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Year : 2013  |  Volume : 5  |  Issue : 1  |  Page : 39-43  

Synthesis and PASS-assisted in silico approach of some novel 2-substituted benzimidazole bearing a pyrimidine-2, 4, 6(trione) system as mucomembranous protector

1 Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, Kerala, India
2 Department of Pharmaceutical Chemistry, Madras Medical College, Chennai, Tamil Nadu, India
3 Department of Pharmaceutical Chemistry, Karuna College of Pharmacy, Palakkad, Kerala, India

Date of Submission22-Jul-2012
Date of Decision05-Sep-2012
Date of Acceptance27-Sep-2012
Date of Web Publication28-Jan-2013

Correspondence Address:
Bijo Mathew
Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0975-7406.106563

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Purpose: The present paper demonstrates the utility of PASS computer-aided program and makes a clear comparison of predicted and observed pharmacological properties of some novel 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] pyrimidine-2, 4, 6 (1H, 3H, 5H)-triones (5a-f). Materials and Methods: The synthesis of the titled derivatives were achieved by the reaction between 2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ones (4a-f) and barbituric acid in the presence of catalytic amount of acetic acid medium. All the final structures were assigned on the basis of IR, 1 HNMR and mass spectra analysis. All the newly synthesized compounds were screened for their antiulcer activity in the pylorus-ligated rats. Results: Compounds 5b, 5e and 5c showed a percentage protection of (69.58, 69.56 and 67.17 at a dose of 50 mg/kg b.w.) when compared to standard omeprazole (77.37%, 2 mg/kg b.w.). Conclusion: Scanning of stomach specimens using electron microscope revealed that the mice treated with standard and synthetic derivatives had no injury observed in stomach mucosa, which is identical to that of the control animal.

Keywords: Acetyl salicylic acid, antiulcer activity, barbituric acid, prediction of activity spectra for substances-program

How to cite this article:
Mathew B, Suresh J, Anbazhagan S. Synthesis and PASS-assisted in silico approach of some novel 2-substituted benzimidazole bearing a pyrimidine-2, 4, 6(trione) system as mucomembranous protector. J Pharm Bioall Sci 2013;5:39-43

How to cite this URL:
Mathew B, Suresh J, Anbazhagan S. Synthesis and PASS-assisted in silico approach of some novel 2-substituted benzimidazole bearing a pyrimidine-2, 4, 6(trione) system as mucomembranous protector. J Pharm Bioall Sci [serial online] 2013 [cited 2016 Oct 1];5:39-43. Available from:

Benzimidazoles were commonly used as proton pump inhibitors, which can control the hyperacidity in the stomach. [1] The recent literature revealed that pyrimidine nucleus has a considerable attention in producing less ulcerogenic index. [2],[3] In the view of above reports, it was thought worthwhile to design a novel framework by which the benzimidazole derivatives were linked with the pyrimidine nucleus and evaluated their anti-ulcer activity. Barbituric acid is a pyrimidine, containing strong acid (pka =4.01, in aqueous medium) with an active methylene group and can be involved in condensation reactions with aldehydes or ketones. Barbituric acid and their 5,5-disubstituted derivatives were extensively used in the class of hypnotics-sedatives. Their pharmacological action mainly constituted with the introduction of dialkyl lipophilic groups in the 5 th position of the activated methylene group. [4] Various barbitone derivatives condensation with carbonyl compounds possessing different pharmacological profiles, such as urease inhibitors, [5] antimicrobial, [6] selective cell adhesion inhibitors, [7] antioxidant and DNA cleavage activities [8] have already been reported.

The aim of our research proposal was the incorporation of barbituric acid to the 2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ones (4a-f) and produce an exocyclic olefinic linkage. The benzimidazole chalcones (4a-f) were prepared by reacting 2-acetyl benzimidazole with appropriate aldehydes in the presence of a base by Claisen-Schmidt condensation. [9] The condensation of benzimidazole chalcones (4a-f) with barbituric acid in acetic acid gave the titled derivatives (5a-f). [10],[11] Novel pharmacological actions can be predicted for 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ylidene]pyrimidine-2, 4, 6 (1H,3H,5H)-triones with the aid of PASS (Prediction of Activity Spectra of the Substances). [12]

   Materials and Methods Top

All the solvents and chemicals were purchased from MERCK, Nice chemicals and SD Fine Chemicals. Melting points were determined by using melting point apparatus MP-DS TID 2000 V and the values were uncorrected. Reactions were monitored by thin layer chromatography (TLC - methanol: acetone, 6: 4) on pre-coated silica gel G plates using iodine vapor as visualizing agent. IR spectra were recorded on JASCO FT/IR-140 spectrophotometer by using KBr pellets technique. PMR spectra were recorded using BRUCKER FT-NMR-500 MHz spectrophotometer by using DMSO as solvent and TMS as internal standard. The chemical shift was expressed in δ ppm. Mass spectra were recorded on a JEOL GCmate mass spectrometer. PASS prediction of the compounds was done from the website:

The experimental protocol for the pharmacological screening on rats were done with an Institutional Animal Ethics Committee, K.M. College of Pharmacy, Madurai, India (Reg no: 661/02/c/CPCSEA).

