Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, HIV-1, NNRTIs, Diarylpyrimidine, Benzophenone, Molecular hybridization, Antiviral activity, COLORIMETRIC ASSAY, CRYSTAL-STRUCTURES, POTENT, NNRTIS, GENERATION, DISCOVERY, ANALOGS, SEARCH, HYBRIDIZATION, FLEXIBILITY, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, 50% cell culture infectious dose, 50% cytotoxic concentration, 50% effective concentration, 50% inhibitory concentration, AZT, BPs, CC(50), CCID(50), DAPYs, DLV, EC(50), EFV, ESI, HIV-1 RT, Human immunodeficiency virus type 1 reverse transcriptase, IC(50), K(d), MTT, NNIBP, NVP, OD, SI, TMC125, TMC278, TMS, USFDA, United States Food and Drug Administration, benzophenone derivatives, delavirdine, diarylpyrimidine derivatives, dissociation constant, efavirenz, electrospray ionization, etravirine, nevirapine, non-nucleoside RT inhibitors, non-nucleoside inhibitor binding pocket, non-nucleoside reverse transcriptase inhibitors, optical density, rilpivirine, selectivity index, tetramethylsilane, wild-type, wt, zidovudine, Anti-HIV Agents, Benzophenones, Cell Line, Tumor, Dose-Response Relationship, Drug, Drug Design, HIV Reverse Transcriptase, HIV-2, Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Pyrimidines, Reverse Transcriptase Inhibitors, Structure-Activity Relationship, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.