An
Pyrimidine is a well-known biologically active nitrogen containing heterocyclic compound. In recent years researchers are much interested in the synthesis of pyrimidine analogues. Pyrimidine derivatives posse fungicidal [
Due to numerous biological applications of 2-aminopyrimidine and acridine amine and its analogues, we have focused our research on synthesis of 2-aminopyrimidine by using pharmacologically important structural scaffold acridine pharmacophore.
Protein-ligand interaction is comparable to the lock-and-key principle, in which the lock encodes the protein and the key is grouped with the ligand. The major driving force for binding appears to be hydrophobic interaction [
In our research group, we have already reported larvicidal activity of 7-chloro-3,4-dihydro-9-phenylacridin-1(2
Melting points were determined by open capillary method and are corrected with standard benzoic acid. All solvents were distilled and dried prior to use. TLC was performed on silica gel G and the spots were exposed to iodine vapour for visualization. A mixture of petroleum ether and ethyl acetate was used as an eluent at different ratio. Column chromatography was performed by using silica gel (60–120 mesh). 1H NMR and 13C NMR spectra were recorded in CDCl3 on a Bruker advance 400 MHz instrument. Chemical shifts are reported in ppm using TMS as the internal standard. IR spectra were obtained on a Perkin-Elmer spectrum RXI FT-IR spectrometer (400–4000 cm−1; resolution: 1 cm−1) using KBr pellets. Molecular mass was determined using ESI-MS THERMO FLEET spectometer.
The dialysis membrane, 1,4-
10-Chloro-4,12-diphenyl-5,6-dihydropyrimido[4,5-
Summary of synthesized 2-aminopyrimidine derivatives (
S. no. | Compounds | R | M.P. (°C) | Yield% |
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1 |
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-H | 194–196 | 70 |
2 |
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-3,4-OCH3 | 218–220 | 81 |
3 |
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-2,5-OCH3 | 212–214 | 75 |
4 |
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-2-OCH3 | 168–170 | 69 |
5 |
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-4-Cl | 210–212 | 71 |
6 |
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-2-Cl | 238–240 | 69 |
Synthesis of 10-chloro-4,12-diphenyl-5,6-dihydropyrimido[4,5-
Spectral data of the synthesized compounds are described below.
Crystals suitable for X-ray analysis were obtained by slow evaporation of a solution of the 10-chloro-4-(2-chlorophenyl)-12-phenyl-5,6-dihydropyrimido[4,5-
The crystallographic data and structure refinement parameters of compound
Empirical formula | C27 H18 Cl2 N4 |
Formula weight | 469.35 |
Temperature | 293(2) K |
Wavelength | 0.71073 Å |
Crystal system, space group | Triclinic, P-1 |
Unit cell dimensions |
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Volume | 1129.39(9) A3 |
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Calculated density | 1.380 Mg/m3 |
Absorption coefficient | 0.311 mm−1 |
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484 |
Crystal size | 0.35 |
Theta range for data collection | 1.96 to 25.00°. |
Limiting indices | −11 ≤ |
Reflections collected/unique | 19503/3929 [ |
Completeness to theta = 25.00 | 98.8% |
Absorption correction | Semiempirical from equivalents |
Max. and min. transmission | 0.9635 and 0.8623 |
Refinement method | Full-matrix least squares on |
Data/restraints/parameters | 3929/6/308 |
Goodness-of-fit on |
1.200 |
Final |
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Largest diff. peak and hole | 0.383 and −0.385 |
Some important bond lengths (A) and bond angles (°) of compound
Bond | Bond length | Bond | Bond angle |
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C(1)–C(6) | 1.371(6) | N(1)–C(4)–C(5) | 123.2(3) |
C(2)–H(2) | 0.9300 | N(1)–C(4)–C(3) | 117.1(4) |
C(11)–H(11A) | 0.9700 | N(1)–C(9)–C(8) | 124.1(4) |
C(11)–H(11A) | 0.9700 | N(1)–C(9)–C(10) | 116.4(3) |
C(11)–H(11B) | 0.9700 | C(8)–C(9)–C(10) | 119.4(3) |
C(11)–H(11B) | 0.9700 | C(9)–C(10)–H(10A) | 109.5 |
C(13)–N(2) | 1.330(4) | C(11)–C(10)–H(10A) | 109.5 |
C(14)–N(2) | 1.332(4) | C(12)–C(11)–C(10) | 109.0(3) |
C(14)–N(3) | 1.344(4) | H(11A)–C(11)–H(11B) | 108.3 |
C(14)–N(4) | 1.354(4) | C(13)–C(12)–C(15) | 115.8(3) |
C(15)–N(3) | 1.339(4) | C(15)–C(12)–C(11) | 124.3(3) |
N(4)–H(4A) | 0.8600 | N(2)–C(13)–C(12) | 123.0(3) |
N(4)–H(4B) | 0.8600 | N(2)–C(13)–C(8) | 117.8(3) |
C(4)–N(1) | 1.361(6) | C(12)–C(13)–C(8) | 119.1(3) |
C(9)–N(1) | 1.317(5) | N(2)–C(14)–N(3) | 126.1(3) |
C(9)–C(10) | 1.496(6) | N(2)–C(14)–N(4) | 117.0(3) |
C(10)–C(11) | 1.525(6) | N(3)–C(14)–N(4) | 116.9(3) |
C(11)–C(12) | 1.508(5) | N(3)–C(15)–C(12) | 122.4(3) |
