Toxicity Originating from Thiophene Containing Drugs: Exploring the Mechanism using Quantum Chemical Methods

Abstract

Drug metabolism of thiophene containing substrates by cytochrome P450s (CYP450) leads to toxic side effects, for example, nephrotoxicity (suprofen, ticlopidine), hepatotoxicity (tienilic acid), thrombotic thrombocytopenic purpura (clopidogrel), and aplastic anemia (ticlopidine). The origin of toxicity in these cases has been attributed to two different CYP450 mediated metabolic reactions: S-oxidation and epoxidation. In this work, the molecular level details of the bioinorganic chemistry associated with the generation of these competitive reactions are reported. Density functional theory was utilized (i) to explore the molecular mechanism for S-oxidation and epoxidation using the radical cationic center Cpd I [(iron(IV)-oxo-heme porphine system with SH(-) as the axial ligand, to mimic CYP450s] as the model oxidant, (ii) to establish the 3D structures of the reactants, transition states, and products on both the metabolic pathways, and (iii) to examine the potential energy (PE) profile for both the pathways to determine the energetically preferred toxic metabolite formation. The energy barrier required for S-oxidation was observed to be 14.75 kcal/mol as compared to that of the epoxidation reaction (13.23 kcal/mol) on the doublet PE surface of Cpd I. The formation of the epoxide metabolite was found to be highly exothermic (-23.24 kcal/mol), as compared to S-oxidation (-8.08 kcal/mol). Hence, on a relative scale the epoxidation process was observed to be thermodynamically and kinetically more favorable. The energy profiles associated with the reactions of the S-oxide and epoxide toxic metabolites were also explored. This study helps in understanding the CYP450-catalyzed toxic reactions of drugs containing the thiophene ring at the atomic level.

HC2091 Kills Mycobacterium tuberculosis by Targeting the MmpL3 Mycolic Acid Transporter

“…An initial SAR study of the aryl R-group supported that this group is required for optimal HC2091 activity, and it provides a foundation for further optimization efforts. Such optimizations could include increased potency and improvements to pharmacokinetic properties, such as replacing the thiophene group, which may be prone to in vivo metabolism (33).…”

Chemical Epigenetics: The Impact of Chemical and Chemical Biology Techniques on Bromodomain Target Validation

“…[98] Exchange of the thiophene for an unsubstituted aryl ring eliminated possible thiophene-linked metabolic issues including S-oxidation and epoxidation. [99] Scaffold hopping from an imine-(31)t oa n aniline-based (32)scaffold was predicted to retain the overall shape of the ligand while providing ad ifferent metabolic profile for the series.C ompound 32 was subjected to af ragment growing strategy,w ith identification of the 4-cyanoaryl substituent on the 6-position nitrogen as optimal, giving compound 33 with an IC 50 value of 550 nm.Ligand efficiency and lipophilic ligand efficiency were largely preserved, despite as ignificant increase in lipophilicity.F urther SAR on the aromatic 8-position and the aliphatic 4-position led to the identification of ac lass of potent ligands,e xemplified by compound 34;h owever, these compounds showed unacceptable in vitro clearance properties.L arger groups at the 4position were detrimental to affinity,i nc ontrast to structurally similar ligands where far larger groups are tolerated (compare with (+ +)-JQ1). Theh igh lipophilicity of the 5,6dihydro-4H-benzo [b]isoxazolo [4,5-d]azepine structure and the unfavorable in vitro clearance properties of this series inspired af urther scaffold hop by replacement of the isoxazole moiety,w hich was been implicated with poor metabolic stability, [100] with the more polar triazole.…”

Thiophene S-Oxides

“…Lastly, both possible metabolic pathways of thiophenes, via thiophene S-oxides and via thiophene epoxides, have been examined as to their energy profiles using density functional theory [129]. It was found that the formation of the thiophene epoxide (À23.24 kcal/mol) is more exothermic than the formation of the thiophene S-oxide (À8.08 kcal/mol) [129]. Also, the formation of thiophene epoxide seems kinetically favored [129].…”