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.
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DOI：
10.1016/j.bmc.2014.11.032
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发表时间：
2015-02
影响因子：
3.5
通讯作者：
Hai-Qiu Wu;Jin Yao;Qiu-Qin He;Wen‐xue Chen;Fener Chen;C. Pannecouque;E. De Clercq;D. Daelemans-D.-Daelema
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文献类型：
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作者：
Hai-Qiu Wu;Jin Yao;Qiu-Qin He;Wen‐xue Chen;Fener Chen;C. Pannecouque;E. De Clercq;D. Daelemans-D.-Daelema
合成了一系列新的DAPY-DPE杂合体，并在MT-4细胞培养上对它们对HIV-1野生株IIIB、双RT突变株RES-056（K103 N + Y181 C）和HIV-2株ROD的抗HIV活性进行了生物学评价。获得了许多具有有效抑制活性（野生型）的有希望的候选物，其EC 50范围为0.16至0.013 μM。尤其是3c、3 p、3rand 3s显示低nM水平的EC 50值（分别为35、13、50和17 nM）和高选择性（分别为9342、25131、2890和11338），其效力远高于NVP（EC 50 = 0.31 μM，SI = 48），3TC（EC 50 = 2.24 μM，SI > 39），DDI（EC 50 = 23.20 μM，SI > 9）和DLV（EC 50 = 0.65 μM，SI > 67），与AZT（EC 50 = 0.0071 μM，SI > 13144）和EFV（EC 50 = 0.0062 μM，SI > 1014）相当。HIV-1逆转录酶抑制试验证实这些DAPY-DPE杂合体靶向HIV-1 RT。分子模拟进行了研究新合成的化合物的潜在结合模式。用对接方法对活性结果进行了合理的解释。
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 EC50range from 0.16 to 0.013 μM were obtained. In particular,3c,3p,3rand3sdisplayed low nM level EC50values (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.