Five neutral heteroleptic mononuclear vanadium(IV) hydrazone complexes ([VOL(bpy)]), derived from 2-hydroxy-5-methylacetophenone and various acid hydrazides (furoic, thiophene, benzoic, nicotinic, and isoniazid), were synthesized and shown to exhibit improved antidiabetic efficacy in streptozotocin-induced diabetic rats, with reduced toxicity and minimal bioaccumulation compared to maltolato- and picolinato-based vanadium species. Structural identity was established by spectroscopic methods. Crystal structures were obtained for four complexes, providing insight into their solid-state chemistry. Stability studies in simulated intestinal and gastric fluids showed that the complexes largely retained their integrity under intestinal conditions, whereas decomposition occurred in the highly acidic gastric environment within several minutes. In vivo experiments revealed a structure-antihyperglycemic activity relationship. The nicotinic-containing complex showed the highest activity, reducing blood glucose levels by 67% within 7 days of treatment, while the remaining complexes improved glycemic control by more than 50%. Bioaccumulation studies demonstrated <1.1% uptake in the liver and kidneys and negligible accumulation in the brain. The presented vanadium compounds enhance antidiabetic potential by addressing key limitations, particularly bioaccumulation and toxicity, associated with vanadium agents previously evaluated in clinical trials.

Four new heteroleptic neutral paramagnetic mononuclear oxidovanadium(IV) complexes, designated as [VOL(phen)], where L corresponds to acetophenone isoniazid hydrazone or its 5-halogenated derivatives and phen stands for 1,10-phenanthroline, were synthesized and thoroughly characterized using chemical analysis, various spectroscopic techniques, and diffraction methods. Single-crystal X-ray diffraction revealed the molecular and crystal structures of two complexes, showing an octahedral coordination environment around the vanadium(IV) center. The coordination includes a tridentate ONO donor hydrazone ligand in its deprotonated enol-imine form, 1,10-phenanthroline as a bidentate NN donor ternary ligand, and one terminal oxygen atom. The biochemical and hematological effects of these complexes were evaluated in a streptozotocin-induced diabetic rat model. All synthesized complexes showed cholesterol-lowering effects compared to the diabetic rat group, with the vanadium complex lacking a substituent on the acetophenone ring of hydrazone showing the strongest effect. Complexes exhibited comparable and significant antidiabetic activity in vivo, effectively reducing hyperglycemia within 1 week of treatment. Additionally, the histopathological effects of complex (4) on liver, kidney, and brain tissues were investigated. All four complexes were found to have low bioaccumulation levels, with total absolute bioaccumulation in all tested organs less than 0.35% of the administered dose.

Wet synthesis approach afforded four new heteroleptic mononuclear neutral diamagnetic oxidovanadium(V) complexes, comprising salicylaldehyde-based 2-furoic acid hydrazones and a flavonol coligand of the general composition [VO(fla)(L-ONO)]. The complexes were comprehensively characterized, including chemical analysis, conductometry, infrared, electronic, and mass spectroscopy, as well as 1D 1H and proton-decoupled 13C(1H) NMR spectroscopy, alongside extensive 2D 1H1H COSY, 1H13C HMQC, and 1H13C HMBC NMR analyses. Additionally, the quantum chemical properties of the complexes were studied using Gaussian at the B3LYP, HF, and M062X levels on the 6-31++g(d,p) basis sets. The interaction of these hydrolytically inert vanadium complexes and the BSA was investigated through spectrofluorimetric titration, synchronous fluorimetry, and FRET analysis in a temperature-dependent manner, providing valuable thermodynamic insights into van der Waals interactions and hydrogen bonding. Molecular docking was conducted to gain further understanding of the specific binding sites of the complexes to BSA. Complex 2, featuring a 5-chloro-substituted salicylaldehyde component of the hydrazone, was extensively examined for its biological activity in vivo. The effects of complex administration on biochemical and hematological parameters were evaluated in both healthy and diabetic Wistar rats, revealing antihyperglycemic activity at millimolar concentration. Furthermore, histopathological analysis and bioaccumulation studies of the complex in the brain, kidneys, and livers of healthy and diabetic rats revealed the potential for further development of vanadium(V) hydrazone complexes as antidiabetic and insulin-mimetic agents.