基于吲哚的HIV-1整合酶变构抑制剂。
Indole-based allosteric inhibitors of HIV-1 integrase.
作者信息
Patel Pratiq A, Kvaratskhelia Nina, Mansour Yara, Antwi Janet, Feng Lei, Koneru Pratibha, Kobe Mathew J, Jena Nivedita, Shi Guqin, Mohamed Mosaad S, Li Chenglong, Kessl Jacques J, Fuchs James R
机构信息
Division of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States; Department of Chemistry, The Ohio State University, Columbus, OH 43210, United States.
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, United States.
出版信息
Bioorg Med Chem Lett. 2016 Oct 1;26(19):4748-4752. doi: 10.1016/j.bmcl.2016.08.037. Epub 2016 Aug 13.
Abstract
Employing a scaffold hopping approach, a series of allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) have been synthesized based on an indole scaffold. These compounds incorporate the key elements utilized in quinoline-based ALLINIs for binding to the IN dimer interface at the principal LEDGF/p75 binding pocket. The most potent of these compounds displayed good activity in the LEDGF/p75 dependent integration assay (IC50=4.5μM) and, as predicted based on the geometry of the five- versus six-membered ring, retained activity against the A128T IN mutant that confers resistance to many quinoline-based ALLINIs.
摘要
采用骨架跃迁方法，基于吲哚骨架合成了一系列变构HIV-1整合酶（IN）抑制剂（ALLINIs）。这些化合物包含了基于喹啉的ALLINIs中用于在主要LEDGF/p75结合口袋处与IN二聚体界面结合的关键元素。这些化合物中最有效的在LEDGF/p75依赖性整合试验中表现出良好的活性（IC50 = 4.5μM），并且如基于五元环与六元环的几何结构所预测的，对赋予许多基于喹啉的ALLINIs抗性的A128T IN突变体仍具有活性。
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