Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus.
Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus.
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靶向 NNIBP 的进入通道：发现二芳基烟酰胺 1,4-二取代 1,2,3-三唑作为新型 HIV-1 NNRTI，对野生型和 E138K 突变病毒具有高效力
DOI：
10.1016/j.ejmech.2018.03.059
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发表时间：
2018-05-10
影响因子：
6.7
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Tian Y;Liu Z;Liu J;Huang B;Kang D;Zhang H;De Clercq E;Daelemans D;Pannecouque C;Lee KH;Chen CH;Zhan P;Liu X
受我们以前将二芳基嘧啶类化合物修饰为HIV-1非核苷类逆转录酶抑制剂(NNRTI)的努力和已报道的结晶学研究的启发，我们设计了新型的二芳基烟酰胺类化合物，它的“三唑尾巴”占据了逆转录酶NNRTI结合口袋的入口通道，以提供额外的相互作用。然后合成了新设计的化合物，并在MT-4细胞中评价了它们的抗HIV活性。所有化合物对野生型HIV1毒株的EC50值均为0.02~1.77μM。对更多的耐药株的评价表明，这些化合物对新一代NNRTIs的关键耐药突变株E138K突变病毒具有明显的抑制作用。其中丙腈(3B2，EC_(50)(IIIB)=0.020μM，EC_(50)(E138K)=0.015μM，CC_(50)=40.15μM)、吡咯烷酮-1-甲基酮(3b8，EC_(50)=0.020μM，EC_(138K)=0.014μM，CC_(50)=58.09μM)和吗啉甲酮(3b9，EC_(50)=0.020μM，EC_(50)(E138K)=0.027μM，CC_(50)=180.90μM)是最有希望的三种化合物，与市售药物依曲韦林对E138K突变株的抑制作用相当，但细胞毒性要低得多。此外，还讨论了具有代表性的化合物的详细的SAR、对RT的抑制活性和对接研究。
Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a “triazole tail” occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC50 of 0.02–1.77 μM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.015 μM, CC50 = 40.15 μM), pyrrolidin-1-ylmethanone (3b8, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.014 μM, CC50 = 58.09 μM) and morpholinomethanone (3b9, EC50(IIIB) = 0.020 μM, EC50(E138K) = 0.027 μM, CC50 =180.90 μM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed.
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影响因子：
3.1
作者：
PAUWELS, R;BALZARINI, J;DECLERCQ, E
通讯作者：
DECLERCQ, E
影响因子：
--
作者：
Chander S;Ashok P;Singh A;Murugesan S
通讯作者：
Murugesan S
影响因子：
7.3
作者：
Liu, Na;Wei, Lei;Huang, Li;Yu, Fei;Zheng, Weifan;Qin, Bingjie;Zhu, Dong-Qin;Morris-Natschke, Susan L.;Jiang, Shibo;Chen, Chin-Ho;Lee, Kuo-Hsiung;Xie, Lan
通讯作者：
Xie, Lan
影响因子：
7.3
作者：
Ragno, Rino;Coluccia, Antonio;Silvestri, Romano
通讯作者：
Silvestri, Romano
影响因子：
2.7
作者：
Kang D;Zhang H;Zhou Z;Huang B;Naesens L;Zhan P;Liu X
通讯作者：
Liu X