18345-22-7Relevant articles and documents
Discovery of Mcl-1 inhibitors based on a thiazolidine-2,4-dione scaffold
Whiting, Ellis,Raje, Mithun R.,Chauhan, Jay,Wilder, Paul T.,Van Eker, Daniel,Hughes, Samuel J.,Bowen, Nathan G.,Vickers, Gregory E.A.,Fenimore, Ian C.,Fletcher, Steven
, p. 523 - 528 (2018)
Inspired by a rhodanine-based dual inhibitor of Bcl-xL and Mcl-1, a focused library of analogues was prepared wherein the rhodanine core was replaced with a less promiscuous thiazolidine-2,4-dione scaffold. Compounds were initially evaluated for their abilities to inhibit Mcl-1. The most potent compound 12b inhibited Mcl-1 with a Ki of 155 nM. Further investigation revealed comparable inhibition of Bcl-xL (Ki = 90 nM), indicating that the dual inhibitory profile of the initial rhodanine lead had been retained upon switching the heterocycle core.
Synthesis and structure-activity-relationship studies of thiazolidinediones as antiplasmodial inhibitors of the Plasmodium falciparum cysteine protease falcipain-2
Sharma, Rajni Kant,Younis, Yassir,Mugumbate, Grace,Njoroge, Mathew,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
, p. 507 - 518 (2015/02/19)
Following a structure-based virtual screening, a series of 2,4 thiazolidinediones was synthesized in order to explore structure activity relationships for inhibition of the Plasmodium falciparum cysteine protease falcipain-2 (FP-2) and of whole cell antiparasitic activity. Most compounds exhibited low micromolar antiplasmodial activities against the P. falciparum drug resistant W2 strain. The most active compounds of the series were tested for in vitro microsomal metabolic stability and found to be susceptible to hepatic metabolism. Subsequent metabolite identification studies highlighted the metabolic hot spots. Molecular docking studies of a frontrunner inhibitor were carried out to determine the probable binding mode of this class of inhibitors in the active site of FP-2.
Systematic Evaluation of the Metabolism and Toxicity of Thiazolidinone and Imidazolidinone Heterocycles
Tang, Shi Qing,Lee, Yong Yang Irvin,Packiaraj, David Sheela,Ho, Han Kiat,Chai, Christina Li Lin
, p. 2019 - 2033 (2015/11/02)
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.
