Zhao Xue Zhi, Semenova Elena A, Vu B Christie, Maddali Kasthuraiah, Marchand Christophe, Hughes Stephen H, Pommier Yves, Burke Terrence R
Laboratory of Medicinal Chemistry and HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
J Med Chem. 2008 Jan 24;51(2):251-9. doi: 10.1021/jm070715d. Epub 2007 Dec 21.
The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg2+ using dihydroxybenzoyl substituents as both the right and left components of the hydrazide moiety. Employing a 2,3-dihydro-6,7-dihydroxy-1 H-isoindol-1-one ring system as a conformationally constrained 2,3-dihydroxybenzoyl equivalent provided good selectivity for IN-catalyzed strand transfer versus the 3'-processing reactions as well as antiviral efficacy in cells using HIV-1 based vectors.
双水杨酰肼类HIV-1整合酶（IN）抑制剂被推测通过金属螯合发挥作用。然而，该系列成员仅在使用Mn2+作为辅因子时才表现出强效抑制作用。当前研究发现，使用二羟基苯甲酰取代基作为酰肼部分的左右两个组分，双芳酰肼在Mg2+存在时可获得抑制活性。采用2,3-二氢-6,7-二羟基-1H-异吲哚-1-酮环系作为构象受限的2,3-二羟基苯甲酰类似物，相对于3'-加工反应，对IN催化的链转移具有良好的选择性，并且在使用基于HIV-1的载体的细胞中具有抗病毒功效。
