Lu Xiao, Chen Yanli, Guo Ying, Liu Zhenming, Shi Yawei, Xu Yang, Wang Xiaowei, Zhang Zhili, Liu Junyi
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
Bioorg Med Chem. 2007 Dec 1;15(23):7399-407. doi: 10.1016/j.bmc.2007.07.058. Epub 2007 Aug 28.
Novel compounds 1a-u, which can be considered as hybrid analogues of MKC-442 and pyridinon, have been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (HIV-1 RT). Starting from 6-methyluracil 2, 1-alkylated-5-bromomethyl-6-methyluracils 8 was prepared in four steps by hydroxymethylation, etherification, N-1 alkylation, and bromination. Finally, compounds 1a-u were achieved in the displacement of 5-bromomethyl group by nucleophiles with amino compounds. Some of compounds 1a-u showed potent inhibitory activity against HIV-1 RT. The most active compounds showed activity in the low micromolecular range with IC(50) values (IC(50) 0.82-5.09 microM) comparable to that of nevirapine (IC(50) 10.60 microM). The biological testing results are in accordance with the docking.
新型化合物1a - u可被视为MKC - 442和吡啶酮的杂合类似物，已被合成并作为HIV - 1逆转录酶（HIV - 1 RT）抑制剂进行评估。从6 - 甲基尿嘧啶2开始，通过羟甲基化、醚化、N - 1烷基化和溴化四个步骤制备了1 - 烷基化 - 5 - 溴甲基 - 6 - 甲基尿嘧啶8。最后，通过亲核试剂与氨基化合物取代5 - 溴甲基基团得到化合物1a - u。部分化合物1a - u对HIV - 1 RT表现出强效抑制活性。活性最强的化合物在低微摩尔范围内表现出活性，其IC(50)值（IC(50)为0.82 - 5.09微摩尔）与奈韦拉平（IC(50)为10.60微摩尔）相当。生物学测试结果与对接结果一致。
