Synthesis of Novel Indolyl Aryl Sulfone-clubbed Hydrazone Derivatives as Potential HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Molecular Modeling and QSAR Studies.

IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hazrat Ali, Abdul Latif, Mumtaz Ali, Ammara, Muhammad Waqas, Manzoor Ahmad, Asaad Khalid, Ajmal Khan, Ahmed Al-Harrasi
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引用次数: 0

Abstract

Background: Non-Nucleoside Reverse Transcriptases Inhibitors (NNRTIs) are among the most extensively studied enzymes for understanding the biology of Human Immunodeficiency Viruses (HIV) and designing inhibitors for managing HIV infections. Indolyl aryl sulfones (IASs), an underexplored class of potent NNRTIs, require further exploration for the development of newer drugs for HIV.

Aims: In this context, we synthesized a series of novels by Indolyl Aryl Sulfones with a hydrazone moiety at the carboxylate site of the indole nucleus. A 2D-QSAR model was developed to predict Reverse Transcriptase inhibitory activity against wild-type RT (WT-RT) enzyme.

Method: The model was successfully applied to predict the HIV-1 inhibitory activity of known Indolyl Aryl Sulfones. Considering the reliability, robustness, and reproducibility of the 2D-QSAR model, we made an in-silico prediction of the RT inhibition for our synthesized compounds (1-14).

Results: Molecular docking and dynamics simulations established our synthesized Indolyl Aryl Sulfones, particularly compounds 23, 24, and 28, as effective NNRTIs by stabilizing HIV reverse transcriptase's structure. Binding energy calculations revealed compound 28 as the strongest inhibitor (-43.21 ± 0.09 kcal/mol), followed by 23 (-40.94 ± 0.10 kcal/mol) and 24 (-39.18±0.08 kcal/mol), emphasizing their binding affinity towards HIV reverse transcriptase.

Conclusion: In summary, the synthesized Indolyl Aryl Sulfones, particularly compounds 23, 24, and 28, demonstrate significant potential as Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) against HIV. These results highlight the promising role of these compounds in developing novel NNRTIs for managing HIV infections.

作为潜在 HIV-1 非核苷逆转录酶抑制剂的新型吲哚基芳基砜腙腙衍生物的合成:分子建模和 QSAR 研究。
背景:非核苷类逆转录酶抑制剂(NNRTIs)是研究最为广泛的酶之一,有助于了解人类免疫缺陷病毒(HIV)的生物学特性,并设计出用于控制HIV感染的抑制剂。吲哚芳基砜(Indolyl aryl sulfones,IASs)是一类尚未充分开发的强效 NNRTIs,需要进一步探索以开发治疗 HIV 的新药物。我们建立了一个二维 QSAR 模型来预测逆转录酶对野生型 RT(WT-RT)酶的抑制活性:该模型被成功应用于预测已知吲哚芳基砜的 HIV-1 抑制活性。考虑到二维 QSAR 模型的可靠性、稳健性和可重复性,我们对合成的化合物(1-14)进行了抑制 RT 的体内预测:分子对接和动力学模拟证实,我们合成的吲哚芳基砜类化合物,尤其是化合物 23、24 和 28,可以稳定 HIV 逆转录酶的结构,从而成为有效的 NNRTIs。结合能计算显示,化合物 28 是最强的抑制剂(-43.21 ± 0.09 kcal/mol),其次是 23(-40.94 ± 0.10 kcal/mol)和 24(-39.18±0.08 kcal/mol),强调了它们与 HIV 逆转录酶的结合亲和力:总之,合成的吲哚基芳基砜,尤其是化合物 23、24 和 28,显示出作为非核苷类逆转录酶抑制剂(NNRTIs)对抗 HIV 的巨大潜力。这些结果凸显了这些化合物在开发新型 NNRTIs 以控制 HIV 感染方面的巨大潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Current medicinal chemistry
Current medicinal chemistry 医学-生化与分子生物学
CiteScore
8.60
自引率
2.40%
发文量
468
审稿时长
3 months
期刊介绍: Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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