Facile 3-chloro-1H-indazole based 1,3,4-thiadiazole derivatives as novel thymidine phosphorylase and anti-diabetic inhibitors: Experimental, in-vitro and molecular modelling approaches

A series of novel 3-chloro-1H-indazole-based 1,3,4-thiadiazole derivatives (1-15) were synthesized, characterized and evaluated for their inhibitory activity against thymidine phosphorylase and α-glucosidase. Several compounds showed potent dual inhibition, with compound 4 exhibiting the highest activity (IC₅₀ = 4.70 ± 1.34 µM for thymidine phosphorylase and IC₅₀ = 1.38 ± 0.46 µM for α-glucosidase), surpassing the standard inhibitors 7-deazaxanthine (IC₅₀ = 12.42 ± 1.27 µM) and acarbose (IC₅₀ = 5.97 ± 0.35 µM). Moreover, other synthesized derivatives included compounds 9, 2, 1 and 6 all showing improved inhibition profiles. Structure activity relationship analysis revealed that the nature and position of substituents on the phenyl ring play a critical role in modulating the enzyme inhibition potential. Similarly, molecular docking confirmed favorable binding interactions with the active sites of both enzymes, while ADMET profiling indicated good drug-likeness and pharmacokinetic potential. These findings suggest that thiadiazole-indazole hybrids represent promising lead candidates for the development of dual targets enzymes inhibitors with potential therapeutic applications in metabolic and proliferative disorders.