三氮杂烯作为HIV-1和HCoV-OC43抑制剂的构效关系研究

Natacha Mérindol , Seyedeh Mahsa Hashemian , Seynabou Sokhna , Marie-Pierre Girard , Marc Presset , Insa Seck , Lalla Aïcha Ba , Seydou Ka , Samba Fama Ndoye , Issa Samb , Erwan Le Gall , Lionel Berthoux , Matar Seck , Isabel Desgagné-Penix
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引用次数: 0

摘要

三氮杂烯或氨基取代二氮杂烯是含有三个相邻氮原子的有机化合物,具有强大的生物活性。我们之前已经证明,三氮杂烯,特别是那些在1位被苯基或3-吡啶环取代,在3位被2-吡啶环取代的三氮杂烯,具有抗denv特性。在这里,我们评估了对乙型冠状病毒(HCoV-OC43)和慢病毒(HIV-1)的抗病毒活性。1-(4-三氟甲基苯基)-2-咪唑-1-基二氮烯(21)具有广谱活性(EC50 = 6.6 ~ 6.8 μM),但对THP-1细胞具有细胞毒性。吡啶基三氮杂烯(14,15)对HCoV-OC43的抑制作用最强,而1-(4-甲氧基苯基)-2-morpholin-4-yldiazene(6)和1-(4-甲氧基苯基)3-(-6-甲基吡啶-2-基)三氮杂烯(10)对HIV-1的抑制作用最强。基于分子对接的构效关系分析表明,对甲氧基倾向于与病毒酶结合口袋相互作用,增强抗病毒效力,而间和对三氟甲基则与活性降低和细胞毒性增加相关。这些发现支持了三氮杂烯作为抗病毒支架的进一步发展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Triazenes as inhibitors of HIV-1 and HCoV-OC43: A structure-activity relationship study

Triazenes as inhibitors of HIV-1 and HCoV-OC43: A structure-activity relationship study
Triazenes, or amino-substituted diazenes, are organic compounds containing three contiguous nitrogen atoms, that have potent biological activities. We previously demonstrated that triazenes, particularly those substituted with a phenyl or 3-pyridyl ring at the 1-position and a 2-pyridyl ring at the 3-position, exhibit anti-DENV properties. Here, we evaluated the antiviral activity against a betacoronavirus (HCoV-OC43) and a lentivirus (HIV-1). 1-(4-trifluoromethylphenyl)-2-imidazole-1-yldiazene (21) exhibited broad-spectrum activity (EC50 = 6.6–6.8 μM) but was cytotoxic to THP-1 cells. Pyridyl triazenes (14, 15) were the most potent against HCoV-OC43, while 1-(4-methoxyphenyl)-2-morpholin-4-yldiazene (6) and 1-(4-methoxyphenyl)3-(-6-methylpyridin-2-yl)triazene (10) inhibited HIV-1 the most. Structure–activity relationship analysis, supported by molecular docking, indicated that para-methoxy groups favored interactions with viral enzyme binding pockets, enhancing antiviral potency, while meta and para-trifluoromethyl groups were associated with reduced activity and increased cytotoxicity. These findings support the further development of triazenes as antiviral scaffolds.
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