1 research outputs found
Systematic Evaluation of the Metabolism and Toxicity of Thiazolidinone and Imidazolidinone Heterocycles
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
(<i>t</i><sub>1/2</sub> < 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