A family of amphiphilic dioxidovanadium(V) hydrazone complexes as potent carbonic anhydrase inhibitors along with anti-diabetic and cytotoxic activities

A family of dioxidovanadium(V) complexes (1–4) of the type [Na(H₂O)_x]⁺[V^VO₂(HL¹⁻⁴)]⁻ (x = 4, 4.5 and 7) where HL²⁻ represents the dianionic form of 2-hydroxybenzoylhydrazone of 2-hydroxyacetophenone (H₂L¹, complex 1), 2-hydroxy-5-methylacetophenone (H₂L², complex 2), 2-hydroxy-5-methoxyacetophenone (H₂L³, complex 3) and 2-hydroxy-5-chloroacetophenone (H₂L⁴, complex 4), have been synthesized and characterized by analytical and spectral methods. These complexes exhibited the potential abilities to suppress the erythrocytes carbonic anhydrase enzymatic activity in type 1 and type 2 diabetic patients (in vitro), promising antidiabetic activity against T2 diabetic mice (in vivo). They also exhibited significant cytotoxic activity against cervical cancer (SiHa) cells (in vitro) as the IC₅₀ value of complexes 1, 2 and 4 is substantially lower than the value found for cisplatin while that of 3 is comparable and follow the order: 4 < 1 < 2 < 3 and can kill the cells by apoptosis via the generation of reactive oxygen species (ROS). The complexes are soluble both in water and octanol media and also non-toxic at working concentrations. The antidiabetic activity of these four complexes follows the order: 4 > 2 > 1 > 3 while both the carbonic anhydrase and cytotoxic activity follow the order: 4 > 1 > 2 > 3 suggesting that complex 4, containing electron withdrawing Cl atom is the most reactive while 3 with electron donating OCH₃ group is the least reactive species. The molecular docking study on hCA-I and hCA-II demonstrates that complexes interact via hydrogen bonding as well as different types of π-stacking.