2,4-二芳基1,3-二氧戊环化合物的合成和iNOS/PAF双重抑制活性

Synthesis and the iNOS/PAF dual inhibitory activities of the 2,4-diaryl-1,3-dioxolane compounds

目的合成既拮抗PAF受体又抑制iNOS活性的化合物 ,期望能获得治疗败血性休克及有关炎症疾病的新型药物。方法以PAF受体拮抗剂 2 ,4 二芳基 1,3 二硫戊环为先导物 ,合成其生物电子等排体二氧戊环化合物 ,并在其 2位芳环上引入有iNOS抑制活性的基团 ,测定所得化合物的iNOS抑制活性和PAF受体拮抗活性。结果与结论共制备了 2 2个未见文献报道的目标化合物 ,对其中 15个进行iNOS抑制活性测试 ,发现有 3个活性与正在Ⅲ期临床研究的氨基胍相当 ,另有 3个活性强于氨基胍。对上述 6个化合物进行PAF受体抑制活性测定 ,发现 2个活性较强 ,其IC50 分别为 2 2 9× 10 -6mol/L和 2 5 7× 10 -6mol/L。

Aim To synthesize iNOS/PAF dual inhibitors and to search for novel drugs for the treatment of septic shock and related inflammatory disorders.Method 2,4 diaryl 1,3 dithiolane was used as a lead and its bioisosteres,the dioxolane compounds were prepared.Some functionals with the iNOS inhibitory activities were incorporated into a 2 aryl ring of 2,4 diaryl 1,3 dioxolane compounds,and the iNOS inhibitory activity and PAF antagonistic activity of the compounds obtained were biologically evaluated.Results and Conclusions Totally twenty two target compounds were designed and synthesized.The iNOS inhibitory effects of 15 target compounds were evaluated.The results showed 6 compounds were potent over the inhibition of the iNOS,among which 3 were comparable to the control aminoguanidine and the other 3 were more potent than aminoguanidine.The PAF inhibitory effects of the 6 target compounds were evaluated.The results showed the IC 50 of the 2 compounds were 2 29×10 -6 mol/L and 2 57×10 6 mol/L respectively.