目的 设计并合成含噻吩并[2,3-e][1,2,4]三氮唑并[4,3-c]嘧啶结构的芳基脲类化合物,测试其抗肿瘤活性.方法 采用杂合体策略,将1,2,4-三氮唑基团并入噻吩并嘧啶环的3,4位,得到噻吩并[2,3-e][1,2,4]三氮唑并[4,3-c]嘧啶骨架,在该骨架5位引入双芳基脲结构,同时对双芳基脲结构进一步修饰,得到目标化合物10a～10s.以3-氨基噻吩-2-甲酸甲酯为起始原料,经环合、氯代、取代、环合4步反应制得关键中间体5,中间体5再与中间体6进行Suzuki偶联反应得到关键中间体8,继而与取代的氨基甲酸苯酯9a～9s反应制得目标化合物10a～10s.采用MTT法评价其体外抗肿瘤活性.结果 与结论共合成了 19个未见文献报道的化合物,其结构经MS、1H-NMR确证.化合物10j对PC-3和HCT-116细胞表现出较好的增殖抑制活性,其IC50值分别为1.88μmol·L-1和1.92μmol·L-1;对A549细胞表现出中等强度的增殖抑制活性,IC50值为13.47 μmol·L-1,并且对HCT-116细胞株的抗增殖活性优于阳性药GDC-0941.

Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a - 6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125 mu g/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125-0.5 mu g/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was noncytotoxic with an IC50 value of 91.04 mu M against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.

Two series of 2-aminopyrimidine derivatives possessing triazolopiperazine or 1,4,8-triazaspiro[4.5]decan-3-one scaffolds were designed, synthesized and evaluated for their biological activity.

Hybridization strategy is an effective strategy to obtain multi-target inhibitors in drug design. In this study, we assembled the pharmacophores of momelotinib and tandutinib to get a series of 4-piperazinyl-2-aminopyrimidine derivatives. All compounds were tested for the inhibition of JAK2 and FLT3 enzymes, of which, compounds with potent enzyme activities were assayed for antiproliferative activities against three cancer cell lines (HEL, MV4-11, and HL60). The structure-activity relationship studies were conducted through variations in two regions, the "A" phenyl ring and "B" phenyl ring. Compound 14j showed the most balanced in vitro inhibitory activity against JAK2 and FLT3 (JAK2 IC50 = 27 nM, FLT3 IC50 = 30 nM), and it also showed potent inhibition against the above tested cell lines. In the cellular context, 14j strongly induced apoptosis by arresting cell cycle in the G1/S phase, and was selected as a promising JAK2/FLT3 dual inhibitor.