Design, Synthesis, in vitro Anti‐inflammatory Activity and in silico Studies of Imidazole‐Based 1,2,3‐Triazole Hybrids Targeting p38 MAP Kinase

• Published in: ChemistrySelect (Weinheim) 2024-01, Vol.9 (4), p.n/a
• Main Authors: Awasthi, Archana, Azizur Rahman, Md, Pingili, Divya, Raju, M. Bhagavan
• Format: Article
• Language: English
• Subjects: Adezmapimod; Imidazole; p38 MAP kinase Activity; Swiss ADME; Triazole
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202303915

p38 MAP kinases are involved in numerous inflammatory diseases. A series of 14 molecules of 1,2,3 triazole linked 4‐((2‐cyclohexyl‐4,5‐diphenyl‐1H‐imidazol‐1‐yl) methyl)‐1‐phenyl hybrids(7 a–7 n) has been synthesized by click reaction. Spectral data characterized all the synthesized compounds. The final compounds were screened for in vitro p38 MAP kinase inhibitory activity. Three compounds from the series 7 c, 7 f, and 7 n expounded superior activity with IC50 values 234.08±19.65 nM, 222.68±20.69 nM, and 241.70±20.51 nM respectively while two compounds (7 d and 7 e) showed considerable activity compared to prototype drug Adezmapimod (SB203580) (IC50 value 257.13±23.94 nM). The docking study of synthesized molecules revealed that the three compounds (7 f,7 g, and 7 n) showed higher binding affinities than Adezmapimod. The “Desmond v3.6 Program” was utilized to conduct MD simulations. The result revealed that compound 7 f was conformationally stable. The ADME studies were performed using the Swiss ADME algorithm. Studies revealed that all the compound‘s defiance of Lipinski's rule is within acceptable ranges with few violations. Compound 7 f was orally active and showed good gastrointestinal absorption within the acceptable range. The search for newer compounds with increased activity compared to Adezmapimod resulted in identifying a novel subclass of p38 MAP kinase inhibitors. The imidazole based 1,2,3 triazole hybrids showed potential p38 MAP kinase anti‐inflammatory inhibitors. Compound 7 c, 7 f and 7 n were found to be most significant comparable to prototype drug Adezmapimod (7 f>7 c>7 n>Adezmapimod). The compound 7 f was the most active compound of the series concerning docking score, ADME studies, and in vitro p38 MAP kinase inhibitory activity.