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Open Access Original

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

Alice MR Bernardino1, Alexandre R Azevedo1, Luiz CS Pinheiro1, Júlio C Borges1, Izabel CP Paixão2, Milene Mesquita23, Thiago ML Souza23 and Maurício S dos Santos4*

Author Affiliations

1 Departamento de Química Orgânica, Instituto de Química, Programa de Pós-Graduação em Química, Universidade Federal Fluminense, Campus do Valonguinho, 24020-150, Niterói, RJ, Brazil

2 Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Campus do Valonguinho, 24020-150, Niterói, RJ, Brazil

3 Programa de Pós-Graduação em Biologia Celular e Molecular, Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, 21040-900, Rio de Janeiro, RJ, Brazil

4 Departamento de Física e Química, Instituto de Ciências Exatas, Universidade Federal de Itajubá, 37500-903, Itajubá, MG, Brazil

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Organic and Medicinal Chemistry Letters 2012, 2:3  doi:10.1186/2191-2858-2-3

Published: 1 February 2012

Abstract

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).

Keywords:
HSV-1; 1,6-naphthyridines; pyrazolonaphthyridines; heterocycles

Graphical abstract