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.

我们在此报告了地芦那韦衍生的 HIV-1 蛋白酶抑制剂的合成和生物学评价及其对 MT-2 细胞系中酶抑制和抗病毒活性的功能影响。 P2' 4-氨基官能团经过修饰，形成许多酰胺衍生物，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级酶抑制和低纳摩尔级抗病毒活性。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，活性氯乙酸酯基团在 X 射线照射过程中转化为乙酸酯官能团。该结构表明，P2'甲酰胺官能团增强了与S2'-子位点中主链原子的氢键相互作用。