C(26)–H(26) | 0.9300 | N(3)–C(15)–C(16) | 116.7(3) |
C(27)–H(27) | 0.9300 | C(13)–N(2)–C(14) | 116.4(3) |
C(9)–N(1) | 1.317(5) | C(15)–N(3)–C(14) | 116.2(3) |
C(1)–Cl(1′) | 1.681(11) | C(14)–N(4)–H(4B) | 120.0 |
C(1)–Cl(1) | 1.99(4) | H(4A)–N(4)–H(4B) | 120.0 |
C(17)–Cl(2) | 1.732(4) |
ORTEP diagram of compound
The packing of the molecules in the unit cell, viewed down the a-axis with the hydrogen bond geometry of compound
Four different concentrations (100, 200, 300, and 400
Various concentrations of samples and standard drug acarbose were prepared.
Triplicates are done for each sample at different concentrations [
Statistical analysis was performed using one-way analysis of variance (ANOVA). Results are expressed as mean ± SD and
The results are summarized in Tables
Release of glucose through dialysis membrane to external solution (mg/dL).
Time (min) | Control |
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30 |
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60 |
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90 |
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120 |
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150 |
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180 |
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Values are mean ± SEM for groups of 3 observations.
% of relative movement in glucose diffusion inhibitory assay.
Time (min) |
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30 |
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60 |
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90 |
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120 |
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150 |
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180 |
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Values are mean ± SEM for groups of 3 observations.
Concentration of glucose (mg/dL).
% of relative movement in glucose diffusion inhibitory assay.
The results are given in Table
% inhibition of
Concentration ( |
Acarbose |
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100 |
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200 |
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300 |
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400 |
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Values are mean ± SEM for groups of 3 observations.
The results are shown in Table
% inhibition of
Concentration ( |
Acarbose |
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100 |
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200 |
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300 |
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400 |
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Values are mean ± SEM for groups of 3 observations.
The synthesized molecules
The crystal structures were refined by removing water molecules and repeating coordinates. Hydrogen atoms were added and charges were assigned to the protein atoms using Kollman united atoms force field by using AutoDockTools-1.5.6. For docking calculations, Gasteiger partial atomic charges were added to the synthesized structures and all possible flexible torsion angles of the ligand were defined by using AUTOTORS. The structures were saved in a PDBQT format for AutoDock calculations.
AutoDock requires precalculated
After docking, the 50 solutions were clustered into groups with RMS deviations lower than 1.0 Å. The clusters were ranked by the lowest energy representative of each cluster.
The binding site of the structures was not identified because of the absence of the crystal structure of the ligand, and a blind docking was performed for all the structures
The binding energy (
Structures |
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−4.52 | −5.31 | −0.40 | −1.57 | 1.19 |
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−4.83 | −5.35 | −0.37 | −1.54 | 0.89 |
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−6.51 | −6.34 | −1.37 | −1.44 | 1.19 |
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−6.61 | −6.95 | −0.56 | −1.41 | 0.89 |
All the binding modes of the structures
In diabetes mellitus, control of postprandial plasma glucose level is critical in the early treatment [
The present study revealed that we have successfully achieved our target title compound 10-chloro-4,12-diphenyl-5,6-dihydropyrimido[4,5-
The authors declare that there is no conflict of interests regarding the publication of this paper.
This study was supported by DST-SERB Fast Track (Sanction no. SR/FT/CS-264/2012), Government of India, New Delhi. The authors gratefully acknowledge DST-FIST for providing NMR facilities to VIT. The authors acknowledge the support extended by VIT-SIF for GC-MS and NMR analysis.