Systematic Evaluation of the Metabolism and Toxicity of Thiazolidinone and Imidazolidinone Heterocycles

Abstract

The thiazolidine and imidazolidine heterocyclic scaffolds, i.e., the rhodanines, 2,4-thiazolidinediones, 2-thiohydantoins, and hydantoins have been the subject of debate on their suitability as starting points in drug discovery. This attention arose from the wide variety of biological activities exhibited by these scaffolds and their frequent occurrence as hits in screening campaigns. Studies have been conducted to evaluate their value in drug discovery in terms of their biological activity, chemical reactivity, aggregation-based promiscuity, and electronic properties. However, the metabolic profiles and toxicities have not been systematically assessed. In this study, a series of five-membered multiheterocyclic (FMMH) compounds were selected for a systematic evaluation of their metabolic profiles and toxicities on TAMH cells, a metabolically competent rodent liver cell line and HepG2 cells, a model of human hepatocytes. Our studies showed that generally the rhodanines are the most toxic, followed by the thiazolidinediones, thiohydantoins, and hydantoins. However, not all compounds within the family of heterocycles were toxic. In terms of metabolic stability, 5-substituted rhodanines and 5-benzylidene thiohydantoins were found to have short half-lives in the presence of human liver microsomes (t1/2 < 30 min) suggesting that the presence of the endocyclic sulfur and thiocarbonyl group or a combination of C5 benzylidene substituent and thiocarbonyl group in these heterocycles could be recognition motifs for P450 metabolism. However, the stability of these compounds could be improved by installing hydrophilic functional groups. Therefore, the toxicities and metabolic profiles of FMMH derivatives will ultimately depend on the overall chemical entity, and a blanket statement on the effect of the FMMH scaffold on toxicity or metabolic stability cannot and should not be made.

5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry

“…The significant biological potency of compounds bearing 5-ene-4-thiazolidinone fragment in combination, for example, with heterocycles [27,34,65,138,160] or other scaffolds [161,162] was discovered. Satisfactory toxicological parameters of such compounds may be an additional argument in favour of their development and study [163].…”

“…Further investigation led to N-substituted (aryl)alkylidenerhodanines synthesis which inhibit HCV NS3 protease and also are good inhibitors of other serine proteases (chymotrypsin and plasmin). But, the selectivity of some compounds (162,163) (Scheme 82) with bulkier C5 fragments bearing hydrophobic functional groups as well as simple analogs (164e166) (Scheme 82) was increased by ten fold towards HCV NS3 protease respectively [39].…”

Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor

“…Overall, however, rhodanine-containing compounds are often associated with off-target effects. 17,18 …”

Sulfenyl Ynamides in Gold Catalysis: Synthesis of Oxo‐functionalised 4‐aminoimidazolyl Fused Compounds by Intermolecular Annulation Reactions

“…Knoevenagel reaction on 8 afforded 5‐benzylidene and 5‐(2‐bromobenzylidene) products 9 a / b . Inverting the order of the synthetic sequence was similarly productive ( 5 → 10 → 9 a ), and this latter approach was also applicable to hydantoin 6 . S ‐Methylation of the Knoevenagel product 11 was followed by a regioselective N ‐alkylation prior to formation of the aminide 15 (Scheme )…”