Synthesis of (2E)-1-(1H-benzimidazol-2-yl)-3-Phenylprop-2-en-1-one (4a-f)

2-Acetyl benzimidazole (0.01 mol) and appropriately substituted aromatic aldehydes (0.012 mol) were mixed in ethanol (20 ml) containing 10% aq. KOH (8 ml) and magnetically stirred the solution constantly at room temperature for 10 h. The whole mixture was transferred into a 100 ml ice cold water and acidified with dil. HCl. The solid formed was washed, filtered and dried, recrystallized from absolute ethanol.

Synthesis of 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-Phenylprop-2-en-1-ylidene] Pyrimidine-2, 4, 6 (1H, 3H, 5H)-triones (5a-f)

To a solution of (4a-f) (0.01 mol) was suspended in 7 ml acetic acid. To this barbituric acid (0.01 mol) was added with constant stirring. The reaction mixture was then refluxed for 7 h with occasional stirring. The reaction progress was monitored by TLC (methanol: acetone, 6: 4). The resultant contents were poured into crushed ice. The crude product was filtered, washed with water and recrystallized from methanol. Physical characterization of all the synthesized derivatives is shown in [Table 1]. The details of the spectral characterization of the final derivatives were given below.
Table 1: Physical characterization and insilico screening of (5a-f)

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5a: FT-IR(KBr,V max cm 1 )

3230(NHstr),1693(C=O),1587 (C=N). 1 HNMR(DMSO-d 6 ), δ ppm9.1(1H,s,NHbenzimidazole), 8.0-8.4(2H,s,pyrimidineNH)6.4-8.1(11H,m,9ArH,2CH=CH).M.S: m/z=359.21 (M + +1).

5b: FT-IR(KBr,V max cm−1 )

3232(NHstr),1678(C=O),1581(C=N),771(Ar-Cl). 1 HNMR(DMSO-d 6 ), δppm:8.9(1H,s,NHbenzimidazole),8.4-8.6(2H,s,pyrimidineNH)6.4-8.3(11H,m,9ArH,2CH=CH).M.S: m/z=394.1 (M + +2)

5c: FT-IR(KBr,V max cm−1 )

3239(NHstr),1681(C=O),1576(C=N), 1 HNMR(DMSO-d 6 ), δ ppm:8.9(1H,s,NHbenzimidazole),8.4-8.6(2H,s,pyrimidineNH),6.4-8.3(10H,m,8ArH,2CH=CH).3.3(3H,s,OCH 3 ). M.S: m/z=390.06 (M + +1).

5d: FTIR(KBr,V max cm 1 )

3227(NHstr).1678(C=O),1569(C=N). 1 HNMR(DMSO-d 6 ), δ ppm:8.9(1H,s,NHbenzimidazole),8.5-8.7(2H,s,pyrimidineN),6.3-8.4(10H,m,8ArH,2CH=CH).3.3(6H,s,N(CH 3 ) 2 M.S: m/z=402.56 (M + +1)

5e: FT-IR(KBr,V max cm−1 )

3227(NHstr).1678(C=O),1569(C=N),1310(Ar-NO 2 ). 1 HNMR(DMSO-d 6 ),δppm:8.5(1H,s,NHbenzimidazole),8.2-8.4(2H,s,pyrimidineNH),6.4-8.4(10H,m,8ArH,2CH=CH) M.S: m/z=405.56 (M + +2)

5f: FT-IR(KBr,V max cm−1 )

3379(ArOH),3231(NHstr),1680(C=O),1562(C=N). 1 HNMR(DMSO-d 6 ),δppm:9.1(1H,s,NHbenzimidazole),8.4-8.8(2H,s,pyrimidineNH)6.4-8.5(10H,m,8ArH,2CH=CH),5.62(1H,s,ArO-H) M.S: m/z=375.65 (M + +1)

Biological activity spectra prediction

Estimation of general biological potential for drug-like compounds on the basis of their structural formulae can be performed with a computer program PASS (Prediction of Activity Spectra for Substances) that predicts more than 780 pharmacological effects. All the structures of the derivatives were built by ACD Chemsketch version 12.0 and saved as mol format. These can mol formats can be imported into the PASS for prediction of the biological activity. This program was based on a robust analysis of structure-activity relationships in a heterogeneous training set. A biological spectrum for a substance is a list of biological activity types for which the probability to be revealed (Pa) and not to be revealed (Pi) values are independent and their values ranges from 0 to 1. The more is the Pa value, the less is the probability of false positives in the set of compounds selected for study. [13],[14],[15] All the titled derivatives predicted a biological activity of mucomembranous protector nature with a Pa values more than 0.70. The details of the activity score are showed in [Table 1].

