Abstract
The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC50 values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.
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References
Ahluwalia VK, Goyal B (1996) A facile synthesis of pyrazolo[3,4-b]pyridines. Synthetic Commun 26(7):1341
Azevedo AR, Ferreira VF, Mello HM, Ferreira LRL, Jabor AV, Frugulhetti ICPP, Pereira HS, Moussatché N, Bernardino AMR (2002a) Synthesis and biological evaluation of 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acids against Vaccinia virus. Heterocycl Comm 8(5):427
Azevedo AR, Frugulhetti ICCP, Khan MA, Khakwani S, Bernardino AMR (2002b) New tetracyclic heteroaromatic ring system 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines. Heterocycl Commun 8(1):47
Bernardino AMR, Romeiro GA, Mello H, Souza MCBV, Ferreira VF (1996a) Synthesis of new 1H-pyrazolo[3,4-b]pyridine derivatives. Heterocycl Comm 2(5):415
Bernardino AMR, Ferreira VF, Fontoura GATI, Frugulhetti ICPP, Lee MY, Romeiro GA, Souza MCBV, Sá PM (1996b) Synthesis of 4-anilino-1H- pyrazolo [3,4-b] pyridine derivatives and their in vitro antiviral activities. J. Braz Chem Soc 7(5):273
Bernardino AMR, Mello H, Echevarria A, Carvalho MG, Silva EF (1999) Novos derivados do sistema heterocíclico 1H-pirazolo[3,4-b]piridina: Síntese e assinalamentos de hidrogênios e carbonos por RMN 1D e 2D. Química Nova, 22(1):26
Bernardino AMR, Castro HC, Frugulhetti ICPP, Loureiro NIV, Azevedo AR, Pinheiro LCS, Souza TML,Giongo V, Passamani F, Magalhães UO, Albuquerque MG, Cabral LM Rodrigues CR (2007) SAR of a series of anti-HSV-1 acridone derivatives, and a rational acridone-based design of a new anti-HSV-1 3H-benzo[b]pyrazolo[3,4-h]-1,6 naphthyridine series. Bioorg Med Chem article in press
Casals J, Whitman L (1957) Mayaro virus: A new human disease agent. I. Relationship to other arborviruses. Am J Trop Med Hyg 6:1004
Causey OR, Maroja OM (1957) Mayaro virus: A new human disease agent. III. Investigation of an epidemic of acute febrile illness on the River Guamá in Pará, Brazil, and isolation of Mayaro virus as a causative agent. Am J Trop Med Hyg, 6:1017
De Clercq E (2005) Recent highlights in the development of new antiviral drugs. Curr Opin Microbiol 8(5):552
Eizuru Y (2003) Development of new antivirals for herpes viruses. Antivir Chem Chemother 14(6):299
Hohn H, Denzel Th, Janssen W (1972) 1H-Pyrazolo[3,4-b]pyridines. J Heterocyclic Chem 9:235
Lucero BA, Gomes CRB, Frugulhetti ICPP, Faro LV, Alvarenga L, Souza MCBV, Souza TML, Ferreira VF (2006) Synthesis and anti-HSV-1 activity of quinolonic acyclovir analogues. Bioorg Med Chem Lett 16(4):1010
Lynch BM, Khan MA, Teo HC, Pedrotti F (1988) Pyrazolo [3,4-b]pyridines: Syntheses, reactions, and nuclear magnetic resonance spectra. Can J Chem 66:420
Mello H, Echevarria A, Bernardino AMR, Canto-Cavalheiro M, Leon LL (2004) Antileishmanial pyrazolopyridine derivatives: Synthesis and structure–activity relationship analysis. J Med Chem 47:5427
Mossmann T (1983) Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 65:55
Pinheiro LCS, Azevedo AR, Frugulhetti ICPP, Carneiro JL de M, Souza TML, Ferreira VF (2004) Synthesis and antiviral activity of new 4-(phenylamino)thieno[2,3-b]pyridine derivatives. Heterocycl Comm 10:5
Quiroga J, Hormaza A, Insuasty B, Marquez M (1998) Reaction of 5-Amino-1-aryl-3-methylpyrazoles with benzylidene derivatives of meldrum’s acid: Synthesis and characterization of pyrazolo[3,4-b]pyridinones. J Heterocycl Chem 35:409
Reed LJ, Muench MA (1938) A simple method of estimating 50% end points. Am J Hyg 27(21):493
Rose JK, Whitt MA (2007) Rhabdoviridae: The viruses and their replication. In Field’s Virology Knipe DM, Howley PM, Griffin DE Lippincott Williams & Wilkins, 5th ed. Philadelphia, U.S.A
Strauss JH, Strauss EG (1994) The alpha viruses: Gene expression, replication and evolution. Microbiol Rev 58:491
Whitley RJ, Roizman B (2001) Herpes simplex virus infections. Lancet 357:1513
Acknowledgments
We thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal Docente (CAPES), and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) for financial support. The technical assistance of Samara and Hania is gratefully acknowledged.
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Bernardino, A.M.R., de Azevedo, A.R., Pinheiro, L.C.d.S. et al. Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives. Med Chem Res 16, 352–369 (2007). https://doi.org/10.1007/s00044-007-9035-6
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DOI: https://doi.org/10.1007/s00044-007-9035-6