新型 2-羟基苯乙酮衍生物的设计、合成、对接研究及抗 HIV-1 活性评价。

Design, Synthesis, Docking Studies, and Biological Evaluation of Novel 2-Hydroxyacetophenone Derivatives as Anti-HIV-1 Agents.

机构信息

Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Department of Medical Lab Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

出版信息

Curr HIV Res. 2023;21(5):290-300. doi: 10.2174/011570162X261377231107110447.

DOI:10.2174/011570162X261377231107110447

PMID:37990893

Abstract

BACKGROUND

The persistence of HIV mutations and the existence of multidrug resistance have produced an opportunity for an array of innovative anti-HIV medicines with a variety of structures that target HIV key enzymes.

OBJECTIVE

The goal of this work was to find a new class of anti-HIV drugs founded on HIV integrase inhibitor pharmacophores.

METHODS

A novel class of 2-hydroxy acetophenone analogs featuring substituted benzamide or N-phenylthiourea groups was designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors (INs).

RESULTS

Most of the synthesized analogs were found to be moderately active against the virus, with EC values ranging from 40 to 140 μM. Additionally, it was found that most of the compounds presented no considerable cytotoxicity (CC > 500 μΜ). The most potent compounds substituting with 4-fluorobenzamide (compound 7) and 4-methylbenzamide (compound 9) rings inhibited the HIV-1 replication by EC values of 40 and 45 μΜ, respectively. Docking studies using the crystallographic data available for PFV IN indicated that the Mg coordination might be the possible mechanism of the anti-viral activity.

CONCLUSION

Our findings proved that the synthesized analogs may suggest a very good basis for the development of new anti-HIV-1 agents.

摘要

背景

HIV 突变的持续存在和多药耐药的存在为一系列具有不同结构的创新抗 HIV 药物提供了机会，这些药物针对 HIV 关键酶。

目的

这项工作的目的是寻找一种基于 HIV 整合酶抑制剂药效团的新型抗 HIV 药物。

方法

根据 HIV-1 整合酶抑制剂（INs）的一般药效团，设计并合成了一类新型的带有取代苯甲酰胺或 N-苯硫脲基团的 2-羟基苯乙酮类似物。

结果

大多数合成的类似物对病毒具有中等活性，EC 值范围为 40 到 140 μM。此外，发现大多数化合物没有明显的细胞毒性（CC > 500 μM）。取代 4-氟苯甲酰胺（化合物 7）和 4-甲基苯甲酰胺（化合物 9）环的最有效化合物的 EC 值分别为 40 和 45 μM，抑制 HIV-1 复制。使用可用的 PFV IN 晶体数据进行对接研究表明，Mg 配位可能是抗病毒活性的可能机制。