title: Synthesis and biological evaluation of DAPY-DPEs hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase.
abstract: A series of new DAPY-DPEs hybrids, combined the important pharmacophores of DAPYs and DPEs, has been synthesized and biologically evaluated for their anti-HIV activities against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Many promising candidates with potent inhibitory activity (wild-type) within the EC50 range from 0.16 to 0.013 μM were obtained. In particular, 3c, 3p, 3r and 3s displayed low nM level EC50 values (35, 13, 50 and 17 nM, respectively) and high selectivity (9342, 25131, 2890 and 11338, respectively), which were much more potent than NVP (EC50=0.31 μM, SI=48), 3TC (EC50=2.24 μM, SI>39), DDI (EC50=23.20 μM, SI>9) and DLV (EC50=0.65 μM, SI>67), and comparable to AZT (EC50=0.0071 μM, SI>13144) and EFV (EC50=0.0062 μM, SI>1014). The HIV-1 reverse transcriptase inhibitory assay confirmed that these DAPY-DPEs hybrids targeted HIV-1 RT. Molecular simulation was performed to investigate the potential binding mode of the newly synthesized compounds. And reasonable explanation for the activity results was discussed with docking method.
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Hai-Qiu
authors.initials: HQ
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Qiu-Qin
authors.initials: QQ
authors.lastname: He
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
authors.forename: Wen-Xue
authors.initials: WX
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China; Institute of Biomedical Science, Fudan University, Shanghai 200433, People's Republic of China. Electronic address: rfchen@fudan.edu.cn.
authors.forename: Fen-Er
authors.initials: FE
authors.lastname: Chen
authors.affiliation: Rega Institute for Medical Research, KU Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Rega Institute for Medical Research, KU Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.affiliation: Rega Institute for Medical Research, KU Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Daelemans
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: DAPYs; DPEs; Hybrids; Molecular hybridization; NNRTIs