1,4-取代-1,2,3-三唑类化合物对 HSV-1 的体外抗病毒活性。

Antiviral activity of 1,4-disubstituted-1,2,3-triazoles against HSV-1 in vitro.

机构信息

LAMCIFAR, Laboratório de Modelagem Molecular e Pesquisa em Ciências Farmacêuticas, Universidade Federal do Rio de Janeiro, Macaé, Rio de Janeiro, Brazil.

Laboratório de Síntese Orgânica, Pontifícia Universidade Católica do Rio de Janeiro, Rio de Janeiro, Brazil.

出版信息

Antivir Ther. 2020;25(8):399-410. doi: 10.3851/IMP3387.

DOI:10.3851/IMP3387

PMID:33705354

Abstract

BACKGROUND

Herpes simplex virus 1 (HSV-1) affects a large part of the adult population. Anti-HSV-1 drugs, such as acyclovir, target thymidine kinase and viral DNA polymerase. However, the emerging of resistance of HSV-1 alerts for the urgency in developing new antivirals with other therapeutic targets. Thus, this study evaluated a series of 1,4-disubstituted-1,2,3-triazole derivatives against HSV-1 acute infection and provided deeper insights into the possible mechanisms of action.

METHODS

Human fibroblast cells (HFL-1) were infected with HSV-1 17syn+ and treated with the triazole compounds at 50 μM for 24 h. The 50% effective drug concentration (EC) was determined for the active compounds. Their cytotoxicity was also evaluated in HFL-1 with the 50% cytotoxic concentration (CC) determined using CellTiter-Glo solution. The most promising compounds were evaluated by virucidal activity and influence on virus egress, DNA replication and transcription, and effect on an acyclovir-resistant HSV-1 strain.

RESULTS

Compounds 3 ((E)-4-methyl-N'-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol1yl)benzylidene)benzenesulfonohydrazide) and 4 (2,2'-(4,4'-((1,3-phenylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1 diyl)) dibenzaldehyde) were the most promising, with an EC of 16 and 21 μM and CC of 285 and 2,593 μM, respectively. Compound 3 was able to inhibit acyclovir-resistant strain replication and to interfere with virus egress. Both compounds did not affect viral DNA replication, but inhibited significantly the expression of ICP0, ICP4 and gC. Compound 4 also affected the transcription of UL30 and ICP34.5.

CONCLUSIONS

Our findings demonstrated that these compounds are promising antiviral candidates with different mechanisms of action from acyclovir and further studies are merited.

摘要

背景

单纯疱疹病毒 1（HSV-1）影响了很大一部分成年人。阿昔洛韦等抗 HSV-1 药物的作用靶点是胸苷激酶和病毒 DNA 聚合酶。然而，HSV-1 耐药性的出现表明迫切需要开发具有其他治疗靶点的新抗病毒药物。因此，本研究评估了一系列 1,4-二取代-1,2,3-三唑衍生物对 HSV-1 急性感染的作用，并深入探讨了可能的作用机制。

方法

人成纤维细胞（HFL-1）感染 HSV-1 17syn+，用三唑化合物在 50 μM 下处理 24 小时。用 50%有效药物浓度（EC）测定活性化合物的半数有效浓度（CC）。用 CellTiter-Glo 溶液测定 50%细胞毒性浓度（CC），评估其在 HFL-1 中的细胞毒性。用病毒杀灭活性和对病毒释放、DNA 复制和转录的影响以及对阿昔洛韦耐药 HSV-1 株的影响来评估最有前途的化合物。

结果

化合物 3（（E）-4-甲基-N'-(2-(4-(苯甲氧基)-1H-1,2,3-三唑-1-基)亚苄基)苯磺酰肼）和 4（2,2'-(4,4'-((1,3-亚苯基双（氧基）)双（亚甲基））双（1H-1,2,3-三唑-4,1-二基）二苯甲醛）是最有前途的化合物，EC 分别为 16 和 21 μM，CC 分别为 285 和 2593 μM。化合物 3 能够抑制阿昔洛韦耐药株的复制，并干扰病毒释放。这两种化合物均不影响病毒 DNA 复制，但显著抑制 ICP0、ICP4 和 gC 的表达。化合物 4 也影响 UL30 和 ICP34.5 的转录。