SAR and 3D-QSAR Studies on Thiadiazolidinone Derivatives:  Exploration of Structural Requirements for Glycogen Synthase Kinase 3 Inhibitors

Abstract

The 2,4-disubstituted thiadiazolidinones (TDZD) are described as the first ATP-noncompetitive GSK-3 inhibitors. Following an SAR study about TDZD, different structural modifications in the heterocyclic ring aimed to test the influence of each heteroatom on the biological study are here reported here. Various compounds such as hydantoins, dithiazolidindiones, rhodanines, maleimides, and triazoles were synthesized and screened as GSK-3 inhibitors. After an extensive SAR study among these different heterocyclic families, TDZDs have been revealed as a privileged scaffold for the selective inhibition of GSK-3. A CoMFA analysis was also performed highlighting the molecular electrostatic field interaction in the interaction of TDZDs with GSK-3. Moreover, first mapping studies indicate two binding modes which in turn might imply relevant differences in the mechanism that underly the inhibitory activity of TDZDs.

Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by Tideglusib

“…This was evidenced by the lack of recovery of enzymatic activity once the unbound drug was removed, but also by the extremely low value of the dissociation rate constant k 4 , which was not significantly different from zero. Such irreversibility may explain the apparent non-competitive pattern with respect to ATP (54) that has been obtained in double titrations and had also been previously reported for other TDZDs (31,34). Thus, it is not possible to derive a straightforward conclusion from such an inhibitory pattern (e.g.…”

“…46 for a detailed review). Nonetheless, the results obtained in classical molecular interaction potential mapping studies led some authors to suggest that TDZDs may bind covalently to GSK-3␤ through its Cys-199 residue (34). Consequently, we believed it appropriate to investigate whether this hypothesis was true and whether such covalent binding took place and was responsible for the irreversible inhibition of GSK-3␤ caused by tideglusib.…”

Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8)

“…These studies included analysis of the compound TDZD-8 (4-benzyl,2-methyl,1,2,4-thiadiazolidine, 3,5 dione), which was originally developed as a non-ATP competitive inhibitor of GSK-3␤. 23,24 To date, TDZD-8 has been evaluated primarily as a cytoprotective agent in multiple rodent models for maladies such as septic and nonseptic shock, lung injury, arthritis, spinal cord injury, colitis, and Alzheimer disease. [25][26][27][28][29][30][31][32][33] However, in the present study we describe an entirely new activity for TDZD-8, which thus far appears to be restricted to cells derived from hematologic malignancies.…”

Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols

“…A lead series may involve a key chiral intermediate, which may be prepared through chiral starting materials, asymmetric synthesis, asymmetric enzymatic transformation, chiral salt resolution, or preparative enantiomeric separation. [1][2][3][4][5][6][7][8][9][10][11] Critical to understanding fully the structure-activity relationships (SAR) [12][13][14] and structure-property relationships (SPR) [15][16][17][18][19] often based on ''pharmaceutical profiling'' 20 is knowing the absolute stereochemistry of each analog prepared or separated, and being able to track the absolute stereochemistry to the final product with the desired biological activity profile (eutomer) and desirable drug-like properties, instead of the undesired profile (distomer). 21,22 Idealized steps in drug discovery can be summarized as follows:…”