title: 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.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore , 18 Science Drive 4, Singapore 117543.
authors.forename: Shi Qing
authors.initials: SQ
authors.lastname: Tang
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore , 18 Science Drive 4, Singapore 117543.
authors.forename: Yong Yang Irvin
authors.initials: YY
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore , 18 Science Drive 4, Singapore 117543.
authors.forename: David Sheela
authors.initials: DS
authors.lastname: Packiaraj
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore , 18 Science Drive 4, Singapore 117543.
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore , 18 Science Drive 4, Singapore 117543.
authors.forename: Christina Li Lin
authors.initials: CL
authors.lastname: Chai
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005978:Glutathione / Q000378:metabolism; D006207:Half-Life; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D048289:Imidazolidines / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D008862:Microsomes, Liver / Q000378:metabolism; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity
chemical_list: D007004:Hypoglycemic Agents; D048289:Imidazolidines; D045162:Thiazolidinediones; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione