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Arylazolyl(azinyl)thioacetanilides. Part 20: Discovery of novel purinylthioacetanilides derivatives as potent HIV-1 NNRTIs via a structure-based bioisosterism approach.

Arylazolyl(azinyl)thioacetanilides. Part 20: Discovery of novel purinylthioacetanilides derivatives as potent HIV-1 NNRTIs via a structure-based bioisosterism approach.
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Lu X, Li X, Yang J, Huang B, Kang D, Zhao F, Zhou Z, De Clercq E, Daelemans D, Pannecouque C, Zhan P, Liu X,


Lu X, Li X, Yang J, Huang B, Kang D, Zhao F, Zhou Z, De Clercq E, Daelemans D, Pannecouque C, Zhan P, Liu X, (click to view)

Lu X, Li X, Yang J, Huang B, Kang D, Zhao F, Zhou Z, De Clercq E, Daelemans D, Pannecouque C, Zhan P, Liu X,

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Bioorganic & medicinal chemistry 2016 07 2124(18) 4424-33 doi 10.1016/j.bmc.2016.07.041

Abstract

By means of structure-based bioisosterism approach, a series of novel purinylthioacetanilide derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the tested compounds were found to be active against wild-type (WT) HIV-1(IIIB) with EC50 in the range of 0.78-4.46μM. Among them, LAD-8 displayed the most potent anti-HIV activity (EC50=0.78μM, SI=24). In addition, LBD-6 showed moderate activity against L100I mutant (EC50=5.64μM) and double mutant strain RES056 (EC50=22.24μM). Preliminary structure-activity relationships (SARs) were discussed in detail. Molecular modeling study was used to predict the optimal conformation in the NNRTI binding site, which may play a guiding role in further rational optimization.

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