香豆素苯并三唑的合成、抗微生物活性及其与氯霉素和氟康唑协同作用研究

Synthesis and antimicrobial evaluation of coumarin-based benzotriazoles and their synergistic effects with chloromycin and fluconazole

以间苯二酚为起始原料,经过环化、醚化、N-烷化等多步反应合成了一系列新型香豆素苯并三唑类化合物,其结构经1H NMR、IR、MS和元素分析证实。体外考察了合成的香豆素类化合物抗革兰阳性菌、革兰阴性菌及真菌活性。结果表明香豆素苯并三唑能有效抑制细菌和真菌的生长,其中化合物11a～11e和13a～13c抗普通变形杆菌ATCC 6896活性强于氯霉素(chloromycin)。化合物11a和11b抑制金葡菌ATCC 25923和藤黄微球菌ATCC 4698的生长能力与氯霉素相当。化合物11a～11d抗烟曲霉菌ATCC 96918活性优于氟康唑(fluconazole)。此外,氯霉素或氟康唑与香豆素苯并三唑联用后,不仅减少了用药剂量,还拓宽了抗微生物谱,尤其增强了抑制耐甲氧西林的金葡菌N 315和氟康唑不敏感的烟曲霉菌的生长能力。

A series of new coumarin-based benzotriazole derivatives were successfully synthesized via a multi-step sequence of cyclization,etherification and N-alkylation,and were confirmed by 1H NMR,IR,MS spectra as well as elemental analyses.All these synthesized coumarin compounds were evaluated for in vitro antimicrobial activities against four Gram-positive bacteria,four Gram-negative bacteria and three fungi by two fold serial dilution technique.The bioactive assay showed that all these prepared coumarin benzotriazoles could inhibit the growth of the tested bacterial and fungal strains.Title compounds 11a–11e and 13a–13c were more active than chloromycin on Proteus vulgaris ATCC 6896.Coumarin benzotriazoles 11a and 11b displayed comparable antibacterial efficacy against Staphylococcus aureus ATCC 25923 and Micrococcus luteus ATCC 4698 in comparison with reference drug chloromycin.Compared to fluconazole,compounds 11a–11d displayed stronger inhibition on Aspergillus fumigatus ATCC 96918.Moreover,coumarin-based benzotriazoles in combination with antibacterial chloromycin or antifungal fluconazole,showed notable antimicrobial efficacy with less dosage and broader antimicrobial spectrum.More importantly,fluconazole-insensitive A.fumigatus and methicillin-resistant Staphylococcus aureus N 315（MRSA） were sensitive to these combined drugs.