Abstract
In an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results.
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Introduction
Diabetes mellitus is a common, chronic disease mainly characterized by the body’s lack of ability to control blood sugar resulted into chronic hyperglycemia. Progression in this metabolic disorder may bring subsequent severe health problems, including abnormally great thrust, excessive appetite, overweight, blindness, excessive urination, leg amputation, cardiovascular complications, as well as renal and neurodegenerative diseases1,2,3,4. According to the World Health Organization (WHO) report, diabetes is increasing with alarming rate worldwide. While 415million people have become infected in 2015, this figure would reach 700 million in 20455. Diabetes is classically classified into three groups: type I diabetes mellitus (T1DM), type II diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM), among which T2DM is the most prevalent6,7,8.
To treat T2DM, traditional medications are reducing the hepatic glucose production, increasing the insulin action and its secretion from β-pancreatic cells, and controlling the digestive carbohydrate enzyme activities9. Carbohydrate digestive enzymes, found in the brush border of the intestine, play the catalyzing role in breaking down the long-chain polysaccharides into absorbable monosaccharide units. Among these enzymes, α-glucosidase has received considerable attention regarding their noticeable role in the lysis of α-glucopyranoside bond in oligosaccharides and disaccharides. The released monosaccharide would increase the postprandial blood glucose levels. Accordingly, α-glucosidase inhibitors preventing the carbohydrate digestion and glucose release in bloodstream efficiently control T2DM10. Acarbose, miglitol, voglibose, and deoxynojirimycin have been clinically used to bind reversibly to α-glucosidase and to interrupt the saccharide hydrolysis11. Various side effects associated with these drugs, including nausea, bloating, diarrhea, abdominal pain, and flatulence12 have been observed; therefore, providing more potent, less toxic α-glucosidase inhibitors is highly demanding.
Over recent decade, various heterocyclic-based compounds possessing α-glucosidase inhibitory activities have been found13,14,15,16,17,18,19,20,21,22,23,24. For example, several pyrimidine derivatives have shown excellent inhibition potency25,26,27,28. Moreover, compounds containing benzimidazole have become an emerging anti-diabetic scaffold during recent years29,30,31,32,33,34. Although there are several reports concerning α-glucosidase inhibitors having benzimidazole and pyrimidine skeletons separately, compounds bearing both of these heterocycles, benzo[4,5]imidazo[1,2-a]pyrimidine, in particular, as anti-diabetic agents have not been proposed yet (Fig. 1). Therefore, design and synthesis of these targeted compounds which are anticipated to possess potent α-glucosidase inhibitory activity could be an interesting challenge in medicinal chemistry.
Design of new 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidine derivatives 3a-ag as novel α-glucosidase inhibitor. *This figure was drawn by ChemDraw Professional 16.0 (https://perkinelmer-chemdraw-professional.software.informer.com).
Benzo[4,5]imidazo[1,2-a]pyrimidines, one of the important fused pyrimidine families, have exhibited various significant biological activities, including anticancer35, anti-tuberculosis36, adenosine receptor inhibitory37, anti-inflammatory38, antimicrobial39,40, calcium channel blocking41, antiviral42, as well as anti- neurodegenerative properties43. As a privileged scaffold, several synthetic approaches toward substituted benzo[4,5]imidazo[1,2-a]pyrimidines have already been reported. Among them, the reactions of 2-aminobenzimidazole with appropriate electrophilic compounds are the most traditional routes. Some noticeable examples include the reaction of this starting material with α,β-unsaturated compounds44, 1,2-diphenylethanones, alkynes, or 1,3-bis electrophilic compounds and aromatic aldehydes45,46,47,48,49,50, acrylamides bearing a leaving group like ethoxy in the β-position51, domino reaction with N-methyl-1-(methylthio)-2-nitroprop-1-en-1-amine and aromatic aldehydes52, as well as four-component reaction with amines, diketene, and aromatic aldehydes53.
Although various synthetic methods for benzo[4,5]imidazo[1,2-a]pyrimidines have been reported, the reaction between 2-aminobenzimidazoles 1 and α-azidochalcones 2 has not been proposed yet. Considering the significant role of α-glucosidase inhibitors in current pharmaceutical science, in present study, we focused on the synthesis of novel series poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3 and subsequently, the evaluation of their inhibitory activity against α-glucosidase (Scheme 1). To achieve this goal, a targeted Michael addition–cyclization of 2-aminobenzimidazoles 1 with α-azidochalcones 2 has been performed to obtain our desirable compounds 3. Moreover, to highlight the role of amine in the anti-α-glucosidase activities, this moiety has been substituted with chlorine and hydrogen (compounds 4a and 6a, respectively), both of which showed considerably less potency (Scheme 2).
Synthesis of 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidine derivatives 3a–ag.
Synthesis of substituted-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidine derivatives 4a and 6a.
Results and discussion
Chemistry
In this paper, an efficient, facile synthetic approach including Michael-addition-cyclization of 2-aminobenzimidazole 1 with α-azidochalcone 2 has been applied to obtain a library of 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag. It is worth mentioning that over recent decade, α-azidochalcones 2 have been widely utilized to synthesize several aza-heterocycles54,55,56,57,58,59,60,61,62,63,64,65,66. To probe the generality of the proposed reaction, a mixture of 2-aminobenzimidazoles 1a,b, α-azidochalcones 2a–m (with electron-donating alkyl or methoxy groups as well as electron-withdrawing chlorine or bromine substituted phenyl, and heteroaryl substituents), and Et3N in EtOH were heated under the reflux conditions for 2 h. TLC and 1H NMR analysis of the reaction mixture confirmed the formation of desirable 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3 in good to excellent yields (Scheme 1).
To study the role of amine functional group in α-glucosidase inhibition, this moiety has been replaced by chlorine (3-chloro-2,4-diphenylbenzo[4,5]imidazo[1,2-a]pyrimidine 4a) and hydrogen (2,4-diphenylbenzo[4,5]imidazo[1,2-a]pyrimidine 6a). Therefore, through sandmayer reaction, a mixture of concentrated sulfuric acid and sodium nitrite was treated with compound 3a to afford corresponding diazonium salt which went through chlorination reaction using cuprous chloride (CuCl) in concentrated hydrochloric acid. On the other hand, heating a mixture of 2-aminobenzimidazoles 1 and chalcone 5a in the presence of Et3N in EtOH for approximately 10 h afforded 2,4-diphenylbenzo[4,5]imidazo[1,2-a]pyrimidine 6a (Scheme 2).
The structures of the isolated products (3a–ag, 4a, and 6a) were deduced on the basis of their IR, 1H- and 13C-NMR spectroscopy, as well as mass spectrometry. Partial assignments of these resonances are provided in the Experimental Part.
A plausible mechanism for the formation of 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3 was outlined in Scheme 3. The reaction may be initiated by Michael addition of 2-aminobenzimidazole 1 activated by Et3N to α-azidochalcone 2 by removal of nitrogen molecule to form adduct 6, followed by an imine-enamine tautomerization (intermediate 7). Afterwards, carbonyl functionality can undergo an intramolecular nucleophilic addition of amine moiety resulted from 2-aminobenzimidazole to cyclize the bicyclic skeleton 8, which may go through dehydration to afford desirable poly substituted benzo[4,5]imidazo[1,2-a]pyrimidine 3.
Proposed reaction mechanism for the formation of 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidine derivatives 3.
Pharmacology
In vitro α-glucosidase inhibitory activity
Various 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidine derivatives 3a–ag were synthesized to evaluate their Saccharomyces cerevisiae α-glucosidase inhibitory activities (Table 1). Results revealed that all targeted compounds exhibited good to excellent inhibitory activities (with IC50 values from 16.4 ± 0.36 μM to 297.0 ± 1.2 μM) in comparison to the standard inhibitor (IC50 = 750.0 ± 1.5 μM). Structurally, synthesized compounds 3a–ag were divided into two main categories based on substituents on the benzimidazole moiety: unsubstituted benzimodazole derivatives 3a–x and 7,8-dichlorosubsittuted benzimodazole derivatives 3y–ag. To obtain an optimized α-glucosidase inhibitor, the substituents on 2-aryl and 4-aryl rings were changed in each category.
Considering the substituents on 4-aryl ring, compounds 3a–x were classified into five subcategories: (1) unsubstituted derivatives 3a–g, (2) 4-chlorophenyl derivatives 3h–l, (3) 4-bromophenyl derivatives 3m,n, (4) 4-methoxyphenyl derivatives 3o–r, (5) thiophene derivatives 3s–x.
Among 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–g, compound 3d was found to be the most potent α-glucosidase inhibitor (IC50 = 26.7 ± 0.28 μM). Removing chlorine (compound 3a) or replacing this atom with methyl or methoxy groups (compounds 3b and 3c, respectively) caused to decrease in inhibitory activity. Moreover, moving chlorine from 4-position to 2- and 3-position (compounds 3e and 3f, respectively) resulted into a considerable deterioration in activity, as compound 3e had the least activity among all of the synthesized compounds (IC50 = 297.0 ± 1.2 μM). Additionally, compound 3g bearing thiophene as 2-aryl ring showed lower activity (IC50 = 91.3 ± 0.4 μM) than compound 3d (IC50 = 26.7 ± 0.28 μM).
