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Novel Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles and Biochemical Valuation on F1FO-ATPase and Mitochondrial Permeability Transition Pore Formation.
Algieri, Vincenzo; Algieri, Cristina; Costanzo, Paola; Fiorani, Giulia; Jiritano, Antonio; Olivito, Fabrizio; Tallarida, Matteo Antonio; Trombetti, Fabiana; Maiuolo, Loredana; De Nino, Antonio; Nesci, Salvatore.
Afiliación
  • Algieri V; Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci, Cubo 12C, 87036 Rende, CS, Italy.
  • Algieri C; Department of Veterinary Medical Sciences, Mitochondrial Biochemistry Lab, Via Tolara di Sopra, 50, 40064 Ozzano Emilia, BO, Italy.
  • Costanzo P; Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci, Cubo 12C, 87036 Rende, CS, Italy.
  • Fiorani G; Department Molecular Sciences and Nanosystems, University Ca' Foscari Venezia, Via Torino 155, 30172 Venezia Mestre, VE, Italy.
  • Jiritano A; Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci, Cubo 12C, 87036 Rende, CS, Italy.
  • Olivito F; Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci, Cubo 12C, 87036 Rende, CS, Italy.
  • Tallarida MA; Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci, Cubo 12C, 87036 Rende, CS, Italy.
  • Trombetti F; Department of Veterinary Medical Sciences, Mitochondrial Biochemistry Lab, Via Tolara di Sopra, 50, 40064 Ozzano Emilia, BO, Italy.
  • Maiuolo L; Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci, Cubo 12C, 87036 Rende, CS, Italy.
  • De Nino A; Department of Chemistry and Chemical Technologies, University of Calabria, Via P. Bucci, Cubo 12C, 87036 Rende, CS, Italy.
  • Nesci S; Department of Veterinary Medical Sciences, Mitochondrial Biochemistry Lab, Via Tolara di Sopra, 50, 40064 Ozzano Emilia, BO, Italy.
Pharmaceutics ; 15(2)2023 Feb 02.
Article en En | MEDLINE | ID: mdl-36839821
An efficient, eco-compatible, and very cheap method for the construction of fully substituted pyrazoles (Pzs) via eliminative nitrilimine-alkene 1,3-dipolar cycloaddition (ENAC) reaction was developed in excellent yield and high regioselectivity. Enaminones and nitrilimines generated in situ were selected as dipolarophiles and dipoles, respectively. A deep screening of the employed base, solvent, and temperature was carried out to optimize reaction conditions. Recycling tests of ionic liquid were performed, furnishing efficient performance until six cycles. Finally, a plausible mechanism of cycloaddition was proposed. Then, the effect of three different structures of Pzs was evaluated on the F1FO-ATPase activity and mitochondrial permeability transition pore (mPTP) opening. The Pz derivatives' titration curves of 6a, 6h, and 6o on the F1FO-ATPase showed a reduced activity of 86%, 35%, and 31%, respectively. Enzyme inhibition analysis depicted an uncompetitive mechanism with the typical formation of the tertiary complex enzyme-substrate-inhibitor (ESI). The dissociation constant of the ESI complex (Ki') in the presence of the 6a had a lower order of magnitude than other Pzs. The pyrazole core might set the specific mechanism of inhibition with the F1FO-ATPase, whereas specific functional groups of Pzs might modulate the binding affinity. The mPTP opening decreased in Pz-treated mitochondria and the Pzs' inhibitory effect on the mPTP was concentration-dependent with 6a and 6o. Indeed, the mPTP was more efficiently blocked with 0.1 mM 6a than with 1 mM 6a. On the contrary, 1 mM 6o had stronger desensitization of mPTP formation than 0.1 mM 6o. The F1FO-ATPase is a target of Pzs blocking mPTP formation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Pharmaceutics Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Pharmaceutics Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Suiza