Synthesis, characterization, in vitro biological and computational evaluation of 5-benzyl-4-(benzylideneamino)-2H-1,2,4-triazole-3(4H)-thiones

Abstract

Triazoles and their heterocyclic analogues are nitrogen-rich versatile pharmacophores easily synthesized and converted to a range of biologically relevant heterocycles. In this context, the present research reports the synthesis, characterization, in vitro antioxidant, cytotoxic and α-glucosidase inhibitory potential of 4-amino-5-benzyl-2H-1,2,4-triazol-3(4H)-thione (3) and 5-benzyl-4-(benzylideneamino)-2H-1,2,4-triazole-3(4H)-thiones 5(a–g). Consequently, the percent DPPH free radical scavenging ability was found to be in the decreasing order of 5 g > 5e > 3 > 5d > 5b > 5c > 5a > 5f. The most potent derivatives (5 g), (5e) and (3) showed significant dose-dependent scavenging ability with IC50 values of 61.22, 74.06 and 94.87 µg/ml, respectively. The antioxidant derivatives were screened in brine shrimp lethality as well as protein kinase inhibitory assay to unveil their toxic nature. The percent mortality was found to be decreasing in the order of 5b > 5f > 3 > 5a > 5 g > 5d > 5e > 5c at 200 µg/ml in brine shrimp lethality assay. Accordingly, three derivatives (5b), (3) and (5f) showed significant percent mortality with LC50 values of 25.88, 32.94 and 34.87 µg/ml, respectively. Similarly, in protein kinase inhibitory assay, maximum inhibitory potential was observed for the derivatives (5 g), (3) and (5e) with MIC values of 50 µg/disc in each case. Likewise, in α-glucosidase inhibition assay, the screened derivatives (3) and (5e) showed notable percent α-glucosidase inhibition (66.78 and 55.15%) with IC50 value of 36.11 µg/ml and 60.33 µg/ml, respectively. Molecular docking studies of the screened derivatives were performed in order to assess their binding potential and mechanism of their binding with α-glucosidase, α-kinase and β-kinase enzymes. Docking simulation revealed that the molecules stabilize themselves inside the active site by establishing non-covalent interactions with critical residues. Noteworthy were the derivatives (3) and (5e) which anchored themselves through various significant electrostatic interactions with the critical residues.