Complexes of hydroxy(thio)pyrone and hydroxy(thio)pyridinone with Zn(II) and Mo(VI). Thermodynamic stability and insulin-mimetic activity

The development of metal-containing pharmaceuticals as insulin-mimetics has been the object of recent worldwide research. We have examined a series of zinc(II) and molybdenum(VI) complexes with model O,S-donor ligands (thiomaltol and 1,2-dimethyl-3-hydroxypyridine-4-thione (DMHTP)) and the corresponding O,O-analogues (maltol and DMHP) for their insulin-mimetic activity. Aimed at getting structure-activity relationships, some physical-chemical properties were also studied, such as metal-complex formation, speciation at different pH conditions and ligand lipophilicity. The Zn-complexes exhibit considerably higher insulin-mimetic activity than the corresponding Mo-analogues. Particularly, the bis(thiomaltolato)zinc(II) complex reveals a very high activity, ascribed to the effect of the thione pi character and to the soft nature of the sulfur donor atom enhancing the Zn(II)-ligand affinity and the ligand/complex lipophilicity, two determinant parameters for delivering the metal-drug into the cells. Hence, these preliminary studies indicate that the Zn(thiomaltol)(2) complex can be considered a potential drug candidate for treatment of diabetes mellitus, upon in vivo evaluations.