2. Academic Validation
  3. Synthesis and biological evaluation of DAPY-DPEs hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Synthesis and biological evaluation of DAPY-DPEs hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase

  • Bioorg Med Chem. 2015 Feb 1;23(3):624-31. doi: 10.1016/j.bmc.2014.11.032.
Hai-Qiu Wu 1,  Jin Yao 1,  Qiu-Qin He 1,  Wen-Xue Chen 1,  Fen-Er Chen 2,  Christophe Pannecouque 3,  Erik De Clercq 3,  Dirk Daelemans 3
Affiliations

Affiliations

  • 1 Department of Chemistry, Fudan University, Shanghai 200433, People's Republic of China.
  • 2 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.
  • 3 Rega Institute for Medical Research, KU Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
PMID: 25537532 DOI: 10.1016/j.bmc.2014.11.032
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.

Keywords

DAPYs; DPEs; Hybrids; Molecular hybridization; NNRTIs.

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