Among 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3h–l, compound 3k with 4-Cl substituent on the both 2- and 4-phenyl rings exhibited the remarkable potency against α-glucosidase (IC50 = 16.4 ± 0.36 μM). It is worth noticing this derivative was 45.7 times more potent than the standard inhibitor (IC50 = 750.0 ± 1.5 μM), and it showed the highest inhibitory activity among all the synthesized compounds. Compound 3l with 2-thiophene ring was the second most potent in this series (IC50 = 28.0 ± 0.26 μM). There was the same trend for the activities of compounds 3h–j with their analogs in the first series (compounds 3a–c). Additionally, results revealed that replacing chlorine at 4-position on 4-aryl ring of compounds 3h and 3i with bromine (compounds 3m and 3n) moderately decreased the α-glucosidase inhibitory activity.
In the fourth subcategory, compound 3o with 2-phenyl exhibited relatively good inhibitory activity against α-glucosidase (IC50 = 75.4 ± 0.42 μM). Methylation on 4-position of this ring improved the activity (compound 3p with IC50 = 65.4 ± 0.03 μM); however, introducing 4-OCH3 substituent (compound 3q) or replacing this ring with thiophene (compound 3r) led to decrease in its activity (IC50 = 122.7 ± 0.6 and 128.4 ± 0.2 μM, respectively).
Among derivatives 3s–x, compound 3w with 4-Cl on 2-phenyl ring was the most potent α-glucosidase inhibitor (IC50 = 136.0 ± 0.08 μM). By comparing the IC50 values of 4-methoxyphenyl derivatives 3o–r and 4-thiophene derivatives 3s–x with their analogs in previous series (compounds 3a–n), it can be implied that methoxy and thiophene substituents caused significant deterioration on the α-glucosidase inhibitory activity. With this in mind, 3-amino-7,8-dichloro-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3y–ag bearing 4-phenyl (compounds 3y and 3z), 4-chlorophenyl derivatives (compounds 3aa–ae), and 4-bromophenyl derivatives (compounds 3af and 3ag) were prepared to investigate their inhibitory activities.
Unsubstituted phenyl ring compound 3y had good activity in comparison with other compounds (IC50 = 78.4 ± 0.06 µM). Introduction of a chlorine atom on the 4-position of the 2-phenyl ring, as in compound 3z caused weaker activity (IC50 = 123.6 ± 0.26 µM). However, introducing this atom on the 4-position of the 4-phenyl ring (compound 3aa) improved inhibitory activity (IC50 = 64.4 ± 0.15 µM). Adding electron-donating substituents including methyl and methoxy on the 4-position of the 2-phenyl ring (compounds 3ab and 3ac, respectively) caused significant decrease in inhibitory activity. Introducing another chlorine (compound 3ad) improved the activity remarkably (IC50 = 48.4 ± 0.39 µM), as it has become the most potent inhibitor in the second category. Moreover, replacing chlorine atom in compound 3aa activity (IC50 = 64.4 ± 0.15 µM) with bromine atom (compound 3af) resulted in increased potency (IC50 = 85.4 ± 0.04 µM). Finally, compound 3ae bearing thiophene as 2-aryl ring (IC50 = 72.9 ± 0.15 µM) showed slightly higher inhibitory comparing with compound 3aa (IC50 = 64.4 ± 0.15 µM).
According to results, among derivatives in the first category (compounds 3a–x), it seems the presence of 4-Cl on 2-aryl ring plays a substantial role in anti-α-glucosidase activities. The presence of electron-donating group (OCH3) on the 4-postion of 2- and 4-phenyl ring caused decrease in activity among all synthesized products. Additionally, the comparison of IC50 values of compounds 3a–x with their corresponding 7,8-dichlorosubsittuted derivatives 3y–ag revealed that the presence of chlorine atoms has deteriorate effect on the inhibitory activity of poly substituted benzo[4,5]imidazo[1,2-a]pyrimidines.
Additionally, the probable role of amine functional group has been investigated. For this goal, the α-glucosidase potency of compound 3a (IC50 = 53.8 ± 0.04 μM) was compared with those of compounds 4a and 6a (the IC50 values were 235.4 ± 0.5 μM and 168.6 ± 1.2 μM, respectively). As it can be observed, the order of activity was NH2 > H > Cl substituted derivatives. Therefore, the necessary, constructive role of amine moiety on the inhibition of α-glucosidase has been confirmed.
To develop this investigation, the ability of our target compounds to inhibit the rat small intestine α-glucosidase have been evaluated. These inhibitory activities exhibited almost similar trend to that of Saccharomyces cerevisiae α-glucosidase. The most active compound was 3k (IC50 value of 45.04 μM) which was 3.23 times more potent than acarbose (IC50 value of 145.74 μM). Moreover, compounds 4a and 6a showed slight inhibitory activities confirmed the significance of amine moiety in targeted compounds 3.
Enzyme kinetic study
To investigate the inhibition mode of synthesized poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidine 3 against α-glucosidase, kinetic study was performed with standard inhibitor, acarbose, and the most potent derivative 3k. To indicate the type of inhibition and Ki, Lineweaver–Burk plots and secondary re-plotting of the mentioned plots were presented (Fig. 2). As it was showed in Fig. 2a, while inhibitor concentration increased, the Km value gradually increased, but Vm value remained unchanged. Therefore, it can be implied compound 3k was a competitive inhibitor and competes with acarbose for binding to the enzyme active site. Moreover, plot of Km versus different concentration of compound 3k gave an estimate of the inhibition constant, Ki of 16 µM (Fig. 2b).
Kinetics of α-glucosidase inhibition by sample 3k. (a) The Lineweaver–Burk plot in the absence and presence of different concentrations of sample 3k; (b) The secondary plot between Km and various concentrations of sample 3k. *This figure was created by Microsoft Excel 2016 (https://www.microsoft.com/en-us/download/office.aspx).
Cytotoxicity studies
Among the potent synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidine 3, the cytotoxicity of some of them including 3a, 3k, 3m and 3ad was evaluated through use of the breast cancer cell lines including MCF-7 and MDA-MB-231, as well as human pancreatic cancer cell lines including HDF and PANC1. The selected compounds did not possess any cytotoxic activity against these cell lines at concentration of 100 µM (IC50 > 200 µM).
Docking study
Molecular docking study was performed on the compounds 3a, 3k and 3ad to study the mode of their interaction in the active site of the yeast isomaltase from Saccharomyces cerevisiae (Pdb id:3A4A) with 84% similarity to S. cerevisiae α-glucosidase using Auto Dock Tools (version 1.5.6). These compounds showed similar binding modes of interaction with catalytic residues. The superimposed structure of acarbose as a standard inhibitor and the most potent compound 3k in the active site of isomaltase was shown in Fig. 3. In the most potent compound 3k, benzimidazole and 4-(4Cl-phenyl) ring units created π–π interaction with Phe 303 and Tyr 158, respectively in the active site of the enzyme (Fig. 4). The 2-(4Cl-phenyl) ring formed π-anion interaction with the aromatic side chains of Asp352. Moreover, a π-cation interaction was observed between pyrimidine moiety and Arg 442.
Acarbose (gray) and most potent compound 3k (blue) superimposed in the active site pocket. *This figure was created by using Discovery Studio 4.0 Client (https://discover.3ds.com/discovery-studio-visualizer-download) and LigPlot (https://www.ebi.ac.uk/thornton-srv/software/LigPlus/download.html).
(a) The 3D and (b) 2D predicted binding mode of the compound 3k in the active site pocket (π–π: yellow, π-Anion: blue, π-cation: red, hydrophobic: pink). *This figure was created by using Discovery Studio 4.0 Client (https://discover.3ds.com/discovery-studio-visualizer-download) and LigPlot (https://www.ebi.ac.uk/thornton-srv/software/LigPlus/download.html).
Compounds 3a and 3k interacted with similar amino acids in the active site of the enzyme. Benzimidazol, pyrimidine, and 4-phenyl ring of compound 3a interacted with Phe303, Arg442, and Tyr158, respectively (Fig. 5). Compound 3k had additional π-alkyl interaction between 4-(4Cl-phenyl) ring and Arg315, as well as 2-(4Cl-phenyl) ring and Val 216. Higher observed inhibitory activity of compound 3k could be attributed to the formation of stabilizing interactions with specific residues like Arg315 and Val 216, which could be resulted from the presence of chlorine atoms led to the electron-deficiency of phenyl rings. Additionally, chlorine atoms in compound 3k could create hydrophobic interactions with Tyr72, His112, Phe178, Arg315 which brought more inhibitory activity in comparison with compound 3a.
(a) The 3D and (b) 2D predicted binding mode of the compound 3a in the active site pocket (π–π: yellow, π-Anion: blue, π-cation: red, hydrophobic: pink). *This figure was created by using Discovery Studio 4.0 Client (https://discover.3ds.com/discovery-studio-visualizer-download) and LigPlot (https://www.ebi.ac.uk/thornton-srv/software/LigPlus/download.html).
In compound 3ad, there was a difference in interaction mode of the 2-(4Cl-phenyl) moiety with the active site of enzyme. Insertion of chlorine in 7 and 8 positions on the benzimidazole moiety led to a significant decrease in the inhibitory activity. However, there was not any interaction between 2-(4Cl-phenyl) moiety and Asp352 (Fig. 6).
(a) The 3D and (b) 2D predicted binding mode of the compound 3ad in the active site pocket (π–π: yellow, π-Anion: blue, π-cation: red, hydrophobic: pink). *This figure was created by using Discovery Studio 4.0 Client (https://discover.3ds.com/discovery-studio-visualizer-download) and LigPlot (https://www.ebi.ac.uk/thornton-srv/software/LigPlus/download.html).