Aspirin induced and pyloric ligation ulcer model

The albino rats were divided into eight groups each group containing six animals. The study was carried out for four days after administration of the treated dose half hour after the rats were treated with aspirin 200 mg/kg. This process was carried out for three days. On the third day after administration of drug, the rats were subjected to fasting. On the next day pyloric ligation was made. The rats were sacrificed four hours later by cervical dislocation and the esophagi were clamped, the stomach was exposed carefully, opened along the greater curvature, the luminal contents were removed, and the total volume of gastric secretion, total acidity, free acidity were estimated by titration method. The ulcer index was calculated according to the method of Ganguly and Bhatnagar. [16] Mean ulcer score for each animal was expressed as ulcer index. The percentage of ulcer inhibition was determined as follows:

Values are expressed as MEAN ± SEM, values were found by using One-way ANOVA followed by Newman Keul's multiple range tests [Table 2]. Probability value <0.01 was considered significant.
Table 2: Antiulcer activity of final derivatives (5a-f)

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   Results and Discussion Top


The present study described a Knoevenagel condensation between a benzimidazole chalcone and barbituric acid by using experimental protocol as shown in [Figure 1]. The structures of all the final derivatives were established on the basis of spectral analysis. IR spectrum of the 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-phenylprop-2-en-1-ylidene] pyrimidine-2, 4, 6 (1H, 3H, 5H)-trione 5b showed a strong absorption band at 3232 cm -1 corresponding to benzimidazole NH and absorption at 2910 and 2878 cm -1 corresponding to pyrimidine NH/NH. A sharp absorption at 1678 cm -1 corresponds to carbonyl stretching and 771 cm -1 due to aryl chloride. The 1 HNMR spectra showed the singlet peak at δ 8.4, and δ 8.6 was assigned to pyrimidine NH/NH. The singlet peak was at δ 8.9 corresponding to benzimidazole NH. The doublet for vicinal protons has been seen along with the aromatic multiplet between δ 6.4δ and 8.3 ppm. Mass spectrum of compound 5b revealed the molecular ion peak [M+2] at m/z 394 corresponding to the molecular mass of the compound. Mass fragmentation pattern of 5b gave a base peak of m/z 58 which corresponds to the molecular formula of CH 2 N 2 O. This splitting of the urea fragment from the 5b also made full agreement with the structure of final barbitone moiety.
Figure 1: Scheme of synthetic route of the titled compounds

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PASS in silico approach

The PASS program predicted the mucomembranous protector nature probabilities 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] pyrimidine-2, 4, 6 (1H, 3H, 5H)-triones (5a-f) showing the following rank order 5d >5b >5c >5a >5e >5f. It is important to note that compounds 5d, 5b and 5c showed a percentage protection of (69.58, 69.56 and 67.17 at a dose of 50 mg/kg b.w.) when compared to standard omeprazole (77.37%, 2 mg/kg b.w.). This suggested a good correlation between the predicted and observed activity score in the final candidates.

Biological evaluation

Administration of 200 mg/kg ASA suspension intragastrically consistently caused hemorrhagic lesions in the mucosa of the glandular stomach, indicating true ulcer formation as stated in histological findings. Pretreatment of rats with intragastric synthetic drugs prevented gastric ulcerogenesis significantly. But it seemed to be less efficient than standard drug like omeprazole. The stomach specimen of aspirin-treated rats was characterized by complete disruption of protective mucosal layer [Figure 2]. The tissue of aspirin-treated rats had shown that some epithelial cells in the ulcer margin had proliferated and migrated over and into the ulcer crater, which was strongly infiltrated by inflammatory cells, fibroblasts and endothelial cells indicating complete disruption of gastric epithelial layer. Scanning of stomach specimens using electron microscope revealed that in the rats treated with omeprazole, 5b and 5d [Figure 3], [Figure 4], [Figure 5], there was no injury observed in stomach mucosa, which is identical to that of the control animal [Figure 6].
Figure 2: Ulcer control

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Figure 3: Positive control

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Figure 4: Treatment with 5b

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Figure 5: Treatment with 5d

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Figure 6: Normal control

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   Conclusion Top

In conclusion, a series of some novel 5-[(2E)-1-(1H-benzimidazol-2-yl)-3-substituted phenylprop-2-en-1-ylidene] pyrimidine-2, 4, 6 (1H, 3H, 5H)-triones were synthesized. We also demonstrated that most of the titled compounds showed moderate in vivo antiulcer activity but all the derivatives exhibited a good mucomembranous protector. The study has also shown an increase probability of compounds to be biologically active if they are selected on the basis of PASS prediction.

   Acknowledgments Top

The authors are highly thankful to Dr. N. Chidambaranathan, K.M. College of Pharmacy, Madurai, India for pharmacological screening. Our sincere thanks also go to SAIF, IIT-Chennai for carrying out the spectral analysis.

   References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1], [Table 2]

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