Synthesis, ADMT prediction, and in vitro and in silico α-glucosidase inhibition evaluations of new quinoline-quinazolinone-thioacetamides

Abstract

In this work, a new series of quinoline-quinazolinone-thioacetamide derivatives 9a-p were designed using a combination of effective pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized by simple chemical reactions and evaluated for their anti-α-glucosidase activity. Among the tested compounds, compounds 9a, 9f, 9g, 9j, 9k, and 9m demonstrated significant inhibition effects in comparison to the positive control acarbose. Particularly, compound 9g with inhibitory activity around 83-fold more than acarbose exhibited the best anti-α-glucosidase activity. Compound 9g showed a competitive type of inhibition in the kinetic study, and the molecular simulation studies demonstrated that this compound with a favorable binding energy occupied the active site of α-glucosidase. Furthermore, in silico ADMET studies of the most potent compounds 9g, 9a, and 9f were performed to predict their drug-likeness, pharmacokinetic, and toxicity properties.

Fig. 1. Design strategy for the new designed compounds as the potent α-glucosidase inhibitors.

Scheme 1. Synthesis pathway of compounds 9a–p.

Scheme 2. Anti-α-glucosidase activity of acridine–thioacetamides C and their corresponding analogs of the new quinoline–quinazolinone–thioacetamide derivatives 9.

Scheme 3. Comparison of α-glucosidase inhibitory activity of benzimidazole derivatives D with their corresponding analogs of the newly synthesized quinazolinone derivatives 9.

Fig. 2. Inhibitory kinetics of compound 9g on α-glucosidase. (a) Lineweaver–Burk plots for inhibition of compound 9g. (b) The secondary plot of Lineweaver–Burk plots for determination K_i value of compound 9g.

Fig. 3. 3D and 2D interaction modes of the most potent compounds 9g and 9a in the active site of α-glucosidase.

Fig. 4. 3D and 2D interaction modes of the most potent compounds 9f and 9k in the active site of α-glucosidase.

Fig. 5. Superimposed RMSD of Cα atoms of α-glucosidase in complex with 9g (red) and acarbose (indigo).

Fig. 6. Superimposed RMSD of 9g (red) and acarbose (indigo) in complex with α-glucosidase.

Fig. 7. (A) RMSF graph of the Cα atoms of α-glucosidase in complex with acarbose (indigo) and 9g (red). (B) Close-up representation of α-glucosidase active site.

Fig. 8. RMSF graph of the heavy atoms of 9g (A) and acarbose (B) in complex with α-glucosidase. Structure of these compounds and parts of these molecules with greatest fluctuations are illustrated.

Fig. 9. Time dependence of the radius of gyration (R_g) graph of α-glucosidase in complex with 9g (red) and acarbose (indigo).