Further studies on the binding energies of selected compounds exhibited that compound 3k had lower free binding energy (− 9.63 kcal/mol) as compared to compounds 3ad (− 8.89 kcal/mol) and 3a (− 9.14 kcal/mol). As observed from the best docking conformations, showed that all three compounds have a lower free binding energy than acarbose (− 8.20 kcal/mol). Therefore, the results emphasized that the target compounds bind more easily to the target enzyme (α-glucosidase) than the reference drug, acarbose. These findings had good agreement with the obtained results through in vitro experiments.
To assess potential inhibition of human α-glucosidase, compound 3a was docked against the crystal structure for C-terminal domain of human intestinal α-glucosidase (PDB Code: 3TOP) comparing with Acarbose. This study exhibited similar interactions with the yeast isomaltase binding site. The superimposed structure of acarbose and compound 3a in the active site of human intestinal α-glucosidase was shown in Fig. 7. Interestingly, compound 3a exhibited better binding energy (− 10.47 kcal/mol) than Acarbose (− 8.85 kcal/mol). Benzimidazole moiety in this compound created hydrogen bond interaction with Asp 1157 and π-anion interaction with Asp 1526. Another important hydrogen bond interaction was observed between pyrimidine moiety and Arg 1510. Phenyl rings and pyrimidine were involved in several π-anion interactions with Asp 1279, Asp 1420, and Asp 1526. Moreover, compound 3a formed π–π stacking interaction with hydrophobic residue including Tyr1251, Trp1355, and Phe1559.
(a) Acarbose (gray) and compound 3a (blue) superimposed in the human intestinal α-glucosidase active site. (b) 3D predicted binding mode of the compound 3a in the human intestinal α-glucosidase active site (H-bond: green, π–π: yellow, π-Anion: blue). *This figure was created by using Discovery Studio 4.0 Client (https://discover.3ds.com/discovery-studio-visualizer-download) and LigPlot (https://www.ebi.ac.uk/thornton-srv/software/LigPlus/download.html).
Conclusion
In conclusion, we introduced a novel, potent series of α-glucosidase inhibitors. Poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines were synthesized through an efficient, short-time, high-yield Michael addition–cyclization between 2-aminobenzimidazoles and α-azidochalcones under the mild conditions. No need to column chromatography led us to obtain a large scope of substrates, all of which exhibited good to excellent inhibitory activity. Among them, compound 3k showed the best inhibitory potency having IC50 value of 16.4 ± 0.36 μM which was 45.7 times more potent than acarbose as standard inhibitor (IC50 = 750.0 ± 1.5 μM). The kinetic study for this compound showed there was a competitive mechanism. Moreover, docking studies revealed that 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines could interact with important amino acids in the active site of α-glucosidase.
Experimental
Methods
All chemicals were purchased from Merck (Germany) and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus and were not corrected. Mass spectra were recorded on an Agilent Technologies (HP) 5973 mass spectrometer operating at an ionization potential of 20 eV. IR spectra were recorded on a Shimadzu IR-460 spectrometer. 1H and 13C NMR spectra were measured (DMSO‑d6 solution) with Bruker DRX-300 AVANCE (at 300.1 and 75.1 MHz) spectrometer with TMS as an internal standard. α-Azido chalcones 2 were obtained from the corresponding benzylidene acetophenones in two steps following the literature procedure15.
General procedure for the preparation of 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag
A solution of 2-aminobenzimidazoles 1 (1.2 mmol), α-azidochalcones 2 (1.0 mmol), Et3N (1.2 mmol) in EtOH (5.0 mL) was magnetically stirred for 2 h under reflux conditions. After completion of the reaction according to the TLC analysis, the mixture was cooled to ambient temperature, the precipitated product was filtered and washed with Et2O (5.0 mL) to afford pure products as yellow powder.
General procedure for the preparation of 3-chloro-2,4-diphenylbenzo[4,5]imidazo[1,2-a]pyrimidine 4a
To a stirring solution of concentrated sulfuric acid (1.6 mmol), sodium nitrite (2.2 mmol) was added gradually over 10–15 min. After addition was completed, the temperature was raised to 70 °C, and the mixture was stirred until sodium nitrite dissolved thoroughly. Then, the mixture is cooled to 25 °C with an ice bath, and a solution of 3-amino-2,4-diphenylbenzo[4,5]imidazo[1,2-a]pyrimidin 3a (2.0 mmol) in glacial acetic acid (4.0 ml) was added slowly with stirring, at such a rate that temperature remains below 40 °C. After 30 min, TLC monitoring confirmed compound 3a was completely converted to corresponding diazonium salt. The obtained mixture was added at 10 °C in portions to a solution of CuCl (4.4 mmol) in concentrated hydrochloric acid (4.0 mmol) over a period of about 5 min. Afterward, temperature was raised to 80 °C and the reaction mixture was heated for almost 5 h. After completion of the reaction which was monitored by TLC, mixture was quenched by iced water. The precipitate was filtered and recrystallized in EtOH to afford the pure product 4a.
General procedure for the preparation of 2,4-diphenylbenzo[4,5]imidazo[1,2-a]pyrimidine 6a
A mixture of 2-aminobenzimidazole 1a (1.2 mmol), chalcone 5a (1.0 mmol), and Et3N (1.2 mmol) in EtOH (5.0 mL) was heated under reflux conditions for 10 h. After completion of the reaction confirmed by the TLC analysis, the solvent was removed under the reduced pressure. The residue was purified by column chromatography using n-hexane/EtOAc (3:1) as eluent to afford pure product 6a.
2,4-Diphenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3a)
Yellow solid; yield: 89%, mp 208–210 °C. IR (KBr) (νmax/cm–1): 3459 and 3372 (NH2), 1594, 1426, 1378, 1302, 1228, 1194, 1148, 1083, 1016, 984, 906, 801, 746, 668, 624. 1H NMR (300.1 MHz, DMSO): δ 8.15 (d, J = 8.4 Hz, 2H, 2CH), 8.10–7.20 (m, 9H, 9CH), 7.11 (t, J = 7.5 Hz, 1H, CH), 6.87 (t, J = 7.4 Hz, 1H, CH), 6.18 (d, J = 8.2 Hz, 1H, CH), 4.13 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 155.2, 148.2, 144.9, 136.8, 136.4, and 130.8 (6C), 130.4 and 130.3 (2CH), 129.9 (2CH), 129.7 (2CH), 129.2 (2CH), 128.6 (CH), 127.9 (2CH), 127.4 and 126.4 (2C), 124.9, 120.0 and 119.2 (3CH). EI-MS, m/z (%): 336 (M+, 27), 133 (100), 105 (80), 79 (43), 52 (35).
2-Phenyl-4-p-tolyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3b)
Yellow solid; yield: 86%, mp 272–274 °C. IR (KBr) (νmax/cm–1): 3428 and 3362 (NH2), 1595, 1434, 1399, 1356, 1256, 1181, 1085, 1014, 991, 829, 754, 685, 650. 1H NMR (300.1 MHz, DMSO): δ 8.17 (d, J = 8.3 Hz, 2H, 2CH), 7.76 (d, J = 7.8 Hz, 1H, CH), 7.60–7.24 (m, 7H, 7CH), 7.10 (t, J = 7.5 Hz, 1H, CH), 6.91 (t, J = 7.4 Hz, 1H, CH), 6.28 (d, J = 8.2 Hz, 1H, CH), 4.04 (s, 2H, NH2), 2.36 (s, 3H, CH3). 13C NMR (75.5 MHz, DMSO-d6): δ 155.3, 148.2, 144.9, 137.5, 136.9 and 136.4 (6C), 130.9 (2CH), 130.6 (CH), 129.7 (2 × 2CH), 129.2 (CH), 128.6 (C), 127.9 (2CH), 127.4 and 126.8 (2C), 124.8, 119.9 and 119.1 (3CH), 21.1 (CH3). EI-MS, m/z (%): 351 (M+ + 1, 100), 332 (18), 273 (72), 257 (15), 169 (48), 91 (10), 76 (25).
4-(4-Methoxy-phenyl)-2-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3c)
Yellow solid; yield: 74%, mp 267–271 °C. IR (KBr) (νmax/cm–1): 3438 and 3389 (NH2), 1592, 1414, 1367, 1283, 1182, 1144, 1068, 991, 947, 843, 805, 753, 675, 623. 1H NMR (300.1 MHz, DMSO): δ 7.91 (d, J = 8.4 Hz, 2H, 2CH), 7.74 (d, J = 8.5 Hz, 1H, CH), 7.63–7.52 (m, 5H, 5CH), 7.37–7.27 (m, 3H, 3CH), 6.94 (t, J = 7.4 Hz, 1H, CH), 6.29 (d, J = 8.4 Hz, 1H, CH), 4.03 (s, 2H, NH2), 3.91 (s, 3H, OCH3). 13C NMR (75.5 MHz, DMSO-d6): δ 160.9, 156.8, 148.1, 144.5 and 137.1 (5C), 131.2 (2CH), 130.2 and 129.9 (2CH), 129.7(C), 128.6 (2 × 2CH), 127.7, 127.2 and 126.6 (3C), 124.6, 119.9 and 119.1 (3CH), 115.7 (2CH), 55.4 (OCH3). EI-MS, m/z (%): 366 (M+, 100), 288 (45), 244 (15), 202 (43), 185 (29), 76 (14), 51 (32).
