Synthesis and bioactive study of tricyclic cyclopentaimidazopyridin-6-carboxylates grafting benzylpiperazyl groups as cytoprotectant agents.

A series of modified Genipin derivatives 6a-d and 7-10, grafted with benzylpiperazyl groups, were synthesized from the tricyclic cyclopentaimidazopyridin-6-carboxylates 3a-d to evaluate their anti-inflammatory and neuroprotective activities. Compounds 3a-d and the benzylpiperazine-substituted tricyclic derivatives 6a-d and 7-10 were preliminarily tested against RAW 264.7 and BV-2 cell lines, as well as for AChE inhibitory activity. Based on the SAR study and inhibition data, the modified benzylpiperazine-substituted cyclopentaimidazopyridin-6-carboxylates 6a-d and 7-10 exhibited superior inhibitory potency compared to the starting materials 3a-d. Particularly, compound 6a demonstrated the most effective anti-inflammatory and neuroprotective activities, with IC₅₀ values of 17.5 μM (RAW 264.7 cells), 3.81 μM (BV-2 cell lines), and 156 nM (AChE activity assay). These values were superior to those of the reference standards Indomethacin (IC50 = 166 μM), Yomogin (IC50 = 5.24 μM), and Donepezil (IC50 = 244 nM). On the other hand, all tricyclic compounds 3a-d, 6a-d, and 7-10 were subjected to safety profile studies, showing cell viability maintained at concentrations exceeding 100 μM. Subsequently, based on further Western blot, cytotoxicity, and molecular simulation studies, cyclopentaimidazopyridine 6a emerged as a promising candidate for development as a potential anti-inflammatory and anti-neuroinflammatory lead compound.