Design, synthesis, biological evaluation and computational studies of 4-Aminopiperidine-3, 4-dihyroquinazoline-2-uracil derivatives as promising antidiabetic agents

Abstract

A novel series of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives (9a-9 L) were logically designed and synthesized as potent DPP4 inhibitors as antidiabetic agents. Chemical structure of all new compounds were confirmed by different spectroscopic methods. The designed compounds were evaluated using a MAK 203 kit as DPP4 inhibitors in comparison with Sitagliptin. The biological evaluation revealed that compound 9i bearing chloro substitution on phenyl moiety of 6-bromo quinazoline ring had promising inhibitory activity with IC₅₀ = 9.25 ± 0.57 µM. The toxicity test of all compounds confirmed safety profile of them. Kinetic studies showed that compound 9i exhibited a competitive-type inhibition with a K_i value of 12.01 µM. Computational approach supported the rationality of our design strategy, as 9i represented appropriate binding interactions with the active sites of DPP4 target. MD simulation outputs validated the stability of ligand 9i at DPP4 active site. Also, Density functional theory (DFT) including HOMO-LUMO energies, ESP map, thermochemical parameters, and theoretical IR spectrum was employed to study the reactivity descriptors of 9i and 9a as the most and least potent compounds respectively. Based on the DFT study, compound 9i was softer and, as a result, more reactive than 9a. Taken together, our results showed the potential of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives as promising candidates for developing some novel DPP4 inhibitors for managing of type 2 diabetes.

Keywords: Aminopiperidine; Antidiabetic; Dihyroquinazoline; Pyrimidine.

Figure 1

Design of new hybrids of quinazoline-uracil-aminopiperidine based on potent DPP4 inhibitors in the literature (B) and three drugs marketed DPP4 inhibitors (A), Alogliptin, Alinagliptin, and Trelagliptin.

Figure 2

Synthesis of 6-(4-Aminopiperidine-1-yl)-3-methyl-1-((4-oxo-3-phenyl-3,4-dihydroquinazoline-2-yl)methyl)pyrimidine-2,4(1H,3H)-diones (9a–9 L). (i): DIPEA, DCM, 2 h, r.t. (ii): CH₃CN, PCl₃, 2 h, 60 ^oC (iii): DIPEA, CH₃CN, reflux. 24 h, (iv): i-PrOH, NaHCO₃, 24 h and ice-water condition.

Figure 3

Antidiabetic activities of the 4-Aminopiperidine-3, 4-dihyroquinazoline-2-uracil derivatives.

Figure 4

Line Weaver-Burk plot of DPP4 inhibitory of compound 9i (left), Line Weaver-Burk secondary plot (right).

Figure 5

The Interactions of 9a, 9d, 9i and 9j with the residues in the binding site of the DPP4 enzyme (4a5s).

Figure 6

The superimposition of some compounds and sitagliptin in the active site of DPP4 enzyme (9a (blue), 9d (green), 9i (orange), 9j (pink) and sitagliptin (yellow)).

Figure 7

Displaying the total RMSD plots as a function of simulation during the time of 100 ns complexed with 4s5a.

Figure 8

RMSF evolution of the protein backbone atoms of the 4s5a in complexes with ligand 9i, Sitagliptin and native ligand.

Figure 9

Radius of gyration value changes of protein during the MD simulations times.

Figure 10

Number of intramolecular hydrogen bonds in the complexes of 4s5a with the ligand 9i, Sitagliptin and native ligand.

Figure 11

Principal component analyses (PCA) were plotted against each other; Ligand 9i, native ligand and Sitagliptin with DPP4 receptor.

Figure 12

DFT calculated HOMO, LUMO and their energies for 9a (left), and 9i (right) at the B3LYP/6–31 + G (d, p) level of theory.

Figure 13

ESP maps for 9a (left) and 9i (right) at B3LYP/6–31 + G (d, p) level of theory.

Figure 14

The IR Spectrum for considered compounds 9a (blue), and 9i (red) was computed at B3LYP/6–31 + G(d, p) level of theory.