4-(4-Chloro-phenyl)-2-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3d)
Yellow solid; yield: 90%, mp 252–253 °C. IR (KBr) (νmax/cm–1): 3448 and 3363 (NH2), 1598, 1458, 1397, 1368, 1287, 1158, 1079, 1012, 994, 935, 897, 752, 689, 623. 1H NMR (300.1 MHz, DMSO): δ 7.95–7.63 (m, 7H, 7CH), 7.60–7.47 (m, 3H, 3CH), 7.33 (t, J = 7.5 Hz, 1H, CH), 6.96 (t, J = 7.4 Hz, 1H, CH), 6.25 (d, J = 8.4 Hz, 1H, CH), 4.20 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 155.4, 148.0, 144.5, 138.8, 136.9 and 135.6 (6C), 132.0 (2CH), 131.5 (CH), 130.5 (2CH), 129.9 (CH), 128.6 (2 × 2CH), 128.1, 127.0 and 126.6 (3C), 124.6, 120.1 and 119.2 (3CH). EI-MS, m/z (%): 372 (M+ + 2, 48), 293 (34), 278 (100), 258 (28), 204 (10), 111 (23).
4-(2-Chloro-phenyl)-2-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3e)
Yellow solid; yield: 68%, mp 276–277 °C. IR (KBr) (νmax/cm–1): 3436 and 3385 (NH2), 1593, 1484, 1389, 1345, 1278, 1169, 1149, 1079, 991, 936, 899, 842, 799, 753, 685, 655. 1H NMR (300.1 MHz, DMSO): δ 8.04–7.71 (m, 6H, 6CH), 7.67 (d, J = 7.6 Hz, 1H, CH), 7.63–7.47 (m, 3H, 3CH), 7.32 (t, J = 7.5 Hz, 1H, CH), 6.95 (t, J = 7.8 Hz, 1H, CH), 6.19 (d, J = 7.8 Hz, 1H, CH), 4.21 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 157.1, 147.9, 144.5, 136.9, 134.8 and 132.2 (6C), 131.8, 130.9, 129.9, 129.8 and 128.72 (5CH), 128.66 (2CH), 128.60 (2CH), 127.8, 127.0 and 126.6 (3C), 124.6, 120.1, 119.2 and 113.5 (4CH). EI-MS, m/z (%): 370 (M+, 100), 334 (18), 294 (34), 189 (28), 204 (10), 111 (23).
4-(3-Chloro-phenyl)-2-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3f)
Yellow solid; yield: 73%, mp 268–269 °C. IR (KBr) (νmax/cm–1): 3443 and 3359 (NH2), 1596, 1501, 1346, 1277, 1182, 1149, 1084, 993, 825, 785, 685, 635. 1H NMR (300.1 MHz, DMSO): δ 7.96–7.85 (m, 3H, 3CH), 7.83–7.67 (m, 4H, 4CH), 7.63–7.50 (m, 3H, 3CH), 7.35 (t, J = 7.7 Hz, 1H, CH), 6.96 (t, J = 7.6 Hz, 1H, CH), 6.13 (d, J = 8.4 Hz, 1H, CH), 4.29 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 157.0, 147.7, 144.4, 136.8 and 133.8 (5C), 133.0, 132.4, 130.7, 130.0 and 129.2 (5CH), 128.7 (2CH), 128.6 (2CH), 128.5, 126.92, 126.85 and 126.1 (4C), 124.7, 120.6, 119.3 and 112.6 (4CH). EI-MS, m/z (%): 370 (M+, 78), 320 (25), 293 (34), 244 (100), 182 (48), 109 (23), 77 (48).
2-Phenyl-4-thiophen-2-yl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3g)
Yellow solid; yield: 69%, mp 246–248 °C. IR (KBr) (νmax/cm–1): 3458 and 3376 (NH2), 1595, 1512, 1397, 1282, 1178, 1132, 1075, 989, 923, 824, 732, 684, 652. 1H NMR (300.1 MHz, DMSO-d6): δ 8.19 (d, J = 3.5 Hz, 1H, CH), 7.89 (d, J = 5.0 Hz, 1H, CH), 7.83–7.48 (m, 6H, 6CH), 7.36–7.21 (m, 2H, 2CH), 6.95 (t, J = 7.4 Hz, 1H, CH), 6.26 (d, J = 8.3 Hz, 1H, CH), 4.25 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 156.1, 150.4, 147.9, 144.6, 141.4 and 131.6 (6C), 131.3 and 130.4 (2CH), 129.9 (2CH), 128.7 (2CH), 128.0 (CH), 127.3 and 126.6 (2C), 125.7, 124.7, 120.2, 119.4 and 113.3 (5CH). EI-MS, m/z (%): 342 (M+, 100), 266 (25), 248 (78), 168 (43), 135 (36), 105 (28), 77 (48), 51 (25).
2-(4-Chloro-phenyl)-4-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3h)
Yellow solid; yield: 84%, mp 265–266 °C. IR (KBr) (νmax/cm–1): 3468 and 3373 (NH2), 1607, 1498, 1424, 1358, 1284, 1203, 1163, 1041, 991, 953, 885, 743, 696, 641. 1H NMR (300.1 MHz, DMSO-d6): δ 7.96 (d, J = 8.4 Hz, 2H, 2CH), 7.85–7.52 (m, 8H, 8CH), 7.31 (t, J = 7.7 Hz, 1H, CH), 6.89 (t, J = 7.9 Hz, 1H, CH), 6.11 (d, J = 8.4 Hz, 1H, CH), 4.14 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 155.8, 148.0, 144.6, 135.9, 134.7 and 134.1 (6C), 130.9 (CH), 130.7 (2CH), 130.4 (2CH), 130.1 (C), 129.71 (2CH), 129.66 (CH), 128.6 (2CH), 127.1 and 126.3 (2C), 124.7, 120.0 and 119.2 (3CH). EI-MS, m/z (%): 370 (M+, 100), 333 (18), 232 (25), 206 (36), 167 (29), 102 (45), 77 (51), 51 (25).
2-(4-Chloro-phenyl)-4-p-tolyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3i)
Yellow solid; yield: 78%, mp 277–278 °C. IR (KBr) (νmax/cm–1): 3468 and 3348 (NH2), 1602, 1487, 1412, 1368, 1294, 1235, 1132, 1098, 1032, 991, 928, 848, 776, 729, 687, 635. 1H NMR (300.1 MHz, DMSO-d6): δ 7.93 (d, J = 8.3 Hz, 2H, 2CH), 7.66–7.46 (m, 7H, 7CH), 7.31 (t, J = 7.9 Hz, 1H, CH), 6.90 (t, J = 7.6 Hz, 1H, CH), 6.22 (d, J = 8.5 Hz, 1H, CH), 4.09 (s, 2H, NH2), 2.43 (s, 3H, CH3). 13C NMR (75.5 MHz, DMSO-d6): δ 155.6, 148.0, 144.5, 135.9 and 134.6 (5C), 131.4 (CH), 130.9 (2CH), 130.6 (2CH), 130.2 and 129.8 (2C), 129.5 (2CH), 128.6 (2CH), 127.1, 126.6 and 126.4 (3C), 124.7, 120.0 and 119.1(3CH), 21.2 (CH3). EI-MS, m/z (%): 384 (M+, 100), 293 (46), 276 (32), 218 (68), 109 (18), 91 (22).
2-(4-Chloro-phenyl)-4-(4-methoxy-phenyl)-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3j)
Yellow solid; yield: 83%, mp 257–258 °C. IR (KBr) (νmax/cm–1): 3446 and 3372 (NH2), 1595, 1493, 1427, 1359, 1295, 1236, 1149, 1085, 1035, 972, 939, 858, 784, 740, 655, 637. 1H NMR (300.1 MHz, DMSO-d6): δ 8.18 (d, J = 8.6 Hz, 2H, 2CH), 7.95 (d, J = 8.4 Hz, 2H, 2CH), 7.74 (d, J = 8.0 Hz, 1H, CH), 7.30 (d, J = 8.4 Hz, 2H, 2CH), 7.09–7.05 (m, 1H, CH), 7.03 (d, J = 8.5 Hz, 2H, 2CH), 6.94 (t, J = 7.8 Hz, 1H, CH), 6.28 (d, J = 8.6 Hz, 1H, CH), 4.12 (s, 2H, NH2), 3.74 (s, 3H, OCH3). 13C NMR (75.5 MHz, DMSO-d6): δ 157.4, 155.6, 147.8, 145.0, 135.9 and 134.6 (6C), 131.3 (2CH), 131.2 (CH), 130.1 (C), 128.6 (2CH), 127.7 (2CH), 127.3, 127.1 and 126.7 (3C), 124.7, 120.0 and 119.1 (3CH), 115.8 (2CH), 55.4 (OCH3). EI-MS, m/z (%): 402 (M+ + 2, 100), 292 (25), 276 (48), 111 (10), 106 (56), 92 (28), 51 (32).
2,4-Bis-(4-chloro-phenyl)-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3k)
Yellow solid; yield: 92%, mp 271–272 °C. IR (KBr) (νmax/cm–1): 3447 and 3356 (NH2), 1599, 1506, 1436, 1348, 1294, 1233, 1172, 1061, 990, 898, 831, 786, 686, 635. 1H NMR (300.1 MHz, DMSO-d6): δ 7.93 (d, J = 8.5 Hz, 2H, 2CH), 7.82 (d, J = 8.4 Hz, 2H, 2CH), 7.75 (d, J = 8.3 Hz, 1H, CH), 7.72 (d, J = 8.5 Hz, 2H, 2CH), 7.62 (d, J = 8.4 Hz, 2H, 2CH), 7.33 (t, J = 7.8 Hz, 1H, CH), 6.96 (t, J = 7.8 Hz, 1H, CH), 6.24 (d, J = 8.4 Hz, 1H, CH), 4.25 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 155.8, 147.9, 144.5, 135.8, 135.6 and 134.7 (6C), 131.9 (2CH), 131.4 (CH), 130.6 (2CH), 130.5 (2CH), 128.6 (2CH), 128.51, 128.48, 127.0 and 126.7 (4C), 124.7, 120.2 and 119.2 (3CH). EI-MS, m/z (%): 404 (M+, 100), 333 (45), 293 (65), 270 (15), 258 (34), 166 (18), 103 (28), 77 (38), 52 (26).
