Nural Yahya, Gemili Muge, Ulger Mahmut, Sari Hayati, De Coen Laurens M, Sahin Ertan
Department of Chemistry, Faculty of Pharmacy, Mersin University, Mersin TR-33169, Turkey.
Department of Chemistry, Faculty of Pharmacy, Mersin University, Mersin TR-33169, Turkey.
Bioorg Med Chem Lett. 2018 Mar 1;28(5):942-946. doi: 10.1016/j.bmcl.2018.01.045. Epub 2018 Feb 9.
In this study, a series of polysubstituted methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives were designed and synthesized by the cyclization reaction of methyl 1-(benzoylcarbamothioyl)-5,5-diphenylpyrrolidine-2-carboxylates and 2-bromo-1-(4-substituted phenyl)ethanones in 70-96% yield. The starting pyrrolidine derivatives were synthesized via a 1,3-dipolar cycloaddition reaction in 83-88% yield. The stereochemistry of one of these methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives was characterized by a single crystal X-ray diffraction study and the acid dissociation constants of these compounds were determined. An antimicrobial screening was performed against different bacterial and fungal strains and against the M. tuberculosis H37Rv strain. Interesting antibacterial activity was observed for two compounds against the A. baumannii strain with MIC values of 31.25 µg/mL (Ampicillin: 125 µg/mL) and against the M. tuberculosis H37Rv strain with MIC values of 0.98-1.96 µg/mL (Isoniazid: 0.98 µg/mL, Ethambutol: 1.96 µg/mL). Therefore, these structures can be considered as good starting points for the development of new powerful antimycobacterial agents.
在本研究中，通过1-(苯甲酰基氨基硫甲酰基)-5,5-二苯基吡咯烷-2-羧酸甲酯与2-溴-1-(4-取代苯基)乙酮的环化反应，设计并合成了一系列多取代的5,5-二苯基-1-(噻唑-2-基)吡咯烷-2-羧酸甲酯衍生物，产率为70 - 96%。起始吡咯烷衍生物通过1,3-偶极环加成反应合成，产率为83 - 88%。通过单晶X射线衍射研究对其中一种5,5-二苯基-1-(噻唑-2-基)吡咯烷-2-羧酸甲酯衍生物的立体化学进行了表征，并测定了这些化合物的酸解离常数。针对不同的细菌和真菌菌株以及结核分枝杆菌H37Rv菌株进行了抗菌筛选。观察到两种化合物对鲍曼不动杆菌菌株具有有趣的抗菌活性，MIC值为31.25 µg/mL（氨苄西林：125 µg/mL），对结核分枝杆菌H37Rv菌株的MIC值为0.98 - 1.96 µg/mL（异烟肼：0.98 µg/mL，乙胺丁醇：1.96 µg/mL）。因此，这些结构可被视为开发新型强效抗分枝杆菌药物的良好起始点。
