标题：Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 2: Discovery of novel [1,2,4]Triazolo[1,5-a]pyrimidines using a structure-guided core-refining approach
作者：Wang, Liu; Tian, Ye; Chen, Wenmin; Liu, Hong; Zhan, Peng; Li, Dongyue; Liu, Huiqing; De Clercq, Erik; Pannecouque, Christophe; Liu, 更多 作者机构：[Wang, Liu; Tian, Ye; Chen, Wenmin; Liu, Hong; Zhan, Peng; Li, Dongyue; Liu, Xinyong] Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Ke 更多
通讯作者地址：[Zhan, P]Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China.
来源：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
关键词：DAPY; [1,2,4]Triazolo[1,5-a]pyrimidine; Bridgehead nitrogen heterocycle; anti-HIV activities; Structure-activity relationships; Molecular; modeling
摘要：Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives were rationally designed via structure-based core refining approach, synthesized through the readily accessible synthetic methods and evaluated for their anti-HIV activities in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against the wild-type HIV-1 IIIB. Particularly, compound 7n was the most potent inhibitor against wild-type and K103N/Y181C double resistant mutant strain of HIV-1, possessing EC50 values of 0.02 mu M and 7.6 mu M, respectively, which were much better than or similar to nevirapine (NVP, EC50 = 0.15 mu M, 2.9 mu M) and delavirdine (DLV, EC50 = 0.07 mu M, >36 mu M). Besides, some other compounds, 5b, 7c, 7e, 7f, and 7m, were also endowed with favorable anti-HIV-1 potency (EC50 = 0.07, 0.05, 0.05, 0.07, and 0.05 mu M, respectively), which were better than or similar to those of NVP and DLV, suggesting a high potential to further develop this type of bridgehead nitrogen heterocycle as a novel class of NNRTIs with improved antiviral efficacy and resistance profile. The selected compound, 7i, was found moderately inhibitory towards RT (IC50 = 0.39 mu M), which was higher than for ETV (IC50 = 0.56 mu M). Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogues were detailed in this manuscript. (C) 2014 Elsevier Masson SAS. All rights reserved.