Novel rhodanine–thiazole hybrids as potential antidiabetic agents: a structure-based drug design approach

New rhodanine-thiazole clubbed compounds (7a-7l) were synthesised and characterised with various spectroscopy methods. The synthesised hybrids underwent <i>in vitro</i> HPA, HLAG inhibition, and peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression assays. Through the biological study, compound 7f showed promising inhibitory activity against HPA with an IC₅₀ value of 27.13 ± 1.02 μM and 7l exhibited better inhibition against HLAG with an IC₅₀ value of 24.21 ± 1.12 μM. In addition, Lineweaver-Burk plot analysis suggested that 7l and 7f behaved as a mixed type of HLAG and HPA inhibitor and further, compound 7f showed significant PPAR-γ expression as compared to controls in a dose dependent manner; the expression can be attributed to its mapped pharmacophoric features with a phase screen score of 1.28 and vector score of 0.62. The proteins modulated by compounds include <i>AMY2A</i>, <i>PPAR</i>, and <i>GAA</i> proteins <i>via MAPK</i>, <i>PPAR</i> signalling pathways identified by cluster analysis and justified by molecular docking studies and MD trajectory analysis to evaluate the binding orientation and stability of the molecules, and the energy profiles of the molecules, both in complex with the protein, were assessed using MM/GBSA and DFT calculations, respectively. Finally, the pharmacokinetic profile was determined using ADMET analysis. Thus, from the above findings, it may demonstrate that rhodanine-thiazole hybrids constitute promising candidates in the pursuit of developing newer oral antidiabetic agents.