Molecular modeling, synthesis, and qsar of 5-o-acylpinostrobin derivatives as promising analgesic agent

Pain remains a major healthcare problem nowadays, despite the recent advances and knowledge about its mechanism and management. Currently marketed analgesics and NSAIDs include both non-selective COX inhibitors and selective COX-2 inhibitors exhibit several disadvantages such as increasing gastrointestinal bleeding and cardiovascular risk. We aimed to develop a potential analgesic by utilizing structural modifications on pinostrobin, which is previously known to possess anti-inflammatory properties. Schotten-Baumann esterification reaction was employed to produce four 5-O-acylpinostrobin derivatives, namely pinostrobin acetate, pinostrobin propionate, pinostrobin butyrate, and pinostrobin pentanoate, with moderate to good yields (61-84%). The acetic acid-induced writhing test using Mus musculus was demonstrated to evaluate the analgesic activity of the compounds. 5-O-Acylpinostrobin derivatives display some improvements in analgesic activity compared to pinostrobin itself. Pinostrobin pentanoate emerges as the most potent compound with an ED₅₀ value of 10.37 mg/kg BW. This result is consistent with the in silico study which we performed before the synthesis. The structural modification of pinostrobin is successful in improving the analgesic potency, resulting in pinostrobin pentanoate as the optimum compound. Furthermore, the increasing analgesic potency is in line with the increasing length of the side alkyl chain, suggesting the importance of the steric parameter in the QSAR formulation which can be invoked as a predictive tool for future optimization.