State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100083, China.
Chem Biol Drug Des. 2010 Aug;76(2):174-80. doi: 10.1111/j.1747-0285.2010.00995.x. Epub 2010 Jun 21.
A series of novel HIV-1 protease inhibitors based on the (hydroxyethylamino)-sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P(2) ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the -CH2- of P(1)-P(2) linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P(1)'group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV-1 protease with an IC(50) value of 5 nM, also exhibited good anti-SIV activity (EC(50) = 0.8 microM) with low toxicity (TC(50) > 100 microM). The flexible docking of inhibitor 23 to HIV-1 protease active site rationalized the interactions with protease.
基于（羟乙氨基）-磺酰胺等排体，我们合成了一系列新型 HIV-1 蛋白酶抑制剂，其中包含取代的苯基和苯并杂环衍生物，作为 P(2)配体，含有丰富的氢键受体。将苯并杂环与羰基拉长链连接会导致结合亲和力部分丧失。在 P(1)-P(2)连接的 -CH2- 上引入适当大小的小烷基取代基作为侧链，会提高抑制活性，在本研究中，异丙基是最佳的侧链。用苯基取代 P(1) '基团上的异丁基取代基会降低抑制活性。其中一个最有效的抑制剂，化合物 23 对 HIV-1 蛋白酶具有高亲和力，IC(50)值为 5 nM，对 SIV 也具有良好的活性（EC(50) = 0.8 microM），且毒性低（TC(50) > 100 microM）。抑制剂 23 与 HIV-1 蛋白酶活性位点的柔性对接解释了与蛋白酶的相互作用。
