新型3H-苯并[b]吡唑并[3,4-h]-1,6-萘啶和3H-吡啶并[2,3-b]吡唑并[3,4-h]-1,6-萘啶的合成及抗单纯疱疹病毒-1活性评价
Synthesis and anti-HSV-1 evaluation of new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines.
作者信息
Bernardino Alice Mr, Azevedo Alexandre R, Pinheiro Luiz Cs, Borges Júlio C, Paixão Izabel Cp, Mesquita Milene, Souza Thiago Ml, Dos Santos Maurício S
机构信息
Departamento de Física e Química, Instituto de Ciências Exatas, Universidade Federal de Itajubá, 37500-903, Itajubá, MG, Brazil.
出版信息
Org Med Chem Lett. 2012 Feb 1;2(1):3. doi: 10.1186/2191-2858-2-3.
BACKGROUND
Herpes simplex virus type-1 (HSV-1) is the primary cause of facial lesions (mouth, lips, and eyes) in humans. The widespread use of acyclovir and nucleoside analogues has led to emergence of HSV strains that are resistant to these drugs. Recently, non-nucleoside anti-HSV compounds have received considerable attention. 1,6-Naphthyridines are a class of heterocyclic compounds that exhibit a broad spectrum of biological activities such as inhibitor of HIV-1 integrase, HCMV, FGF receptor-1 tyrosine kinase, and the enzyme acetylcholinesterase. We previously reported the synthesis, SAR studies, and evaluation anti-HSV-1 activity of 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines. In the course of our search for new 1,6-naphthyridines derivatives with potential activity against HSV-1, we have synthesized and evaluated new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines (1a-k) and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines (2a-c).
RESULTS
A known synthetic approach was used for preparing new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines (1a-k) and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines (2a-c), starting from ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (7). All compounds were identified by FTIR, 1H NMR, and mass spectrometry. The antiviral effect on HSV-1 virus replication was determined.
CONCLUSIONS
The compounds 1d, 1f, 1g, and 1h exhibited the highest anti-HSV-1 activity. In general, 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines were more effective inhibitors than their corresponding 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines. The compound 1h reduced the virus yield in 91% at 50 μM and exhibited a low cytotoxicity (CC50 600 μM).
背景
单纯疱疹病毒1型（HSV - 1）是人类面部病变（口腔、嘴唇和眼睛）的主要病因。阿昔洛韦和核苷类似物的广泛使用导致了对这些药物耐药的HSV毒株的出现。最近，非核苷类抗HSV化合物受到了相当大的关注。1,6 - 萘啶是一类杂环化合物，具有广泛的生物活性，如HIV - 1整合酶抑制剂、人巨细胞病毒（HCMV）抑制剂、成纤维细胞生长因子受体 - 1酪氨酸激酶抑制剂以及乙酰胆碱酯酶抑制剂。我们之前报道了3H - 苯并[b]吡唑并[3,4 - h] - 1,6 - 萘啶的合成、构效关系研究以及抗HSV - 1活性评估。在寻找具有抗HSV - 1潜在活性的新型1,6 - 萘啶衍生物的过程中，我们合成并评估了新型3H - 苯并[b]吡唑并[3,4 - h] - 1,6 - 萘啶（1a - k）和3H - 吡啶并[2,3 - b]吡唑并[3,4 - h] - 1,6 - 萘啶（2a - c）。
结果
采用一种已知的合成方法，从4 - 氯 - 1 - 苯基 - 1H - 吡唑并[3,4 - b]吡啶 - 5 - 羧酸乙酯（7）开始制备新型3H - 苯并[b]吡唑并[3,4 - h] - 1,6 - 萘啶（1a - k）和3H - 吡啶并[2,3 - b]吡唑并[3,4 - h] - 1,6 - 萘啶（2a - c）。所有化合物均通过傅里叶变换红外光谱（FTIR）、核磁共振氢谱（1H NMR）和质谱进行了鉴定。测定了对HSV - 1病毒复制的抗病毒效果。
结论
化合物1d、1f、1g和1h表现出最高的抗HSV - 1活性。一般来说，3H - 苯并[b]吡唑并[3,4 - h] - 1,6 - 萘啶比其相应的3H - 吡啶并[2,3 - b]吡唑并[3,4 - h] - 1,6 - 萘啶是更有效的抑制剂。化合物1h在50 μM时使病毒产量降低了91%，并且表现出低细胞毒性（半数细胞毒性浓度CC50为600 μM）。
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