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

Abstract

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.

Improving Antimicrobial Activity and Physico-Chemical Properties by Isosteric Replacement of 2-Aminothiazole with 2-Aminooxazole

“…Despite its apparent success, 2-AMT is considered very problematic for drug design due to often observed unspecific reactivity or promiscuous behavior. The presence of sulfur infers the possibility of undesirable interactions with the GSH system or unwanted biotransformation, e.g., S-oxidation or oxidative ring openings [ 12 , 13 ]. As a consequence, several 2-AMT-containing groups are currently categorized as PAINS and thus often disqualified in the discovery of new chemical entities [ 14 , 15 ].…”

Theoretical study of thiazole activation in sudoxicam and meloxicam: Reaction center, biotransformation, and methyl effects

“…The ω value of 5‐PC is close to that of thioamide, which indicates that nucleophilic residues or GSH can attack at C5 position of 5‐PC and generate adducts. [ 28 ] The ω values of 5‐PC and thioamide generated by sudoxicam are higher than that of meloxicam, which may be one of the reasons for the different toxicity of the two drugs.…”

“…[ 19–23 ] Cpd I has two closely exposed spin states (S = 3/2 and S = 1/2), so the metabolic pathways were studied with high spin (HS) and low spin (LS) state Cpd I. [ 19,24–26 ] The electrophilicity analysis [ 27,28 ] is useful in estimating the toxicities of important reactive metabolites. Chemical hardness ( η ) shown in equation ( η = ε HOMO − ε LUMO ) is a useful global index of reactivity in atoms, molecules, and clusters, where ε HOMO and ε LUMO are the energies of highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LOMOs), respectively.…”

In Vitro and In Vivo Metabolic Activation and Hepatotoxicity of Environmental Pollutant 2,6-Dimethylphenol

“…15 The biochemical transformation results in the generation of metabolites/intermediates with chemical reactivity, which initiates the varieties of toxicities. 16 Quinone methides are often reported to be reactive metabolites formed via oxidation and elimination reactions. 17 Phenolic derivatives or phenolic structures, such as 4-trifluoromethylphenol and phencyclidine compounds, can be oxidized to reactive intermediates with a quinone methide structure, leading to liver damage or even death.…”

“…However, increasing studies have demonstrated that biotransformation also can induce toxicities . The biochemical transformation results in the generation of metabolites/intermediates with chemical reactivity, which initiates the varieties of toxicities . Quinone methides are often reported to be reactive metabolites formed via oxidation and elimination reactions .…”