3-(4-Chloro-phenyl)-1-thiophen-2-yl-benzo[4,5]imidazo[1,2-a]pyridin-2-ylamine (3l)
Yellow solid; yield: 71%, mp 246–245 °C. IR (KBr) (νmax/cm–1): 3459 and 3374 (NH2), 1586, 1502, 1435, 1370, 1283, 1256, 1082, 1046, 932, 845, 760, 638. 1H NMR (300.1 MHz, DMSO-d6): δ 8.23 (d, J = 3.6 Hz, 1H, CH), 8.02 (d, J = 8.4 Hz, 2H, 2CH), 7.90 (d, J = 4.8 Hz, 1H, CH), 7.75 (d, J = 8.3 Hz, 1H, CH), 7.40 (d, J = 8.4 Hz, 2H, 2CH), 7.32–7.21 (m, 2H, 2CH), 6.98 (t, J = 7.5 Hz, 1H, CH), 6.31 (d, J = 8.4 Hz, 1H, 1CH), 4.15 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 155.7, 151.0, 148.2, 144.8, 142.4 and 135.4 (6C), 131.1 (CH), 130.9 (2CH), 130.8 and 128.3 (2C), 128.2 (2CH), 127.4 (CH), 126.7 (C) 125.6, 124.7, 119.2, 118.9 and 114.0 (5CH). EI-MS, m/z (%): 376 (M+, 38), 265 (100), 294 (48), 209 (10), 184 (75), 167 (20), 128 (13), 99 (27).
2-(4-Bromo-phenyl)-4-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3m)
Yellow solid; yield: 83%, mp 268–271 °C. IR (KBr) (νmax/cm–1): 3429 and 3384 (NH2), 1583, 1498, 1445, 1358, 1267, 1242, 1145, 1061, 995, 846, 789, 748, 674, 625. 1H NMR (300.1 MHz, DMSO-d6): δ 8.10 (d, J = 8.3 Hz, 2H, 2CH), 7.75 (d, J = 7.8 Hz, 1H, CH), 7.64–7.48 (m, 7H, 7CH), 7.33 (t, J = 7.7 Hz, 1H, CH), 6.85 (t, J = 7.4 Hz, 1H, CH), 6.17 (d, J = 8.4 Hz, 1H, CH), 4.15 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 155.1, 147.9, 144.9, 136.3 and 136.0 (5C), 131.6 (2CH), 130.92 (C), 130.86 (2CH), 130.4 and 130.1 (2CH), 129.8 (2CH), 129.1 (2CH), 127.3 and 126.4 (2C), 124.8 (CH), 123.6 (C), 119.9 and 119.2 (2CH). EI-MS, m/z (%): 416 (M+, 100), 333 (17), 232 (15), 206 (22), 167 (35), 133 (16), 102 (33), 77 (38), 51 (13).
2-(4-Bromo-phenyl)-4-p-tolyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3n)
Yellow solid; yield: 90%, mp 278–279 °C. IR (KBr) (νmax/cm–1): 3469 and 3342 (NH2), 1605, 1492, 1428, 1371, 1295, 1245, 1180, 1045, 1015, 923, 879, 753, 695, 634. 1H NMR (300.1 MHz, DMSO-d6): δ 7.87 (d, J = 8.3 Hz, 2H, 2CH), 7.80–7.65 (m, 5H, 5CH), 7.64–7.48 (m, 4H, 4CH), 7.31 (t, J = 7.5 Hz, 1H, CH), 6.91 (t, J = 7.5 Hz, 1H, CH), 6.23 (d, J = 8.7 Hz, 1H, CH), 4.10 (s, 2H, NH2), 2.29 (s, 3H, CH3). 13C NMR (75.5 MHz, DMSO-d6): δ 155.7, 148.0, 144.6, 136.2, 135.5 (5C), 131.5 (2 × 2CH), 130.89 (2CH), 130.85 (2CH), 130.7 (CH), 129.5 (2CH), 129.2, 127.1, 126.6 and 126.4 (4C), 124.7 (CH), 123.5 (C), 120.0 and 119.1 (2CH), 21.2 (CH3). EI-MS, m/z (%): 428 (M+, 100), 338 (64), 273 (26), 184 (47), 172 (10), 156 (28), 107 (22).
2-(4-Methoxy-phenyl)-4-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3o)
Yellow solid; yield: 65%, mp 248–250 °C. IR (KBr) (νmax/cm–1): 3473 and 3359 (NH2), 1604, 1458, 1388, 1292, 1239, 1198, 1132, 1043, 994, 926, 831, 756, 698, 624. 1H NMR (300.1 MHz, DMSO-d6): δ 7.82 (d, J = 8.5 Hz, 2H, 2CH), 7.70 (d, J = 8.0 Hz, 1H, CH), 7.60–7.42 (m, 5H, 5CH), 7.38 (t, J = 7.9 Hz, 1H, CH), 7.07 (d, J = 8.5 Hz, 2H, 2CH), 6.96 (t, J = 7.6 Hz, 1H, CH), 6.30 (d, J = 8.3 Hz, 2H, 2CH), 4.13 (s, 2H, NH2), 3.82 (s, 3H, OCH3). 13C NMR (75.5 MHz, DMSO-d6): δ 160.0, 158.7, 148.2, 145.3 and 136.3 (5C), 130.5 (2CH), 130.2 and 129.9 (2CH), 129.4 (C), 129.3 (2CH), 128.6 (2CH), 127.7, 127.3 and 126.5 (3C), 124.6, 120.6 and 119.2 (3CH), 114.2 (2CH), 55.0 (OCH3). EI-MS, m/z (%): 366 (M+, 100), 274 (58), 201 (23), 188 (26), 92 (46), 79 (10), 51 (45).
2-(4-Methoxy-phenyl)-4-p-tolyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3p)
Yellow solid; yield: 84%, mp 274–275 °C. IR (KBr) (νmax/cm–1): 3438 and 3329 (NH2), 1605, 1458, 1401, 1376, 1273, 1178, 1075, 1023, 983, 878, 768, 659, 621. 1H NMR (300.1 MHz, DMSO-d6): δ 7.92 (d, J = 8.4 Hz, 2H, 2CH), 7.72 (d, J = 7.8 Hz, 1H, CH), 7.56 (d, J = 8.3 Hz, 2H, 2CH), 7.53 (d, J = 8.3 Hz, 2H, 2CH), 7.30 (t, J = 7.5 Hz, 1H, CH), 7.09 (d, J = 8.6 Hz, 2H, 2CH), 7.01 (t, J = 7.8 Hz, 1H, CH), 6.90 (d, J = 7.7 Hz, 1H, CH), 4.03 (s, 2H, NH2), 3.83 (s, 3H, OCH3), 2.39 (s, 3H, CH3). 13C NMR (75.5 MHz, DMSO-d6): δ 156.5, 155.2, 147.5, 144.5 and 137.7 (5C), 131.5 (CH), 130.9 (2CH), 129.9 (2CH), 129.5 (2CH), 129.3, 128.8, 127.1, 126.8 and 126.4 (5C), 124.5, 119.8 and 119.1 (3CH), 111.5 (2CH), 55.3 (OCH3), 21.2 (CH3). EI-MS, m/z (%): 380 (M+, 43), 278 (66), 167 (100), 135 (39), 77 (28), 51 (16).
2,4-Bis-(4-methoxy-phenyl)-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3q)
Yellow solid; yield: 70%, mp 291–292 °C. IR (KBr) (νmax/cm–1): 3452 and 3369 (NH2), 1587, 1498, 1354, 1298, 1134, 1065, 1022, 983, 933, 886, 798, 702, 649. 1H NMR (300.1 MHz, DMSO-d6): δ 7.96 (d, J = 8.5 Hz, 2H, 2CH), 7.74 (d, J = 8.0 Hz, 2H, 2CH), 7.72 (d, J = 7.9 Hz, 1H, CH), 7.35–7.18 (m, 5H, 5CH), 6.90 (t, J = 7.8 Hz, 1H, CH), 6.11 (d, J = 8.4 Hz, 1H, CH), 4.14 (s, 2H, NH2), 3.76 and 3.75 (2 s, 6H, 2OCH3). 13C NMR (75.5 MHz, DMSO-d6): δ 160.9, 160.2, 156.5, 148.4, 144.7 and 136.2 (6C), 130.5 (CH), 129.7 (C), 129.2 (2CH), 128.6 (2CH), 128.2, 127.1 and 126.2 (3C), 124.8, 120.3 and 119.2 (3CH), 116.0 (2CH), 115.1 (2CH), 55.2 and 53.6 (2OCH3). EI-MS, m/z (%): 396 (M+, 75), 288 (36), 230 (100), 212 (14), 184 (27), 108 (29).
