Design, Synthesis, In Vitro, and In Silico Studies of Some Newly Fused Thiadiazole and Thiadiazine Derivatives Incorporating 1,2,4-Triazole Derivatives as Aromatase Enzyme Inhibitor

Objective: A series of 4-amino-5-((2,4-substituted phenoxy)methyl)-4H-1,2,4-triazole-3-thiol derivatives (Ia-Ib) were synthesized and tested as aromatase enzyme inhibitor. Methods: 4-Amino-5-((2,4-substituted phenoxy)methyl)-4H-1,2,4-triazole-3-thiol derivatives (Ia-Ib) were synthesized via fusion of substituted phenoxycarboxylic acid derivatives with thiocarbohydrazide. Three series of the newly title compounds were prepared by reaction of (Ia-Ib) with aromatic acid derivatives in presence of POCl3 to give [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives (IIa-IIh) or by reaction with phenacyl bromide derivatives in presence of sodium acetate to produce [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives (IIIa-IIIh). Moreover, (Ia-Ib) were used as a precursor for synthesizing of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives (Va-Vd) by reaction with dibromochalcone compounds (IVa-IVb) in presence of triethylamine. The aromatase activities of the newly created compounds were examined. Results and Discussion: Seven triazoles were shown to have significant aromatase inhibitory activity (IC50 = 0.07-1.92 mu M). It's interesting to note that analogue (Vb), which substituted a p-chlorophenyl ring at the triazole ring, had the greatest aromatase-inhibitory action (IC50 = 70 mu M). Conclusions: The result of the present work indicated that compound (Vb) would be valuable as a potent anticancer agent. Moreover, docking study has been done into aromatase cytochrome P450 enzyme active site (PDB ID: 3EQM) for lead optimization of the aforementioned compounds as prospective tyrosine kinase inhibitors.