Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives

Daniel Silva; Mourad Chioua; Abdelouahid Samadi; M. Carmo Carreiras; María Luisa Jimeno; Eduarda Mendes; Cristóbal De Los Ríos; Alejandro Romero; Mercedes Villarroya; Manuela G. López; José Marco-Contelles

doi:10.1016/j.ejmech.2011.05.068

Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives

Daniel Silva, Mourad Chioua, Abdelouahid Samadi, M. Carmo Carreiras, María Luisa Jimeno, Eduarda Mendes, Cristóbal De Los Ríos, Alejandro Romero, Mercedes Villarroya, Manuela G. López, José Marco-Contelles

Research output: Contribution to journal › Article › peer-review

52 Citations (Scopus)

Abstract

The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedländer-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H- benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC ₅₀ (EeAChE) = 0.069 ± 0.006 μM; IC ₅₀ (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K _i = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.

Original language	English
Pages (from-to)	4676-4681
Number of pages	6
Journal	European Journal of Medicinal Chemistry
Volume	46
Issue number	9
DOIs	https://doi.org/10.1016/j.ejmech.2011.05.068
Publication status	Published - Sept 2011
Externally published	Yes

Keywords

AChE/BuChE inhibitors
Alzheimer's disease
Neuroprotection
Oxidative stress
Pyrazolotacrines

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2011.05.068

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Silva, D., Chioua, M., Samadi, A., Carmo Carreiras, M., Jimeno, M. L., Mendes, E., Ríos, C. D. L., Romero, A., Villarroya, M., López, M. G., & Marco-Contelles, J. (2011). Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives. European Journal of Medicinal Chemistry, 46(9), 4676-4681. https://doi.org/10.1016/j.ejmech.2011.05.068

Silva, D, Chioua, M, Samadi, A, Carmo Carreiras, M, Jimeno, ML, Mendes, E, Ríos, CDL, Romero, A, Villarroya, M, López, MG & Marco-Contelles, J 2011, 'Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives', European Journal of Medicinal Chemistry, vol. 46, no. 9, pp. 4676-4681. https://doi.org/10.1016/j.ejmech.2011.05.068

@article{42f64905b0e942e0ad79b6c592d61b48,

title = "Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives",

abstract = "The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedl{\"a}nder-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H- benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC 50 (EeAChE) = 0.069 ± 0.006 μM; IC 50 (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K i = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.",

keywords = "AChE/BuChE inhibitors, Alzheimer's disease, Neuroprotection, Oxidative stress, Pyrazolotacrines",

author = "Daniel Silva and Mourad Chioua and Abdelouahid Samadi and {Carmo Carreiras}, M. and Jimeno, {Mar{\'i}a Luisa} and Eduarda Mendes and R{\'i}os, {Crist{\'o}bal De Los} and Alejandro Romero and Mercedes Villarroya and L{\'o}pez, {Manuela G.} and Jos{\'e} Marco-Contelles",

note = "Funding Information: We thank V. G{\'o}mez and L. Gonz{\'a}lez-Lafuente for technical support. D. Silva thanks Funda{\c c}{\~a}o para a Ci{\^e}ncia e Tecnologia do Minist{\'e}rio da Ci{\^e}ncia , Tecnologia e Ensino Superior of Portugal for his grant belonging to project PTDC/SAU-NEU/64151/2006. M. Chioua thanks Instituto de Salud Carlos III (MICINN) for a “Sara Borrell” post-doctoral contract. JMC thanks MICINN (SAF2006-08764-C02-01; SAF2009-07271) financial support. MGL thanks MICINN Ref. SAF2009-12150. DS thanks COST Action D34. This work was partly supported by grants RD06/0026/1002 ( RENEVAS ), ISCIII , MICINN, S/SAL-0275-2006, Comunidad de Madrid , and Fundaci{\'o}n CIEN , project 1004040042. JMC thanks Prof. A. Garc{\'i}a for his continuous interest and support. ",

year = "2011",

month = sep,

doi = "10.1016/j.ejmech.2011.05.068",

language = "English",

volume = "46",

pages = "4676--4681",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson SAS",

number = "9",

}

TY - JOUR

T1 - Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives

AU - Silva, Daniel

AU - Chioua, Mourad

AU - Samadi, Abdelouahid

AU - Carmo Carreiras, M.

AU - Jimeno, María Luisa

AU - Mendes, Eduarda

AU - Ríos, Cristóbal De Los

AU - Romero, Alejandro

AU - Villarroya, Mercedes

AU - López, Manuela G.

AU - Marco-Contelles, José

N1 - Funding Information: We thank V. Gómez and L. González-Lafuente for technical support. D. Silva thanks Fundação para a Ciência e Tecnologia do Ministério da Ciência , Tecnologia e Ensino Superior of Portugal for his grant belonging to project PTDC/SAU-NEU/64151/2006. M. Chioua thanks Instituto de Salud Carlos III (MICINN) for a “Sara Borrell” post-doctoral contract. JMC thanks MICINN (SAF2006-08764-C02-01; SAF2009-07271) financial support. MGL thanks MICINN Ref. SAF2009-12150. DS thanks COST Action D34. This work was partly supported by grants RD06/0026/1002 ( RENEVAS ), ISCIII , MICINN, S/SAL-0275-2006, Comunidad de Madrid , and Fundación CIEN , project 1004040042. JMC thanks Prof. A. García for his continuous interest and support.

PY - 2011/9

Y1 - 2011/9

N2 - The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedländer-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H- benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC 50 (EeAChE) = 0.069 ± 0.006 μM; IC 50 (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K i = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.

AB - The synthesis and pharmacological analyses of a number of pyrazolo[3,4-b]quinoline and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives are reported. We have synthesized the diversely substituted tacrine analogues 1-6, by Friedländer-type reaction of readily available o-amino-1-methyl-pyrazole-dicarbonitriles with cyclohexanone. The biological evaluation showed that pyrazolotacrines 1-6 are inhibitors of Electrophorus electricus acetylcholinesterase (EeAChE), in the micromolar range, and quite selective in respect to serum horse butyrylcholinesterase (eqBuChE) inhibition; the most interesting inhibitor is N-(5-amino-1-methyl-6,7,8,9-tetrahydro-1H- benzo[b]pyrazolo[4,3-g][1,8]naphthyridin-3-yl)acetamide (5) [IC 50 (EeAChE) = 0.069 ± 0.006 μM; IC 50 (eqBuChE) = 6.3 ± 0.6 μM]. Kinetic studies showed that compound 5 is a mixed-type inhibitor of EeAChE (K i = 155 nM). Inhibitor 5 showed a 45% neuroprotection value against rotenone/oligomycin A-induced neuronal death.

KW - AChE/BuChE inhibitors

KW - Alzheimer's disease

KW - Neuroprotection

KW - Oxidative stress

KW - Pyrazolotacrines

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SN - 0223-5234

VL - 46

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EP - 4681

JO - European Journal of Medicinal Chemistry

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ER -

Synthesis and pharmacological assessment of diversely substituted pyrazolo[3,4-b]quinoline, and benzo[b]pyrazolo[4,3-g][1,8]naphthyridine derivatives

Abstract

Keywords

ASJC Scopus subject areas

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