A simple and cheap three-step procedure for the synthesis of three (5Z)-5-[3(4)-(1H-benzimidazol-2-ylmethoxy)benzylidene]-1,3-thiazolidine-2,4-diones has been described via a SN2 reaction of generally recognized as safe hydroxybenzaldehydes and 2-(chloromethyl)-1H-benzimidazole, followed by a Knoevenagel condensation with thiazolidine-2,4-dione in moderated yields. All the newly synthesized compounds were characterized using analytical and spectral studies. In vitro treatment on adipocytes with compounds increased the mRNA expression of two proteins recognized as strategic targets in diabetes: PPARγ and GLUT-4. In silico studies were conducted in order to explain the interaction binding mode of the synthesized compounds on PPARγ. In vivo studies confirmed that compounds 1–3 have robust antihyperglycemic action linked to insulin sensitization mechanisms. The present study provides three compounds with a promising antidiabetic action.
Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation.
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