, and IBD. However, combination therapy has limitations such as poor patient compliance, drug-drug interactions, and complexity in pharmacokinetic profiles. The present study aims to design and synthesize benzimidazole-coumarin hybrids as dual inhibitors of IL-6 and TNF-α using a structure-guided approach, including computational tools like QsAR, docking, toxicity, and ADME parameters. The selected compounds will be synthesized using energy-conservative methods, characterized, and evaluated in-vitro for IL-6 and TNF-α inhibitory activities. The compounds exhibiting promising dual inhibitory activities will be further evaluated for in-vivo use in rheumatoid arthritis, a disease with increased prevalence in India. The findings of this project are expected to produce novel dual inhibitors of IL-6 and TNF-α that can be further evaluated for their efficacy in other complex multifactorial inflammatory or autoimmune diseases. |