Discovery of Epinastine-NSAID Hybrids as Potential Anti-inflammatory Agents: Synthesis and In Vitro Nitric Oxide Production Inhibitory Activity Study
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A novel pharmacophore with epinastine (1) and NSAID moieties (2–5) was designed by molecular hybridization approach. The hybrid compounds 6–9 were synthesized by EDCI/HOBt or HATU-mediated coupling of 1 with salicylic acid (2), mefenamic acid (3), indomethacin (4) and naproxen (5), respectively, and were assessed for their inhibitory effect against NO production in LPS-induced RAW-264.7 macrophages in vitro. The Hybrids were found to exhibit significant NO production inhibitory effects with half-maximal inhibitory concentration (IC50) values ranging in between 15.96 ± 1.32 and 36.68 ± 2.53 μM and were non-cytotoxic to macrophages. Comparing the inhibition concentration (IC50), cytotoxicity concentration (CC50) and in vitro efficacy index (iEI), 6 (IC50 = 17.97 ± 1.92 μM; iEI = 11.13) and 9 (IC50 = 15.96 ± 1.32 μM; iEI = 12.53) were better suited than other hybrids as well as their parent compound. Our findings signify that hybrids 6 and 9 may serve as platforms for continued investigations for the development of more efficient anti-inflammatory agents.
Abstract
A novel pharmacophore with epinastine (1) and NSAID moieties (2–5) was designed by molecular hybridization approach. The hybrid compounds 6–9 were synthesized by EDCI/HOBt or HATU-mediated coupling of 1 with salicylic acid (2), mefenamic acid (3), indomethacin (4) and naproxen (5), respectively, and were assessed for their inhibitory effect against NO production in LPS-induced RAW-264.7 macrophages in vitro. The Hybrids were found to exhibit significant NO production inhibitory effects with half-maximal inhibitory concentration (IC50) values ranging in between 15.96 ± 1.32 and 36.68 ± 2.53 μM and were non-cytotoxic to macrophages. Comparing the inhibition concentration (IC50), cytotoxicity concentration (CC50) and in vitro efficacy index (iEI), 6 (IC50 = 17.97 ± 1.92 μM; iEI = 11.13) and 9 (IC50 = 15.96 ± 1.32 μM; iEI = 12.53) were better suited than other hybrids as well as their parent compound. Our findings signify that hybrids 6 and 9 may serve as platforms for continued investigations for the development of more efficient anti-inflammatory agents.
참고문헌 (15)
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