含1,3,4-噁二唑侧链氮唑衍生物的合成及抗真菌活性

Synthesis and in vitro Antifungal Activity of Azole Derivatives Containing 1,3,4-Thiadiazole

以取代苯甲酸为原料,经亲核加成-消除、醇解、胺解和环合反应,合成2-巯基-5-取代苯基-1,3,4-噁二唑中间体5a—5r,再与环氧化物中间体1-[2-(2,4-二氟苯基)-2,3-环氧丙基]-1H-1,2,4-三唑甲烷磺酸盐发生亲核取代反应,得到18个含1,3,4-噁二唑侧链的氮唑衍生物6a—6r。所有目标化合物的结构均经过;H NMR、^(13)C NMR和MS确证,并对其进行了抗真菌活性检测。抗真菌活性结果表明,化合物6c、6d和6f对7个菌株均表现出良好的抗真菌活性,其中化合物6c对所有供试菌株的活性最强。构效关系分析显示,1,3,4-噁二唑侧链有氟或氯原子取代对抗真菌活性有利,总体表现出明显的取代基效应。该研究对于寻找高效、抗菌谱广的替代药物具有重要的理论意义。

The synthesis of the intermediates 2-sulfydryl-5-substituted phenyl-1, 3, 4-oxadiazole(5 a-5 r) is based on nucleophilic addition-elimination, alcoholysis, aminolysis and cyclization reaction from the substituted benzoic acids. Then, they undergo nucleophilic substitution with the key intermediate 1-[2-(2,4-difluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole methanesulfonate to generate the target compounds 6 a-6 r. Structures of the azole derivatives 6 a-6 r are confirmed by ~1H NMR,^(13)C NMR and MS, and their antifungal activities are tested. Compounds 6 c, 6 d and 6 f show excellent antifungal activity against seven strains, in particular, compound 6 c exhibits the most potent activity against all the tested strains. The structure activity relationship analysis shows that the side chain of 1,3,4-oxadiazole has fluorine or chlorine atom substitution, and shows obvious substituent effect. This study is of great theoretical significance for finding alternative drugs with high efficiency and wide antibacterial spectrum.