2-(4-Methoxy-phenyl)-4-thiophen-2-yl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3r)
Yellow solid; yield: 82%, mp 274–277 °C. IR (KBr) (νmax/cm–1): 3488 and 3362 (NH2), 1596, 1503, 1487, 1363, 1278, 1243, 1137, 1041, 985, 962, 876, 795, 687, 632. 1H NMR (300.1 MHz, DMSO-d6): δ 8.24 (d, J = 3.8 Hz, 1H, CH), 7.90–7.68 (m, 4H, 4CH), 7.28–7.08 (m, 4H, 4CH), 6.94 (t, J = 7.8 Hz, 1H, CH), 6.17 (d, J = 8.4 Hz, 1H, CH), 4.24 (s, 2H, NH2), 3.91 (s, 3H, OCH3). 13C NMR (75.5 MHz, DMSO-d6): δ 159.2, 155.9, 150.4, 148.2, 144.8 and 141.8 (6C), 131.9 (CH), 131.8 (2CH), 131.6 (CH), 128.7, 127.4 and 126.5 (3C), 125.4, 124.9, 119.8 and 119.6 (4CH), 114.2 (2CH), 112.0 (CH), 54.3 (OCH3). EI-MS, m/z (%): 373 (M+ + 1, 100), 288 (16), 266 (72), 206 (38), 109 (49), 91 (14), 83 (23).
4-Phenyl-2-thiophen-2-yl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3s)
Yellow solid; yield: 78%, mp 265–267 °C. IR (KBr) (νmax/cm–1): 3473 and 3345 (NH2), 1589, 1495, 1432, 1386, 1241, 1174, 1098, 1028, 934, 859, 743, 659. 1H NMR (300.1 MHz, DMSO-d6): δ 8.19 (d, J = 3.5 Hz, 1H, CH), 7.87 (d, J = 5.2 Hz, 1H, CH), 7.72 (d, J = 8.0 Hz, 1H, CH), 7.62–7.45 (m, 4H, 4CH), 7.30 (t, J = 7.4 Hz, 1H, CH), 7.24 (d, J = 4.6 Hz, 1H, CH), 6.95–6.75 (m, 2H, 2CH), 6.16 (d, J = 8.1 Hz, 1H, CH), 4.26 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 155.3, 150.2, 147.7, 144.9, 141.7, 132.3 (6C), 131.6 (CH), 130.9 (2CH), 130.8 (CH), 129.5 (2CH), 128.6 (CH), 127.2 and 126.5 (2C), 125.3, 124.7, 119.9, 119.0 and 113.6 (5C). EI-MS, m/z (%): 342 (M+, 89), 258 (100), 228 (34), 189 (53), 177 (10), 91 (27), 82 (64).
2-Thiophen-2-yl-4-p-tolyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3t)
Yellow solid; yield: 69%, mp 276–277 °C. IR (KBr) (νmax/cm–1): 3474 and 3352 (NH2), 1585, 1522, 1486, 1448, 1346, 1220, 1188, 1072, 952, 899, 848, 774, 646, 623. 1H NMR (300.1 MHz, DMSO-d6): δ 8.19 (d, J = 3.5 Hz, 1H, CH), 7.89 (d, J = 5.0 Hz, 1H, CH), 7.70 (d, J = 8.2 Hz, 1H, CH), 7.58 (d, J = 8.4 Hz, 2H, 2CH), 7.55 (d, J = 8.3 Hz, 2H, 2CH), 7.38–7.22 (m, 2H, 2CH), 7.13–7.04 (m, 1H, CH), 6.90 (d, J = 8.4 Hz, 1H, CH), 4.26 (s, 2H, NH2), 2.29 (s, 3H, CH3). 13C NMR (75.5 MHz, DMSO-d6): δ 155.2, 150.2, 147.7, 144.9, 141.7, 140.7 and 132.4 (7C), 131.7 (CH), 130.9 (2CH), 129.5 (2CH), 128.7 (CH), 127.2 and 126.5 (2C), 125.3, 124.8, 119.9, 119.0 and 113.6 (5CH). EI-MS, m/z (%): 358 (M+ + 2, 100), 266 (8), 202 (45), 166 (32), 133 (24), 91 (63).
4-(4-Methoxy-phenyl)-2-thiophen-2-yl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3u)
Yellow solid; yield: 72%, mp 271–273 °C. IR (KBr) (νmax/cm–1): 3468 and 3343 (NH2), 1568, 1483, 1353, 1279, 1234, 1149, 1098, 983, 886, 785, 683, 642. 1H NMR (300.1 MHz, DMSO-d6): δ 8.13 (d, J = 3.4 Hz, 1H, CH), 7.91 (d, J = 4.8 Hz, 1H, CH), 7.84 (d, J = 8.6 Hz, 2H, 2CH), 7.71 (d, J = 8.0 Hz, 1H, CH), 7.35–7.20 (m, 2H, 2CH), 7.11 (d, J = 8.6 Hz, 2H, 2CH), 6.90 (t, J = 7.6 Hz, 1H, CH), 6.31 (d, J = 8.4 Hz, 1H, CH), 4.24 (s, 2H, NH2), 3.82 (s, 3H, OCH3). 13C NMR (75.5 MHz, DMSO-d6): δ 159.9, 155.8, 150.4, 147.6, 144.9, 141.8 and 132.8 (7C), 131.5 and 128.7 (2CH), 128.6 (2CH), 127.6 and 126.9 (2C), 125.5, 124.8, 120.5 and 119.2 (4CH), 115.3 (2CH), 113.5 (CH), 55.8 (OCH3). EI-MS, m/z (%): 372 (M+, 58), 296 (23), 273 (42), 265 (100), 248 (15), 206 (34), 108 (76).
4-(4-Chloro-phenyl)-2-thiophen-2-yl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3w)
Yellow solid; yield: 79%, mp 283–284 °C. IR (KBr) (νmax/cm–1): 3479 and 3326 (NH2), 1598, 1543, 1478, 1398, 1306, 1211, 1189, 1090, 973, 879, 837, 768, 723, 678, 641. 1H NMR (300.1 MHz, DMSO-d6): δ 8.17 (d, J = 2.9 Hz, 1H, CH), 7.87 (d, J = 5.4 Hz, 1H, CH), 7.83 (d, J = 8.3 Hz, 2H, 2CH), 7.74 (d, J = 8.3 Hz, 2H, 2CH), 7.70 (d, J = 7.8 Hz, 1H, CH), 7.31 (t, J = 7.8 Hz, 1H, CH), 7.25 (t, J = 3.3 Hz, 1H, CH), 6.93 (t, J = 7.6 Hz, 1H, CH), 6.18 (d, J = 8.3 Hz, 1H, CH), 4.36 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 155.4, 150.3, 147.6, 144.9, 141.6 and 135.8 (6C), 131.9 (2CH), 131.6 (CH), 130.7 (C), 130.5 (2CH), 128.6 (CH), 128.4 and 127.1 (2C), 125.5, 124.7, 120.0, 118.9 and 113.3 (5CH). EI-MS, m/z (%): 376 (M+, 100), 341 (10), 266 (12), 240 (22), 205 (48), 170 (32), 138 (15), 102 (30), 75 (20), 51 (14).
2,4-Di-thiophen-2-yl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3x)
Yellow solid, yield: 72%, mp 280–282 °C. IR (KBr) (νmax/cm–1): 3458 and 3306 (NH2), 1567, 1499, 1427, 1356, 1307, 1242, 1199, 1115, 1066, 960, 876, 824, 782, 716, 683, 642. 1H NMR (300.1 MHz, DMSO-d6): δ 8.21 (d, J = 3.2 Hz, 1H, CH), 8.07 (d, J = 4.3 Hz, 1H, CH), 7.89 (d, J = 4.4 Hz, 1H, CH), 7.87–7.67 (m, 3H, 3CH), 7.45–7.29 (m, 2H, 2CH), 7.06 (t, J = 7.6 Hz, 1H, CH), 6.62 (d, J = 8.3 Hz, 1H, CH), 4.43 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 155.7, 155.4, 151.0, 144.8, 142.7 and 142.4 (6C), 132.8 (CH), 131.1 (C), 130.9 130.4, 129.1 and 128.2 (4CH), 127.4 (C), 125.6, 121.0, 119.2, 118.9 and 114.0 (5CH). EI-MS, m/z (%): 348 (M+, 100), 272 (39), 266 (15), 182 (64), 174 (18), 82 (43).
7,8-Dichloro-2,4-diphenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3y)
Yellow solid, yield: 70%, mp 267–270 °C. IR (KBr) (νmax/cm–1): 3464 and 3325 (NH2), 1597, 1539, 1501, 1419, 1360, 1295, 1190, 1067, 966, 906, 879, 753, 683, 642. 1H NMR (300.1 MHz, DMSO-d6): δ 8.13 (dd, J = 2.1, 7.3 Hz, 2H, 2CH), 8.01 (s, 1H, CH), 7.89 (dd, J = 2.4, 7.5 Hz, 1H, CH), 7.79 (t, J = 7.4 Hz, 2H, 2CH), 7.62–7.45 (m, 5H, 5CH), 6.12 (s, 1H, CH), 4.23 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 157.3, 149.6, 144.4, 136.6, 136.4 (5C), 129.8 (2CH), 129.72 (2CH), 129.69 (CH), 129.6 (2CH), 128.71 (C), 128.67 and 128.6 (2CH), 128.1 (2CH), 127.5, 127.2, 126.6 and 126.2 (4C), 119.9 (CH). EI-MS, m/z (%): 405 (M+ + 1, 100), 327 (34), 250 (75), 233 (66), 170 (29), 133 (22), 76 (34).
