Imidazo[1,2-c]quinazolines as a novel and potent scaffold of α-glucosidase inhibitors: design, synthesis, biological evaluations, and in silico studies

Abstract

α-Glucosidase inhibition is an approved treatment for type 2 diabetes mellitus (T2DM). In an attempt to develop novel anti-α-glucosidase agents, two series of substituted imidazo[1,2-c]quinazolines, namely 6a-c and 11a-o, were synthesized using a simple, straightforward synthetic routes. These compounds were thoroughly characterized by IR, ¹H and ¹³C NMR spectroscopy, as well as mass spectrometry and elemental analysis. Subsequently, the inhibitory activities of these compounds were evaluated against Saccharomyces cerevisiae α-glucosidase. In present study, acarbose was utilized as a positive control. These imidazoquinazolines exhibited excellent to great inhibitory potencies with IC₅₀ values ranging from 12.44 ± 0.38 μM to 308.33 ± 0.06 μM, which were several times more potent than standard drug with IC₅₀ value of 750.0 ± 1.5 μM. Representatively, compound 11j showed remarkable anti-α-glucosidase potency with IC₅₀ = 12.44 ± 0.38 μM, which was 60.3 times more potent than positive control acarbose. To explore the potential inhibition mechanism, further evaluations including kinetic analysis, circular dichroism, fluorescence spectroscopy, and thermodynamic profile were carried out for the most potent compound 11j. Moreover, molecular docking studies and in silico ADME prediction for all imidazoquinazolines 6a-c and 11a-o were performed to reveal their important binding interactions, as well as their physicochemical and drug-likeness properties, respectively.

Figure 1

α-Glucosidase inhibitors bearing substituted quinazolines A–F and substituted imidazoles G–L. The IC₅₀ values are written in black for inhibitors and red for acarbose.

Figure 2

Design strategy toward two series substituted imidazo[1,2-c]quinazolines. The IC₅₀ values are written in black for inhibitors and red for acarbose.

Scheme 1

Synthesis of substituted imidazo[1,2-c]quinazolines 6a–c and 11a–o.

Figure 3

Kinetics of α-glucosidase inhibition by sample 11j: (A) the Lineweaver–Burk plot in the absence and presence of different concentrations of sample 11j; (B) the secondary plot between K_m and various concentrations of sample 11j.

Figure 4

Circular dichroism (CD) spectra of the α-glucosidase: (A) in the absence of inhibitor (control); (B) in the presence of imidazoquinazoline 11j.

Figure 5

Fluorescence spectra of α-glucosidase: (A) in the absence of compound 11j at 20–60 ℃, (B) in the presence of compound 11j at inhibitory concentration (12.4 µM) at 20–60 ℃.

Figure 6

The plots F₀/F Vs. function of [D_t] F₀/(F₀−F) at 20 ℃ for imidazoquinazoline 11j.

Figure 7

Interactions and structures of (a) compound 6a and (b) compound 11a in the binding pocket of human acid-α-glucosidase visualized using PyMOL 2.5.2 and PLIP online service.

Figure 8

The interactions and structure of compound 11j in the binding pocket of human acid-α-glucosidase (it must be noted that the hydrogen bond and hydrophobic interactions are displayed in blue color and dashed lines, respectively).

Figure 9

Superimposition of acarbose and compound 11j in the binding pocket of human acid-α-glucosidase. Acarbose is colored in blue, and compound 11j is colored in red.

Figure 10

Compounds 6a–c and 11a–o were examined by the boiled-egg method available on SWISS ADME.