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. 2020 Jul;28(7):819-827.
doi: 10.1016/j.jsps.2020.06.001. Epub 2020 Jun 12.

Experimental and theoretical study on structure-tautomerism among edaravone, isoxazolone, and their heterocycles derivatives as antioxidants

Auriekson N Queiroz  1 , Camila C Martins  1 , Kelton L B Santos  1   2 , Ederson S Carvalho  1 , Alex O Owiti  3 , Karen R M Oliveira  4 , Anderson M Herculano  4 , Albérico B F da Silva  5 , Rosivaldo S Borges  1
Affiliations

Experimental and theoretical study on structure-tautomerism among edaravone, isoxazolone, and their heterocycles derivatives as antioxidants

Auriekson N Queiroz et al. Saudi Pharm J. 2020 Jul.

Abstract

Edaravone is a heterocyclic pyrazolone compound. It has pronounced effect against free radicals, however renal and hepatic disorders have been reported. Isoxazolones are considered bioisosteric analogues of pyrazolones and may have comparable properties. Thus, we investigated the structural and electronic influences for edaravone, isoxazolone, and their tautomers on antioxidant process. Structure and tautomerism study among edaravone, isoxazolone and their heterocycles derivatives were related to antioxidant mechanisms by using the hybrid DFT method B3LYP with the basis sets 6-31++G(2d,2p). The C-H tautomer was the most stable and energetically favored among them. Intramolecular N-H-N hydrogen bonds and polar medium were responsible for the low energy differences among all possible tautomers. N-H tautomers in both systems proved to be better antioxidant by SET (single electron transfer), while O-H tautomers were better antioxidant on HAT (homolytic hydrogen atom transfer) mechanism. Theoretical calculation showed that edaravone is more potent than phenylisoxazolone, however, both has similar antioxidant scavenging on experimental DPPH. The carbonyliminic system played a very important role in the antioxidant activity for both studied classes.

Keywords: Antioxidant; DFT; DPPH; Edaravone; Heterocycles; Isoxazolone; Tautomerism.

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Figures

Fig. 1
Fig. 1
Edaravone (1–3) and isoxazolone derivatives (4–6) and their tautomers (a-c), where R is H, CH3 or C6H5 and X  = O or N.
Fig. 2
Fig. 2
Heterocycle derivatives of edaravone (7) and phenylisoxazolone (8) and their tautomers a (C—H), b (N—H) and c (O—H).
Fig. 3
Fig. 3
HOMO topology of the most stable tautomers in gas phase calculated at the B3LYP 6-31++G(2d,2p) level.
Fig. 4
Fig. 4
Contribution of free radical cation spin density among the most stable tautomers of edaravone (2a), pyridinyl edaravone (7b and 7c) and isoxazolones (6a and 8b).
Fig. 5
Fig. 5
Contribution of spin density of semiquinones among the most stable tautomers of edaravone (2a), pyridinyl edaravone (7b and 7c) and isoxazolones (6a and 8b).
Fig. 6
Fig. 6
Evaluation of scavenging capacity of edaravone (2) and isoxazolone (6) at different concentrations (250-1 μM) in methanolic solution against DPPH radical (25 μM).
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