7,8-Dichloro-4-(4-chloro-phenyl)-2-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3z)
Yellow solid, yield: 74%, mp 291–293 °C. IR (KBr) (νmax/cm–1): 3461 and 3384 (NH2), 1585, 1532, 1486, 1425, 1386, 1220, 1188, 1082, 1020, 958, 848, 784, 646, 621. 1H NMR (300.1 MHz, DMSO-d6): δ 8.00 (s, 1H, CH), 7.89–7.82 (m, 4H, 4CH), 7.74 (d, J = 8.5 Hz, 2H, 2CH), 7.63–7.46 (m, 3H, 3CH), 6.22 (s, 1H, CH), 4.34 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 157.3, 149.2, 143.8, 136.6, 135.9 (5C), 132.0 (2CH), 130.6 (2CH), 130.2 (CH), 129.7 (C), 128.73 (2CH), 128.66 (2CH), 128.2, 127.9 and 127.7 (3C), 127.6 (CH), 127.2 and 126.2 (2C), 120.0 (CH). EI-MS, m/z (%): 438 (M+, 43), 362 (100), 328 (22), 248 (72), 182 (36), 144 (12), 111 (24), 76 (10).
7,8-Dichloro-2-(4-chloro-phenyl)-4-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3aa)
Yellow solid, yield: 75%, mp 302–304 °C. IR (KBr) (νmax/cm–1): 3419 and 3329 (NH2), 1578, 1483, 1426, 1353, 1279, 1204, 1149, 1092, 963, 876, 832, 775, 683. 1H NMR (300.1 MHz, DMSO-d6): δ 8.15 (d, J = 8.6 Hz, 2H, 2CH), 7.99 (s, 1H, CH), 7.74–7.58 (m, 5H, 5CH), 7.45 (d, J = 8.6 Hz, 2H, 2CH), 6.15 (s, 1H, CH), 4.28 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 157.3, 149.1, 144.4, 135.2 and 134.9 (5C), 131.3 (2CH), 130.5 (CH), 129.8 (2CH), 129.3 (2CH), 129.2 and 128.7 (2C), 128.6 (CH), 127.9 (2CH), 127.3, 127.2, 126.4 and 126.2 (4C), 119.8 (CH). EI-MS, m/z (%): 436 (M+-2, 100), 360 (26), 328 (68), 249 (28), 184 (10), 111 (22), 82 (43).
7,8-Dichloro-2-(4-chloro-phenyl)-4-p-tolyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3ab)
Yellow solid, yield: 81%, mp 289–290 °C. IR (KBr) (νmax/cm–1): 3486 and 3362 (NH2), 1588, 1487, 1359, 1291, 1140, 1088, 959, 929, 846, 797, 683, 642. 1H NMR (300.1 MHz, DMSO-d6): δ 8.15 (d, J = 8.6 Hz, 2H, 2CH), 8.02 (s, 1H, CH), 7.58 (d, J = 8.2 Hz, 2H, 2CH), 7.57 (d, J = 8.4 Hz, 2H, 2CH), 7.50 (d, J = 8.2 Hz, 2H, 2CH), 6.24 (s, 1H, CH), 4.27 (s, 2H, NH2), 2.47 (s, 3H, CH3). 13C NMR (75.5 MHz, DMSO-d6): δ 157.3, 149.4, 144.4, 137.0, 136.5 and 135.2 (6C), 131.50 (2CH), 131.46 (CH), 130.7 (C), 130.0 (2CH), 129.6 (2CH), 129.2 and 128.6 (2C), 128.2 (2CH), 127.6, 126.6 and 125.6 (3C), 119.9 (CH), 21.1 (CH3). EI-MS, m/z (%): 452 (M+, 100), 308 (42), 266 (15), 218 (73), 202 (42), 133 (15), 111 (18), 91 (26).
7,8-Dichloro-2-(4-chloro-phenyl)-4-(4-methoxy-phenyl)-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3ac)
Yellow solid, yield: 75%, mp 294–295 °C. IR (KBr) (νmax/cm–1): 3466 and 3394 (NH2), 1579, 1498, 1362, 1294, 1247, 1183, 1096, 1043, 954, 879, 812, 772, 739, 690, 627. 1H NMR (300.1 MHz, DMSO-d6): δ 7.98 (s, 1H, CH), 7.86 (d, J = 8.9 Hz, 2H, 2CH), 7.77 (d, J = 8.5 Hz, 2H, 2CH), 7.61 (d, J = 8.5 Hz, 2H, 2CH), 6.98 (d, J = 8.9 Hz, 2H, 2CH), 6.50 (s, 1H, CH), 4.22 (s, 2H, NH2), 3.74 (s, 3H, OCH3). 13C NMR (75.5 MHz, DMSO-d6): δ 160.6, 157.3, 149.5, 144.8, 137.3 and 135.3 (6C), 132.7 (2CH), 131.3 (2CH), 131.0 (C), 130.1 (CH), 129.3 and 128.8 (2C), 128.6 (2CH), 127.4, 126.3 and 125.5 (3C), 119.9 (CH), 114.1 (2CH), 55.3 (OCH3). EI-MS, m/z (%): 468 (M+, 88), 357 (43), 346 (100), 234 (15), 133 (62), 125 (10), 108 (15), 51 (24).
7,8-Dichloro-2,4-bis-(4-chloro-phenyl)-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3ad)
Yellow solid, yield: 82%, mp 308–310 °C. IR (KBr) (νmax/cm–1): 3435 and 3384 (NH2), 1505, 1461, 1370, 1287, 1123, 1090, 965, 835, 791, 725, 646, 634. 1H NMR (300.1 MHz, DMSO-d6): δ 8.25 (s, 1H, CH), 8.03 (d, J = 8.5 Hz, 2H, 2CH), 7.93 (d, J = 8.4 Hz, 2H, 2CH), 7.82 (d, J = 8.5 Hz, 2H, 2CH), 7.72 (d, J = 8.4 Hz, 2H, 2CH), 6.24 (s, 1H, CH), 4.30 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 157.6, 149.5, 144.7, 137.3 and 135.7 (5C), 132.1 (2CH), 131.6 (2CH), 131.3 (C), 130.6 (CH), 129.9 (2CH), 129.5, 128.8 and 128.6 (3C), 128.4 (2CH), 127.2, 126.3 and 125.6 (3C), 119.9 (CH). EI-MS, m/z (%): 480 (M+, 100), 370 (37), 250 (45), 112 (67), 78 (19), 51 (25). EI-MS, m/z (%): 474 (M+, 100), 360 (49), 288 (10), 249 (34), 238 (26), 133 (16), 111 (38).
7,8-Dichloro-2-(4-chloro-phenyl)-4-thiophen-2-yl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3ae)
Yellow solid, yield: 73%, mp 275–278 °C. IR (KBr) (νmax/cm–1): 3489 and 3347 (NH2), 1585, 1522, 1486, 1448, 1346, 1340, 1288, 1173, 1062, 952, 949, 858, 774, 701, 646. 1H NMR (300.1 MHz, DMSO-d6): δ 8.15 (d, J = 3.1 Hz, 1H, CH), 7.95–7.82 (m, 4H, 4CH), 7.79 (s, 1H, CH), 7.76 (d, J = 2.0 Hz, 1H, CH), 6.11 (s, 1H, CH), 4.47 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 157.3, 150.8, 148.8, 144.1, 141.1 and 136.1 (6C), 132.4 (CH), 132.0 (2CH), 131.3 (CH), 130.6 (2CH), 130.3, 128.7, 127.7 and 127.2 (4C), 126.33 (CH), 126.25 (C), 120.6 and 114.5 (2CH). EI-MS, m/z (%): 444 (M+, 62), 360 (24), 332 (100), 266 (15), 208 (52), 113 (29), 82 (10).
2-(4-Bromo-phenyl)-7,8-dichloro-4-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3af)
Yellow solid, yield: 84%, mp 293–296 °C. IR (KBr) (νmax/cm–1): 3487 and 3328 (NH2), 1588, 1521, 1487, 1341, 1310, 1221, 1168, 1072, 978, 924, 851, 767, 697, 642. 1H NMR (300.1 MHz, DMSO-d6): δ 8.09 (d, J = 8.6 Hz, 2H, 2CH), 8.01 (s, 1H, CH), 7.74–7.64 (m, 7H, 7CH), 6.13 (s, 1H, CH), 4.29 (s, 2H, NH2). 13C NMR (75.5 MHz, DMSO-d6): δ 157.4, 149.4, 144.5, 136.6 and 135.4 (5C), 131.7 (2CH), 131.6 (C), 131.1 (2CH), 130.7 (CH), 129.8 (2CH), 129.7 (C), 129.5 (2CH), 128.9 (CH), 127.5, 127.3, 126.5 and 123.8 (4C), 119.9 (CH). EI-MS, m/z (%): 482 (M+, 100), 389 (23), 327 (44), 234 (86), 182 (64), 174 (18), 77 (15).
