An Ongoing Search for Multitarget Ligands as Potential Agents for Diabetes Mellitus and Its Long-Term Complications: New Insights into (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic Acid Derivatives

<b>Background</b>: Diabetes mellitus is a multifactorial disease characterized by complex metabolic dysfunctions and chronic complications induced by hyperglycaemia. The design of multitarget ligands, capable of simultaneously controlling different pathogenic processes, was proposed as a promising approach to identify novel antidiabetic drugs endowed with improved efficacy. <b>Methods</b>: (5-Arylidene-4-oxothiazolidin-3-yl)alkanoic acid derivatives <b>1a</b>-<b>g</b> and <b>2a</b>-<b>g</b> were synthesized as potential multitarget antidiabetic agents. They were tested in vitro as inhibitors of both human recombinant AKR1B1 and PTP1B, and kinetic studies and molecular docking simulations for both enzymes were performed. Their effects on cellular glucose uptake, insulin signalling, and mitochondrial potential were assayed in cultures of murine C2C12 myocytes. A lipid accumulation assay was performed in HepG2 liver cells. The effects on high glucose-induced sorbitol accumulation were evaluated in lens HLE and retinal MIO-M1 cells. <b>Results</b>: All compounds displayed excellent AKR1B1 inhibitory activity (IC₅₀ 0.03-0.46 μM <b>1a</b>-<b>g</b>; IC₅₀ 0.48-6.30 μM <b>2a</b>-<b>g</b>); <b>1g</b> and <b>2e</b>-<b>g</b> also appreciably inhibited PTP1B at micromolar concentrations. Propanoic derivatives <b>2e</b>-<b>g</b> significantly stimulated glucose uptake in C2C12 myocytes, in an insulin-independent way, reduced lipid accumulation in HepG2 liver cells, and caused hyperpolarization of C2C12 mitochondria at 10 μM concentration. Derivative <b>2e</b> significantly reduced sorbitol accumulation in both HLE and MIO-M1 cells at a 5 μM concentration. <b>Conclusions</b>: The results reported here provided new insights into the mechanisms of action and structure/activity relationships of 4-thiazolidinone derivatives, underscoring the capability of compounds <b>2e</b>-<b>g</b> of eliciting insulin-mimetic effects independent of hormone signalling. Among them, compound <b>2e</b> also proved to inhibit AKR1B1-dependent sorbitol accumulation and, thus, emerged as a promising multitarget agent that can be considered for further investigations.