Structural Modifications of Diarylpyrimidine-quinolone Hybrids as Potent HIV-1 NNRTIs with an Improved Drug Resistance Profile.
Structural Modifications of Diarylpyrimidine-quinolone Hybrids as Potent HIV-1 NNRTIs with an Improved Drug Resistance Profile.
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DOI：
10.2174/1381612823666161122125657
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发表时间：
2017-01
影响因子：
3.1
通讯作者：
Tian-Qi Mao;Qiu-Qin He;Wen‐xue Chen;Gang-Feng Tang;Fener Chen;E. De Clercq;D. Daelemans;C. Pannecouque
中科院分区：
文献类型：
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作者：
Tian-Qi Mao;Qiu-Qin He;Wen‐xue Chen;Gang-Feng Tang;Fener Chen;E. De Clercq;D. Daelemans;C. Pannecouque
早些时候，我们报道了二芳基嘧啶-喹诺酮杂交物作为一类新的HIV-1NNRTIs的鉴定。其中少数杂交物在亚微摩尔水平上显示出对wt HIV-1复制的中等抑制活性，但对临床上观察到的最常见的NNRTI耐药相关双突变株K103N/Y181C都缺乏抑制活性。在本研究中，我们设计并合成了一系列新的二芳基嘧啶-喹诺酮杂化化合物，在喹诺酮环的C-6‘位带有卤素基团。生物学结果表明，大多数杂交种都能在纳摩尔水平上抑制HIV-1的复制，最有希望的杂交种5c对HIV-1 IIIB的EC50值为0.0096μM，对K103N/Y181C的EC50值为0.98μM。进一步的对接研究表明，这些杂交物可以很好地定位在HIV-1RT的疏水NNIBP上，尽管分子中的喹诺酮3-羧酸支架具有笨重和极性的性质。这些有希望的结果表明，进一步开发这些杂交种作为下一代NNRTI的潜力很大，具有更好的抗病毒效果和耐药性。
Earlier we reported the identification of diarylpyrimidine-quinolone hybrids as a new class of HIV-1 NNRTIs. A few of these hybrids displayed moderate inhibitory activity against wt HIV-1 replication at submicromolar level, however, all of them lacked inhibitory activity against the double mutant virus (K103N/Y181C), which is the most prevalent NNRTI resistant-associated double mutant observed in the clinic. In the present study, we designed and synthesized a new series of diarylpyrimidine-quinolone hybrids featuring a halogen group at C-6' position of quinolone ring. The biological results indicated that most of these hybrids could inhibit wt HIV-1 replication at nanomolar level ranging from 0.088 to 0.0096 μM. The most promising hybrid 5c displayed a significant EC50 value of 0.0096 μM against HIV-1 IIIB and of 0.98 μM against K103N/Y181C. Further docking studies revealed that these hybrids could be well located in the hydrophobic NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid scaffold in the molecules. These promising results suggested a high potential to further develop these hybrids as next-generation NNRTIs with improved antiviral efficacy and resistance profile.