Convergent synthesis, kinetics insight and allosteric computational ascriptions of thiazole-(5-aryl)oxadiazole hybrids embraced with propanamides as alkaline phosphatase inhibitors

Abstract

Considering the varied pharmacological prominence of thiazole and oxadiazole heterocyclic moieties, a unique series of bi-heterocyclic hybrids, 8a–h, was synthesized in a convergent manner. The structures of newly synthesized compounds were characterized by ¹H-NMR, ¹³C-NMR, and IR spectral studies. The structure–activity relationship of these compounds was predicted by examining their inhibitory effects against alkaline phosphatase, whereby all these molecules exhibited superb inhibitory potentials relative to the standard used. The kinetics mechanism was determined by Lineweaver–Burk plots which revealed that 8g inhibited the studied enzyme non-competitively by forming an enzyme-inhibitor complex. The inhibition constant K_i calculated from Dixon plots for this compound was 0.42 μM. The allosteric computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal mol⁻¹). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules have potential to be nontoxic medicinal scaffolds for the treatment of alkaline phosphate-associated ailments.