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- Title
Novel Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles and Biochemical Valuation on F 1 F O -ATPase and Mitochondrial Permeability Transition Pore Formation.
- Authors
Algieri, Vincenzo; Algieri, Cristina; Costanzo, Paola; Fiorani, Giulia; Jiritano, Antonio; Olivito, Fabrizio; Tallarida, Matteo Antonio; Trombetti, Fabiana; Maiuolo, Loredana; De Nino, Antonio; Nesci, Salvatore
- Abstract
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.
- Subjects
PYRAZOLES; ISOXAZOLIDINES; PERMEABILITY; MITOCHONDRIA; NITRILIMINES; VALUATION
- Publication
Pharmaceutics, 2023, Vol 15, Issue 2, p498
- ISSN
1999-4923
- Publication type
Article
- DOI
10.3390/pharmaceutics15020498