新型苯并恶嗪-3-酮衍生物的设计、合成、分子模拟及抗 HIV-1 和整合酶抑制活性研究
Novel Benzoxazin-3-one Derivatives: Design, Synthesis, Molecular Modeling, Anti-HIV-1 and Integrase Inhibitory Assay.
机构信息
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Medical Lab Technology Department, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
出版信息
Med Chem. 2020;16(7):938-946. doi: 10.2174/1573406415666190826161123.
INTRODUCTION
Integrase is a validated drug target for anti-HIV-1 therapy. The second generation integrase inhibitors display π-stacking interaction ability with 3'-end nucleotide as a streamlined metal chelating pharmacophore.
METHODS
In this study, we introduced benzoxazin-3-one scaffold for integrase inhibitory potential as bioisostere replacement strategy of 2-benzoxazolinone.
RESULTS
Molecular modeling studies revealed that amide functionality alongside oxadiazole heteroatoms and sulfur in the second position of oxadiazole ring could mimic the metal chelating pharmacophore. The halobenzyl ring occupies hydrophobic site created by the cytidylate nucleotide (DC-16).
CONCLUSION
The most potent and selective compound displayed 110 μM IC50 with a selectivity index of more than 2.
简介
整合酶是抗 HIV-1 治疗的一种经过验证的药物靶点。第二代整合酶抑制剂与 3'端核苷酸显示π堆积相互作用能力，作为简化的金属螯合药效团。
方法
在这项研究中，我们引入苯并恶嗪-3-酮支架作为 2-苯并恶唑啉酮的生物等排替代策略，以评估其对整合酶的抑制潜力。
结果
分子建模研究表明，酰胺官能团以及噁二唑杂原子和噁二唑环的第二个位置上的硫原子可以模拟金属螯合药效团。卤代苄基环占据了胞苷核苷酸 (DC-16) 产生的疏水区。
结论
最有效和选择性的化合物显示出 110 μM 的 IC50，选择性指数超过 2。
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