Repository logo

Structure-activity relationship studies of anti-diabetic dioxidovanadium(V) benzimidazole complexes.

Thumbnail Image



Journal Title

Journal ISSN

Volume Title



Organovanadium compounds have been widely investigated for the potential use in Diabetes Mellitus. However, most of these metal complexes has failed during studies using in vivo Streptozotocin (STZ)-diabetic rat models and human clinical trials. For candidate vanadium-based insulin enhancing agents to meet the stringent demands of the United States of America’s Federal Agency of Food and Drug Administration, these metal complexes should be benign to healthy cells, should pose a target-specific biodistribution as well as illustrate optimal and prolonged control of blood-glucose levels. In the first experimental chapter, the synthesis and characterization of new derivatives of the metal-based drugs (viz. cis-[VO2(Hpybz)(pybz)] (1) (Hpybz = 2-pyridyl-1H-benzimidazole) and cis-[VO2(obz)py] (2) (Hobz = 2-hydroxyphenyl-1H-benzimidazole) is described and discussed. The novel and potential metal-based anti-diabetic drugs, cis-[VO2(Hmpybz)(mpybz)] (3) and cis-[VO2(mobz)py] (4) constitute a structure-activity relationship study. The metal complexes were characterized via various spectroscopic techniques, high resolution mass spectrometry and structural elucidations were confirmed using single crystal X-ray analysis and elemental analysis. In the second experimental chapter, the CT-DNA UV/Visible absorption spectroscopic titration studies of 1 - 4 were conducted. The results revealed that these metal complexes exhibit low binding affinities with intrinsic binding constants (Kb) in the order 103 M-1. BSA emission spectroscopic titrations showed high BSA apparent association constants and quenching constants (Ka and KSV) > 106 M-1. The binding strengths of the individual metal complexes onto one of the key enzyme, Protein Tyrosine Phosphatase (PTP)-1B which is involved in insulin production were evaluated using fluorescence emission spectroscopy. Affinities of the pro-drugs 1 and 2 as well as their analogues towards Protein Tyrosine Phosphatase were monitored using various physicochemical techniques. The in vitro inhibitory activities of 1 and 4 were classed as non-significant since they afforded relatively low PTP-1B inhibitory activities relative to the untreated enzyme (viz. basal/control agent). Compounds 2 and 3 showed significant PTP-1B inhibition activity when compared to the basal. However, compound 3 exhibited the most significant lowering of the in vitro PTP-1B enzymatic activity with binding strength Kb of 3.9 × 103 M-1 and affinity constant KSV = 9.0 × 104 M-1. The glycolytic flux assays flux proved that compounds 2 and 3 inhibit the rate of glycolysis based on the rate of the lactate products. The glucose consumption assays also revealed that via the potential inhibition of PTP1B, the glucose turnover is increased in HEK293T cells.


Masters Degree. University of KwaZulu-Natal, Pietermaritzburg.