Synthesis and biological evaluation of dihydroquinazoline-2-amines as potent non-nucleoside reverse transcriptase inhibitors of wild-type and mutant HIV-1 strains
Synthesis and biological evaluation of dihydroquinazoline-2-amines as potent non-nucleoside reverse transcriptase inhibitors of wild-type and mutant HIV-1 strains
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二氢喹唑啉-2-胺作为野生型和突变型 HIV-1 毒株的有效非核苷逆转录酶抑制剂的合成和生物学评价
DOI：
10.1016/j.ejmech.2019.05.011
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发表时间：
2019-08-15
影响因子：
6.7
通讯作者：
Chen, FenEr
中科院分区：
文献类型：
--
作者：
Jin, KaiJun;Sang, YaLi;Chen, FenEr
合成了一系列新的二氢喹唑啉-2-胺衍生物，并在MT-4细胞培养中评价了它们的抗HIV-1活性。所有的分子都对野生型HIV-1有活性，EC 50值范围为0.61 μ M至0.84 nM。最有效的抑制剂化合物4 b对HIV-1菌株1118的EC 50值为0.84 nM，因此比参比药物依法韦仑和依曲韦林更有效。此外，大多数化合物对携带逆转录酶（RT）E138 K突变的菌株保持高活性（低微摩尔EC 50值）。化合物4 b对具有RT E138 K和RES 056突变的非核苷逆转录酶突变体抗性菌株具有3.5 nM和66 nM的EC 50值。在酶活性测定中，化合物4 b对HIV-1 RT的IC 50值为10 nM。初步SAR和分子对接研究为进一步优化提供了有价值的见解。(C)2019 Elsevier Masson SAS。All rights reserved.
A novel series of dihydroquinazolin-2-amine derivatives were synthesized and evaluated for their anti HIV-1 activity in MT-4 cell cultures. All of the molecules were active against wild-type HIV-1 with EC50 values ranging from 0.61 mu M to 0.84 nM. The most potent inhibitor, compound 4b, had an EC50 value of 0.84 nM against HIV-1 strain 1118, and thus was more active than the reference drugs efavirenz and etravirine. Moreover, most of the compounds maintained high activity (low-micromolar EC50 values) against strains bearing the reverse transcriptase (RT) E138K mutation. Compound 4b had EC50 values of 3.5 nM and 66 nM against non-nucleoside reverse transcriptase inhibitor-resistant strains bearing the RT E138K and RES056 mutations. In enzyme activity assays, compound 4b exhibited an IC50 value of 10 nM against HIV-1 RT. Preliminary SARs and molecular docking studies provide valuable insights for further optimization. (C) 2019 Elsevier Masson SAS. All rights reserved.