Premium
Radical Scavenging Potential of the Phenothiazine Scaffold: A Computational Analysis
Author(s) -
Dalla Tiezza Marco,
Hamlin Trevor A.,
Bickelhaupt F. Matthias,
Orian Laura
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100546
Subject(s) - phenothiazine , scavenging , chemistry , scaffold , combinatorial chemistry , computer science , pharmacology , biochemistry , biology , antioxidant , database
The reactivity of phenothiazine ( PS ), phenoselenazine ( PSE ), and phenotellurazine ( PTE ) with different reactive oxygen species (ROS) has been studied using density functional theory (DFT) in combination with the QM‐ORSA (Quantum Mechanics‐based Test for Overall Free Radical Scavenging Activity) protocol for an accurate kinetic rate calculation. Four radical scavenging mechanisms have been screened, namely hydrogen atom transfer (HAT), radical adduct formation (RAF), single electron transfer (SET), and the direct oxidation of the chalcogen atom. The chosen ROS are HO . , HOO . , and CH 3 OO . . PS , PSE , and PTE exhibit an excellent antioxidant activity in water regardless of the ROS due to their characteristic diffusion‐controlled regime processes. For the HO . radical, the primary active reaction mechanism is, for all antioxidants, RAF. But, for HOO . and CH 3 OO . , the dominant mechanism strongly depends on the antioxidant: HAT for PS and PSE , and SET for PTE . The scavenging efficiency decreases dramatically in lipid environment and remains only significant (via RAF) for the most reactive radical (HO . ). Therefore, PS , PSE , and PTE are excellent antioxidant molecules, especially in aqueous, physiological environments where they are active against a broad spectrum of harmful radicals. There is no advantage or significant difference in the scavenging efficiency when changing the chalcogen since the reactivity mainly derives from the amino hydrogen and the aromatic sites.