Optimization of the Antioxidant Activity of Hydroxy‐Substituted 4‐Thiaflavanes: A Proof‐of‐Concept Study

Abstract

The design and the synthesis of a new family of hydroxy-4-thiaflavanes, in which the reactive phenolic OH is ortho to the sulfur atom of the benzofused oxathiin ring, allowed to prepare antioxidants that show rate constants for the reaction with peroxyl radicals (k(inh)), and bond dissociation energies (BDE), of the ArO-H group identical to those of α-tocopherol, the main component of vitamin E and the most effective lipophilic antioxidant known in nature. The peculiar conformation of the six-membered heterocyclic ring prevents the formation of an intramolecular hydrogen bond between the OH group and the S atom, while ensuring a good stabilization by electron donation of the phenoxyl radical formed after the reaction with peroxyl radicals. The preparation of these compounds was achieved through an inverse electron demand hetero Diels-Alder reaction of styrenes with o-thioquinones, in turn prepared from accurately designed 1,3-dihydroxy arenes. Properly arranging the substitution pattern on the aromatic ring, as in derivatives 9 and 11, allowed to reach values of k(inh) up to 4.0×10(6) M(-1) s(-1) and BDE((OH)) of 77.2 kcal mol(-1). This approach represents an innovative way to obtain highly active antioxidants without using strongly electron donating alkylamino groups which are associated with adverse toxicological profiles.

Modulation of Biorelevant Radical Reactions by Non‐covalent Interactions

“…If the ortho substituent is included in a cycle, as in the case of 4, the strength of the intramolecular H-bond drops to nearly zero, as assessed by FTIR spectroscopy, and the reactivity toward ROO• drastically increases [28]. The thiaflavane antioxidant 5 was designed to exploit this feature and was found to have the same k inh as α-tocopherol (3.2 × 10 6 M −1 s −1 ), the most active natural lipophilic antioxidant (Table 20.2) [29].…”

Ditocopheryl Sulfides and Disulfides: Synthesis and Antioxidant Profile

“…Autoxidation were performed in a two‐channel oxygen uptake apparatus, based on a Validyne DP 15 differential pressure transducer built in our laboratory . The chain‐breaking antioxidant activity was evaluated by studying the inhibition of the thermally initiated autoxidation of either styrene or cumene in chlorobenzene or acetonitrile.…”

“…in which R 0 and R inh are the O 2 consumption in the absence and in the presence of the antioxidant, respectively, [ArOH] is the concentration of the antioxidant, 2 k t is the termination constant of either styrene (4.2×10 7 m −1 s −1 ) or cumene (4.6×10 4 m −1 s −1 ) …”

“…The stoichiometric coefficient n was obtained by Equation from the length of the inhibition period …”

“…Autoxidation were performed in at wo-channel oxygen uptake apparatus, based on aV alidyne DP 15 differential pressure transducer built in our laboratory. [38] The chain-breaking antioxidant activity was evaluated by studying the inhibition of the thermally initiated autoxidation of either styrene or cumene in chlorobenzene or acetonitrile. In atypical experiment, an air-saturated mixture of the oxidizable substrate and the solvent, 1:1( v/v), containing AIBN (0.05 m)a sa ni nitiator was equilibrated with an identical reference solution containing an excess of 2,2, 5,7,.…”