ISSN: 2278-778X Research Article www.ijbio.com International Journal of Bioassays (IJB) 256 SYNTHESIS AND EVALUATION OF NOVEL PYRIMIDYLTHIOMETHYL AND PYRIMIDYL- SULFINYLMETHYL BENZIMIDAZOLES DERIVATIVES FOR THEIR ANTIULCER ACTIVITY Tribhuvan Singh* 1 , SA Sreenivas 1 , R Parameshwar 1 , Abhimanyu 2 , K Indira 1 , Vyashnavi Vuppala 1 , CH Lavanya 1 , M Srinivas 1 1 Department Of Pharmaceutical Chemistry, Guru Nanak School of pharmacy, Ibrahimpatnam, Hyderabad- 501506 2 Gurukulkanri Vishwavidyalaya, Haridwar, Uttarakhand-249404 *Corresponding Author: Mr. Tribhuvan Singh, Department Of Pharmaceutical Chemistry, Guru Nanak School of pharmacy, Ibrahimpatnam, Hyderabad- 501506 Received for publication: October 02, 2012; Accepted: October 28, 2012. Abstract: A series of novel pyrimidylthiomethyl benzimidazole (IIa-c) and pyrimidylsulfinylmethyl benzimidazolles (III a-c) have been synthesized and evaluated for their antiulcer activity, by the pylorus ligation of rats (say method). Compound IIa and IIIa when evaluated significantly decreased the gastric acid secretion, free acidity, as well as gastric ulcer in the pylorus ligated rats and the effects are dose dependent and comparable to omeprazole of the two compounds, the sulfinyl derivative IIIa is more effective then the thio analog IIa. Keywords: Antiulcer agents, H/K ATPase inhibitors, Pyridylmethylsulfinyl benzimidazole, Pyrimidylthiomethyl benzimidazole, Pyrimidylsulfinylmethyl benzimidazole. INTRODUCTION Pyridylmethylsulfinyl benzimidazoles derivatives such as omeprazole, rebeprazole, lansoprazole, pantoprazole, esomptazole are the drug of choice for the acid related gastrointestinal disorders. These drugs act by inhibiting the proton pump (H/K ATPase ) which is involved in the acid secretion in the stomach 1 . The proton pump is responsible for the exchange of K ions with the H of the parietal cells in the stomach 2 . The proton pump inhibitors bind covalently to the cysteine 813 and cystine -822 residues of the H/ K ATPase, which leads to the inhibition of acid secretion 3 . Acid catalyzed activation of pyridylmethylsulfinyl benzimidazole with in the acidic medium in the parietal cells leads to the formation of a reactive intermediate, sulfonamide that irreversibly binds to the thiol group of the enzyme present in the apical membrane of parietal cells 4 . We here in report two novel series pyrimidylmethyl thio/ sulfinyl benzimidazoles IIa-c and III a-c as potent reversible proton pump inhibitors. The target compounds were prepared from the appropriate 4, 6- disubstituted-2-mercaptopyrimidines and their subsequent condensation with 2- chloromethylbenzimidazole, followed by controlled oxidation of the condensation products (IIa-c) to the corresponding sufinyl derivatives (IIIa-c). The 2- chloromethylbenzimidazole has been prepared in excellent yield and purity through the microwave irradiation based condensation of o- phenyldiamine and chlorlacetic acid. + Conc.HCl EtOH Reflux N N R 1 R 2 SH + N N H Cl N H 2 N H 2 ClCH 2 .COOH Con.HCl NaOH RT N H N S N N R 1 R 2 N H S N N O N R 1 R 2 m-CPBA 0 - 2 0 c III a - c II a - c SCHEME O O R 1 R 2 N H 2 NH 2 S MWI,300W a=R 1 =R 2 =CH 3 b=R 1 =CH 3 ,R 2 =C 6 H 5 c=R 1 =OH,R 2 =CH 3 MATERIALS AND METHODS All the chemicals used in the synthesis were of laboratory grade (Loba chem., Mumbai). The melting points were determined in open capillary on veego (VMP) electronic apparatus and uncorrected. The IR spectra of the entire synthesized compound were recorded on Perkin Elmer BX2 FTIR Spectrometer in potassium bromide (anhydrous IR grade) pellets. 1 H NMR spectrum was recorded in DMSO- d 6 NMR Varian- Mercury 300 MHz with super conducting magnet. Mass spectra were obtained on an electron impact mass spectrometer at 70ev ionizing beam and using direct insertion probe Shimadzu GCMS- QP- 2010. Progress of the reaction were monitored TLC, performed on microscopic glass slides coated with silica gel-G, using benzene-methanol (4.5:0.5) or hexane, ethyl acetate and glacial acetic acid (3:2:2 drops) as the solvent system and the spot were visualized by expose to iodine vapors or under uv light.