Design, Synthesis and Evaluation of Benzimidazole Derivatives as IL‐6 Inhibitors and Their Role in Rheumatoid Arthritis

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a major role in the development of Rheumatoid Arthritis (RA). In the present study, benzimidazole and benzene sulfonyl scaffold were identified as pharmacophore by analysis of literature reports and novel small molecule IL-6 inhibitors were designed. These were screened via docking with IL-6 (PDB: 1ALU), then and through Lipinski's rule of 5. Based on docking score, 10 best compounds (4a-4e and 7a-7e) were selected for synthesis and evaluated for IL-6 inhibitory activity in vitro. Compounds 4b and 7b showed the maximum inhibition of IL-6 (87.55% and 82.75%, respectively). These compounds were further explored for anti-arthritic activity in vivo using the Incomplete Freund's Adjuvant Model and by morphological and histopathological studies of the inflamed paw. Compound 4b was significantly more active than compound 7b and both were found to be slightly less active than methotrexate. These findings indicate that a benzimidazole nucleus linked to a benzene sulphonyl moiety may prove to be a useful template for the development of new chemical moieties against RA.