Hydrazones Containing 4-Hydroxy Benzoxazolone And 4-Hydroxy Benzoxazole-2-Thione Derivatives:Sythesis,Anti-Inflammatory And Analgesic Activity

Objective:Design and synthesis of some novel derivatives of 4-hydroxy benzoxazolone(HBOA)and 4-hydroxy benzoxazole-2-thione(HBOT)by docking study and structural modification on 3-N in HBOA and 2-S in HBOT,and screening for the anti-inflammatory and analgesic activity of the synthesized compounds for discovering novel anti-inflammatory and analgesic leading compounds.Methods:Based on previous research on HBOA and HBOT,some novel hydrazones containing derivatives were designed by docking study.HBOA and HBOT were synthesized by using the starting material 2-nitroresorcinol and 2-aminoresorcinal hydrochloride respectively.Then,4-OH in HBOA and HBOT was protected by acetylation,which afforded AcO-BOA and AcO-BOT.After the incorporation of ethyl acetate group on 3-N in AcO-BOA and 2-S in AcO-BOT,the corresponding hydrazides of HBOA and HBOT were afforded by hydrozinolysis of the ester derivatives of AcO-BOA and AcO-BOT mentioned above.Finally,the target compounds were obtained by treanting hydrazides of HBOA and HBOT with the corresponding benzaldehydes.The structures of the synthesized compunds were elucidated by IR,1H-NMR,13C-NMR and HR-MS spectra analysis.All the target compounds were screened for their anti-inflammatory and analgesic activity by xylene-induced ear edema test,acetic acid-induced writhing test and hot-plate test in mice,and ibuprofen was involved as reference drug.Results:Twenty-eight derivatives of HBOA and HBOT were synthesized,and the structures of the synthesized compounds were confirmed by IR,1H-NMR,13C-NMR and HR-MS spectra analysis.According to the results,at the same dosage of 100 mg/Kg,compounds 5b,51,5n,6b,6e,6m and 6n showed comparable anti-inflammatory activity with ibuprofen in xylene-induced ear edema test,and compound 61 displayed the strongest anti-inflammatory activity,which was more potent than ibuprofen.Meanwhile,in acetic acid-induced writhing test,compounds 5e,6a,6j exhibited moderate analgesic activity,and compounds 5f and 6k showed comparable inhibitory effect with the reference drug,while compound 5k displayed the strongest analgesic activity.Moreover,compounds 5i,6i,6k exhibited similar analgesic effect with ibuprofen in hot-plate test,and compounds 5c,5d,5m,6d,6n showed favorable analgesic activity,whereas compound 6m displayed the strongest inhibitory effect.Conclusion:The synthesized compounds 5a-5n and 6a-6n have not been reported before,among which several compounds displayed significant anti-inflammatory and analgesic activity.Therefore,these two scaffolds could be served as promising leads for novel anti-inflammatory/analgesic agents.