Abstract
Based on the data about structure and antidiabetic activity of twenty seven vanadium and zinc coordination complexes collected from literature we developed QSAR models using the GUSAR program. These QSAR models were applied to 10 novel vanadium coordination complexes designed in silico in order to predict their hypoglycemic action. The five most promising substances with predicted potent hypoglycemic action were selected for chemical synthesis and pharmacological evaluation. The selected coordination vanadium complexes were synthesized and tested in vitro and in vivo for their hypoglycemic activities and acute rat toxicity. Estimation of acute rat toxicity of these five vanadium complexes was performed using a freely available web-resource (http://way2drug.com/GUSAR/acutoxpredict.html). It has shown that the selected compounds belong to the class of moderate toxic pharmaceutical agents, according to the scale of Hodge and Sterner. Comparison with the predicted data has demonstrated a reasonable correspondence between the experimental and predicted values of hypoglycemic activity and toxicity. Bis{tert-butyl[amino(imino)methyl]carbamato}oxovanadium (IV) and sodium(2,2′-Bipyridyl)oxo-diperoxovanadate(V) octahydrate were identified as the most potent hypoglycemic agents among the synthesized compounds.
Highlights
Vanadium is a biologically important element involved in numerous physiological processes
During the n-fold validation each compound may be used as a test compound only once, but during the multiple splitting validation each compound may be used as a test compound several times, which depends from splitting
The training sets were used for creation of Quantitative structure-activity relationships (QSAR) models and test sets for the assessment of external predictive accuracy
Summary
Vanadium is a biologically important element involved in numerous physiological processes. The presence of transition valence determines wide distribution of vanadium compounds in nature that are found only in chemically combined form. In particular organic derivatives, are effective oral insulinomimetics, which inhibit lipolysis, decrease blood glucose levels (BGL) in animals and in clinical trials, and stimulate insulin secretion in experimental models of Diabetes Mellitus (DM) [1,2,3,4,5]. According to the Integrity database (http://integrity.thomsonpharma.com), vanadium compounds have been developed as drugs for treatment of Diabetes, Hypertension, Ischemia and Myocardial Stroke. The major problem limiting further clinical applications of inorganic vanadium compounds is a low oral absorption (1–10%) Mechanisms of the insulin mimetic effect of vanadium complexes still have to be clarified, their ability to sensitize peripheral tissues to insulin and to reduce insulin resistance attracts significant attention in the context of their potential use for the treatment of Diabetes Type 1 (DM1), Diabetes Type 2 (DM2) and obesity [6,7].
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