Synthesis, crystal structure, and insulin-mimetic activity of zinc(ii) complexes with 4-alkyl- and 4,5-dialkyl-3-hydroxythiazole-2(3H)-thiones as a new class of hypoglycemic agent candidates†

Abstract

The development of potent hypoglycemic zinc complexes is important for treating diabetes mellitus. In this study, 3-hydroxythiazole-2(3H)-thiones (3,2-HTTs) with alkyl groups at the 4- and 4,5-positions were synthesized, and the insulin-mimetic activities of their zinc(II) complexes were evaluated by determining the 50% inhibitory concentration (IC₅₀) of free fatty acids released from isolated rat adipocytes treated with epinephrine. The structures of the complexes were unambiguously determined by means of X-ray crystallographic analyses. The IC₅₀ values of the newly synthesized complexes with 4,5-dialkyl-3,2-HTTs ranged from 16 to 24 μM, indicating higher inhibitory activities than those of previously reported 4-aryl-3,2-HTT-zinc(II) complexes (30–44 μM). The correlation between some properties of the complexes showed that complexes with smaller sizes tended to have higher insulin-mimetic activity. Besides, for all complexes, the stability constant were estimated to be less than 10.5, confirming the usefulness of the stability constant as a parameter for identifying zinc(II) complexes with high insulin-mimetic activity.