Quinoline-thiosemicarbazone-1,2,3-triazole-acetamide derivatives as new potent α-glucosidase inhibitors

Abstract

In this work, a novel series of quinoline-thiosemicarbazone-1,2,3-triazole-aceamide derivatives 10a-n as new potent α-glucosidase inhibitors was designed, synthesized, and evaluated. All the synthesized derivatives 10a-n were more potent than acarbose (positive control). Representatively, (E)-2-(4-(((3-((2-Carbamothioylhydrazineylidene)methyl)quinolin-2-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-phenethylacetamide (10n), as the most potent entry, with IC₅₀ = 48.4 µM was 15.5-times more potent than acarbose. According to kinetic study, compound 10n was a competitive inhibitor against α-glucosidase. This compound formed the desired interactions with important residues of the binding pocket of α-glucosidase with favorable binding energy in the molecular docking and molecular dynamics. Compounds 10n, 10e, and 10 g as the most potent compounds among the synthesized compounds were evaluated in term of pharmacokinetics and toxicity via online servers. These evaluations predicted that compounds 10n, 10e, and 10 g had good pharmacokinetic properties and toxicity profile.

Keywords: 1,2,3-Triazole; Quinoline; Thiosemicarbazone; α-Glucosidase inhibitors.

Fig. 1

Structures and inhibitory activities of the reported compounds A-C that were used in the design of quinoline-thiosemicarbazone-1,2,3-triazole-aceamide skeleton as a new scaffold with anti-α-glucosidase property.

Fig. 2

Synthesis of quinoline-thiosemicarbazone-1,2,3-triazole-aceamide derivatives 10a-n: (a) K₂CO₃, Aceton, RT, 1 h; (b) DMF, RT, 1 h; (c) Et₃N, H₂O/t-BuOH, RT, 1 h; (d) CuSO₄·5H₂O, Sodium ascorbate, RT, 24–48 h; (e) Methanol, Acetic acid, Reflux, 4 h.

Fig. 3

The proposed reaction mechanism for the formation of quinoline-thiosemicarbazone-1,2,3-triazole-aceamide derivatives 10a-n.

Fig. 4

Diagram of SAR of compounds 10a-m against α-glucosidase.

Fig. 5

Comparison of α-glucosidase inhibitory activity between template compounds A, B1 and C1 with the most potent new compound 10n.

Fig. 6

(a) Lineweaver–Burk plot for compound 10n (the concentrations of compound 10n were 0, 12.1, 24.2, and 48.4 µM. (b) Secondary re-plot of slopes of Lineweaver–Burk plot vs various concentrations of the compound 10n.

Fig. 7

Acarbose (cyan) and the most potent compound 10n (pink) superimposed in the α-glucosidase active site.

Fig. 8

Interaction modes of acarbose and the most potent compounds 10n, 10e, and 10 g in the active site of α-glucosidase.

Fig. 9

Superimposed structure of acarbose (cyan) and the most potent compound 10n (pink) in the human α-glucosidase active site.

Fig. 10

Interaction modes of acarbose and the most potent compound 10n in the active site of human α-glucosidase.

Fig. 11

Superimposed RMSD of Cα atoms of α-glucosidase in complex with 10n (blue) and acarbose (red) (A). Superimposed RMSD of 10n (blue) and acarbose (red) in complex with α-glucosidase (B). Time dependence of the radius of gyration (Rg) graph of α-glucosidase in complex with 10n (blue) and acarbose (red) (C).

Fig. 12

(A) RMSF graph of the Cα atoms of α-glucosidase in complex with 10n (blue) and acarbose (red). Close-up representation of α-glucosidase active site (B). RMSF graph of the heavy atoms of 10n (C) and acarbose (D) in complex with α-glucosidase. Structure of these compounds are illustrated.