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Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.

Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.
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Huang B, Wang X, Liu X, Chen Z, Li W, Sun S, Liu H, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X,


Huang B, Wang X, Liu X, Chen Z, Li W, Sun S, Liu H, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X, (click to view)

Huang B, Wang X, Liu X, Chen Z, Li W, Sun S, Liu H, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X,

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Bioorganic & medicinal chemistry 2017 06 1525(16) 4397-4406 pii 10.1016/j.bmc.2017.06.022

Abstract

Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC50 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC50=76.0μM) and comparable to 3TC (EC50=2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed.

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