2-(4-Bromo-phenyl)-7,8-dichloro-4-p-tolyl-benzo[4,5]imidazo[1,2-a]pyrimidin-3-ylamine (3ag)
Yellow solid, yield: 76%, mp 306–308 °C. IR (KBr) (νmax/cm–1): 3467 and 3343 (NH2), 1578, 1483, 1353, 1279, 1204, 1149, 1092, 963, 876, 832, 775, 743, 663. 1H NMR (300.1 MHz, DMSO): δ 8.05 (d, J = 8.6 Hz, 2H, 2CH), 7.95 (s, 1H, CH), 7.68 (d, J = 8.6 Hz, 2H, 2CH), 7.58 (d, J = 8.0 Hz, 2H, 2CH), 7.50 (d, J = 8.0 Hz, 2H, 2CH), 6.22 (s, 1H, CH), 4.26 (s, 2H, NH2), 2.48 (s, 3H, CH3). 13C NMR (75.5 MHz, DMSO-d6): δ 157.3, 149.4, 144.4, 136.84, 136.78 and 135.3 (6C), 131.7 (2CH), 131.6 (CH), 131.1 (2CH), 130.8 (C), 130.0 (2CH), 129.7 (2CH), 129.5, 127.6, 126.5, 125.9 and 123.8 (5C), 119.9 (CH), 21.2 (CH3). EI-MS, m/z (%): 496 (M+, 100), 342 (25), 326 (74), 263 (14), 167 (48), 133 (25), 79 (33), 51 (18).
3-Chloro-2,4-diphenyl-benzo[4,5]imidazo[1,2-a]pyrimidine (4a)
Yellow solid, yield: 56%, mp 228–229 °C. IR (KBr) (νmax/cm–1): 1578, 1529, 1474, 1437, 1376, 1297, 1251, 1214, 1175, 1091, 1026, 954, 908, 834, 805, 728, 637. 1H NMR (300.1 MHz, DMSO): δ 7.64 (dd, J = 1.6, 7.2 Hz, 2H, 2CH), 7.45–7.20 (m, 9H, 9CH), 7.00 (t, J = 7.8 Hz, 1H, CH), 6.86 (t, J = 7.6 Hz, 1H, CH), 6.32 (d, J = 8.1 Hz, 1H, CH). 13C NMR (75.5 MHz, DMSO-d6): δ 156.7, 143.1, 136.8, 135.3 and 131.2 (5C), 130.6 (CH), 130.3 (2CH), 129.5 (CH), 129.4 (2 × 2CH), 128.7 (2CH), 128.5 (C), 127.8 (CH), 126.2 and 126.1 (2C), 124.9, 120.2 and 119.2 (3CH). EI-MS, m/z (%): 355 (M+, 100), 204 (48), 145 (52), 167 (75), 77 (32), 51 (25).
2,4-Diphenyl-benzo[4,5]imidazo[1,2-a]pyrimidine (6a)
Yellow solid, yield: 65%, mp 206–208 °C. IR (KBr) (νmax/cm–1): 1603, 1505, 1461, 1370, 1302, 1250, 1187, 1090, 1048, 1006, 965, 897, 834, 785, 732, 634. 1H NMR (300.1 MHz, DMSO): δ 8.40 (d, J = 8.0 Hz, 2H, 2CH), 7.90–7.35 (m, 9H, 9CH), 7.29 (s, 1H, CH), 7.05 (t, J = 7.8 Hz, 1H, CH), 6.93 (t, J = 7.5 Hz, 1H, CH), 6.53 (d, J = 7.9 Hz, 1H, CH). 13C NMR (75.5 MHz, DMSO-d6): δ 159.9, 152.4, 144.5, 138.6, 136.4 and 131.8 (6C), 130.8 and 130.4 (2CH), 130.2 (2CH), 130.0 (2CH), 129.7 (2CH), 128.6 (CH), 128.2 (2CH), 127.8 and 126.9 (2C), 125.4, 120.4, 118.7 and 108.5 (4CH). EI-MS, m/z (%): 321 (M+, 100), 244 (18), 167 (25), 79 (65), 52 (45).
Saccharomyces cerevisiae α-glucosidase inhibition assay
α-Glucosidase enzyme ((EC3.2.1.20, Saccharomyces cerevisiae, 20 U/mg) and substrate (p-nitrophenyl glucopyranoside) were purchased from Sigma-Aldrich. Enzyme was prepared in potassium phosphate buffer (pH 6.8, 50 mM), and ploy-substituted-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag, 4a, and 6a was dissolved in DMSO (10% final concentration). The various concentrations of these compounds (20 mL), enzyme solution (20 mL) and potassium phosphate buffer (135 mL), were added in the 96-well plate and incubated at 37 °C for 10 min. Then, the substrate (25 mL, 4 mM) was added to the mentioned mixture and allowed to incubate at 37 °C for 20 min. Finally, the change in absorbance was measured at 405 nm by using spectrophotometer (Gen5, Power wave xs2, BioTek, America). DMSO (10% final concentration) and acarbose were used respectively as control and standard drug. The percentage of enzyme inhibition was calculated and IC50 values were obtained from non-linear regression curve using the Logit method67. The statistical analyses were provided using SigmaStat 14.0 (Systat Software, Inc | Tools For Science).
Kinetic studies
The kinetic analysis was carried out to determine inhibition mode of most potent compound 3k. The 20 mL of enzyme solution (1 U/mL) was incubated with different concentrations (0, 45, 65, and 80 mM) of compound 3k for 15 min at 30 °C. The reaction was then started by adding different concentrations of substrate (p-nitrophenyl glucopyranoside,1–4 mM), and change in absorbance was measured for 20 min at 405 nm by using spectrophotometer (Gen5, Power wave xs2, BioTek, America).
Rat α-glucosidase assay
Rat small intestine α-glucosidase (EC 3.2.1.20) was prepared according to the method provided by Lossow et al. (1964). Enzyme in vitro activity was determined by recording the release of 4-nitrophenol from Pnitrophenyl α-D glucopyranoside according to the method described by Kim68,69. Final volume of 200 μL of assay solution was prepared in a 96-well plate as follow: the enzyme solution (190 μL, 0.15 units/ml), different concentrations of ploy-substituted-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag, 4a, and 6a (1, 10, 20, 50, 100, 500 and 1000 μM (5 μL)), and potassium phosphate buffer. Test compounds were dissolved in DMSO (not exceed than 5% of final volume). After 10 min. of pre-incubation at 37 ◦C, p-nitrophenyl glucopyranoside as substrate (5 μL, 3 mM), was added to the enzyme solution and let to be incubated for one hour at 37 ◦C. Finally, the change in the absorbance was followed at 405 nm using Cytation 3 hybrid microplate reader (BioTek, USA). DMSO and acarbose were used as the control and standard inhibitor, respectively. IC50 values of tested compounds were obtained from the nonlinear regression curve using GraphPadprism 6.0 (San Diego, California, USA) (https://www.graphpad.com/scientific-software/prism/).
All experimental animal procedures were approved by the Animal Care, use Ethics Committee at Shahid Beheshti University of Medical Sciences (SBMU), and comply with the Animal Research Reporting of In Vivo Experiments (ARRIVE) guidelines. All methods proposed here were performed in accordance with relevant institutional guidelines and regulations.
Molecular docking study
Since the X-ray crystallographic structure S. cerevisiae α-glucosidase isn’t accessible, the 3D structure of S.cerevisiae isomaltase with PDB ID: 3A4A was downloaded from RCSB web site with 84% similarity to S. cerevisiae α-glucosidase15.
Docking studies were performed based on previous studies34,70,71 using Auto Dock Tools (version1.5.6), and the pdb structure of 3A4A and 3TOP were taken from the Brookhaven protein database (http://www.rcsb.org). The 3D structures of the selected compounds were created by MarvineSketch 5.8.3, 2012, ChemAxon (http://www.chemaxon.com) and converted to pdbqt coordinate using Auto dock Tools. Before preparation of auto dock format of protein, the water molecules and the inhibitors were removed from it. Then, using Auto Dock Tools, polar hydrogen atoms were added, Kollman charges were assigned, and the obtained enzyme structure was used as an input file for the AUTOGRID program. In AUTOGRID for each atom type in the ligand, maps were calculated with 0.375 A spacing between grid points, and the center of the grid box was placed at x = 22.625, y = − 8.069, and z = 24.158 for 3A4A and x = − 51.5, y = 9, and z = − 64.8 for 3TOP. The dimensions of the active site box were set at 50 × 50 × 50 A. Each docked system was carried out by 150 runs of the AUTODOCK search by the Lamarckian genetic algorithm. The best pose of each ligand was selected for analyzing the interactions between α-glucosidase and the inhibitor. The results were visualized using Discovery Studio 4.0 Client (https://discover.3ds.com/discovery-studio-visualizer-download) and LigPlot (https://www.ebi.ac.uk/thornton-srv/software/LigPlus/download.html) (Figs. 3, 4, 5, 6, 7).
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Acknowledgements
This work was supported and funded by Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences; Gran No. 1400-1-109-51439.
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A.F. and P.R.-R. designed the study and conducted the experiments. F.P., G.T., and T.S. synthesized the targeted compounds. F.P. and H.R.B. wrote the manuscript, analyzed the characterization data, and prepared the Supporting Information File. L.F., M.N., and Z.E. carried out the docking studies. M.N. and S.M. revised the manuscript. M.A.F. and S.M. performed the in vitro Saccharomyces cerevisiae analysis, kinetic study against α-glucosidase, and cytotoxicity studies. S.K. and R.P. prepared the rat small intestine α-glucosidase and performed the inhibition investigations.
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Peytam, F., Takalloobanafshi, G., Saadattalab, T. et al. Design, synthesis, molecular docking, and in vitro α-glucosidase inhibitory activities of novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines against yeast and rat α-glucosidase. Sci Rep 11, 11911 (2021). https://doi.org/10.1038/s41598-021-91473-z
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DOI: https://doi.org/10.1038/s41598-021-91473-z
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