Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity

Drugs containing thiazole and aminothiazole
groups are known to
generate reactive metabolites (RMs) catalyzed by cytochrome P450s
(CYPs). These RMs can covalently modify essential cellular macromolecules
and lead to toxicity and induce idiosyncratic adverse drug reactions.
Molecular docking and quantum chemical hybrid DFT study were carried
out to explore the molecular mechanisms involved in the biotransformation
of thiazole (TZ) and aminothiazole (ATZ) groups leading to RM epoxide, S-oxide, N-oxide, and oxaziridine. The
energy barrier required for the epoxidation is 13.63 kcal/mol, that
is lower than that of S-oxidation, N-oxidation, and oxaziridine formation (14.56, 17.90, and 20.20, kcal/mol
respectively). The presence of the amino group in ATZ further facilitates
all the metabolic pathways, for example, the barrier for the epoxidation
reaction is reduced by ∼2.5 kcal/mol. Some of the RMs/their
isomers are highly electrophilic and tend to form covalent bonds with
nucleophilic amino acids, finally leading to the formation of metabolic
intermediate complexes (MICs). The energy profiles of these competitive
pathways have also been explored.