Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2′ amide-derivatives: Synthesis, biological evaluation and structural studies
Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2′ amide-derivatives: Synthesis, biological evaluation and structural studies
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包含 P2 酰胺衍生物的地芦那韦衍生 HIV-1 蛋白酶抑制剂的评价：合成、生物学评价和结构研究
DOI：
10.1016/j.bmcl.2023.129168
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Mitsuya Hiroaki
中科院分区：
文献类型：
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作者：
Ghosh Arun K.;Shahabi Dana;Kipfmiller Maya;Ghosh Ajay K.;Johnson Megan;Wang Yuan-Fang;Agniswamy Johnson;Amano Masayuki;Weber Irene T.;Mitsuya Hiroaki
本文报道了地瑞那韦衍生的HIV-1蛋白酶抑制剂的合成和生物学评价，以及它们在MT-2细胞系中对酶抑制和抗病毒活性的功能效应。对P2′ 4-氨基官能团进行了修饰，以制备许多酰胺衍生物，从而与HIV-1蛋白酶活性位点的S2′亚位点中的残基相互作用。几种化合物表现出皮摩尔的酶抑制和低纳摩尔的抗病毒活性。测定了与HIV-1蛋白酶结合的氯乙酸衍生物的X-射线晶体结构。有趣的是，在X射线暴露期间，活性氯乙酸酯基团转化为乙酸酯官能团。结构表明P2′羧酰胺官能团与S2′-亚位骨架原子的氢键相互作用增强。
We report here the synthesis and biological evaluation of darunavir derived HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. The P2′ 4-amino functionality was modified to make a number of amide derivatives to interact with residues in the S2′ subsite of the HIV-1 protease active site. Several compounds exhibited picomolar enzyme inhibitory and low nanomolar antiviral activity. The X-ray crystal structure of the chloroacetate derivative bound to HIV-1 protease was determined. Interestingly, the active chloroacetate group converted to the acetate functionality during X-ray exposure. The structure revealed that the P2′ carboxamide functionality makes enhanced hydrogen bonding interactions with the backbone atoms in the S2′-subsite.