Biological Evaluations of some Synthesized Pyrimidothieno [2,3-b] Pyrimidine...

[Full title: Biological Evaluations of some Synthesized Pyrimidothieno [2,3-b] Pyrimidine Candidates as Antiulcer Agents]

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International Journal of Pharmacology 11 (7): 840-845, 2015 ISSN 1811-7775 © 2015 Asian Network for Scientific Information Asian Network for Scientific Information ans net . RESEARCH ARTICLE OPEN ACCESS DOI: 10.3923/ijp.2015.840.845 Biological Evaluations of some Synthesized Pyrimidothieno [2,3-b] Pyrimidine Candidates as Antiulcer Agents 1,2 Abd El-Galil E. Amr, 1 Mohamed A. Al-Omar and 3 Mohamed M. Abdalla 1 Department OF Pharmaceutical Chemistry, Drug Exploration and Development Chair (DEDC), College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia 2 Department of Applied Chemistry, National Research Center, Dokki, Cairo, Egypt 3 Research Unit, Saco Pharm. Co., 6 th October City, 11632, Egypt A R T I C L E I N F O Article History: Received: May 25, 2015 Accepted: August 28, 2015 Corresponding Author: Mohamed M. Abdalla Research Unit, Saco Pharm. Co., 6 th October City, 11632, Egypt A B S T R A C T Here the report antiulcer activity of some 2,6-bis substituted pyrimidothienopyridine (1-9). Eighteen pyrimidothienopyridine derivatives were synthesized and screened as analgesic, anticonvulsant and antiparkinsonian agent before. Many pyrimidines derivatives were synthesized and showed wide diversity of excellent biological activities, the most interesting one amongest these activities the antiulcer activates. It was proven that the antiulcer activities of many pyrimidines derivatives were due to their proton Pump Inhibitor Activities (PPI). Herein and due to structure similarity between the compounds in study and some pyrimidines derivatives showed potent antiulcer activities, the antiulcer activities of these compounds were evaluated using pyloric ligation ulcer model. All the tested compounds showed potent antiulcerogenic activities and the potency descending order was 6 b, 6 a, 5 b, 5 a, 7 b, 7 a, 9 b, 9 a, 8 b, 8 a, 2 b, 2 a, 3 b, 3 a, 4 b, 4 a, 1 b and 1 a. To specify the accurate mechanism of antiulcer activity, many animal models were used the only one that give fruit results was H+/K+-ATPase inhibition in membrane vesicles of stomach mucosa that proved all antiulcer activities of the tested compounds accomplished via H+/K+-ATPase (proton pump) inhibition activities Key words: 2 , 6 - b i s [ p y r i m i d o t h i e n o p y r i d i n e ] p y r i d i n e , 2 , 6 - b i s [triazinothienopyridine] pyridine, antiulcer activity INTRODUCTION The thienopyridines are prodrugs and metabolized in the liver to active metabolites that are non-competitive antagonists of the platelet adenosine diphosphate receptor, P 2 Y 12 (Kam and Nethery, 2003). Thienopyridine derivatives are heterocyclic system and have high pharmacological activity and they have found practical application in medicine as anti-inflammatory and analgesic activities (Madhusudana et al ., 2012). Additionally, several types of thiophene and their derivatives were reported to possess cytotoxicity (Pinney et al ., 1999; Romagnoli et al ., 2006, 2010). One the other hand, antitumor activity of some, thiazole, thiophene and pyridine derivatives were reported (Ghorab and Al-Said, 2012). Recently, some of heterocyclic system incorporated with thiophene ring has been reported as (Abdalla et al ., 2014; Amr et al ., 2010; Hossan et al ., 2012; Assy et al ., 2013). In view of these observations, we have herein synthesized of some pyrimidothieno[2,3-b]pyrimidine candidates for their evaluation as antiulcerogenic agents MATERIALS AND METHODS Chemistry: All the tested compounds were confirmed by physical and spectroscopic evidences according to the previously reported procedures (Amr et al ., 2003) 840 www.ansinet.com | Volume 11 | Issue 7 | 2015 |

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Int. J. Pharmacol., 11 (7): 840-845, 2015 Pharmacological screening Anti-ulcer activity: Male rats (140 and 175 g) were selected for pyloric ligation ulcer model and they are divided into eleven groups consisting of six animals each and were fasted overnight. One group received normal saline 2 mL kg G 1 (negative control). The second group received omeprazole 40 mg kg G 1 (positive control) and the other groups received test compounds (100 mg kg G 1 ) by oral route 30 min prior to pyloric ligation. Animals were sacrificed 4 h later and the stomach was opened to collect the gastric contents. The gastric contents were centrifuged at 1000 rpm for 10 min. One milliliter of the supernatant liquid was pipetted out and diluted to 10 mL with distilled water. The solution was titrated against 0.01 N sodium hydroxide solution using Topfer’s reagent as indicator to the end point when the solution turned to orange color. The volume of sodium hydroxide consumed was taken as corresponding to the free acidity. Titration was further continued till the solution regained pink color. The volume of sodium hydroxide solution required was noted and total acidity calculated. After opening the stomach the ulcer index was calculated. The results are expressed as Mean±SEM. The difference between groups was determined using the one way analysis of variance (ANOVA) followed by Dunnett’s test and p<0.05 was considered significant (Table 1) (Kulkarni, 1999) H+/K+-ATPase (proton pump) inhibition Procedure for H+/K+-ATPase inhibition in membrane vesicles of stomach mucosa: Membrane vesicles containing H+/K+-ATPase are prepared from pig stomachs obtained from the local slaughter house (Ljungstrom et al ., 1984). Pigs are fasted overnight before slaughter. The gastric mucosa of four stomachs is rinsed with cold saturated NaCl solution for 3-5 min. The superficial cells, cell debris plus the mucus are wiped off with the edge of a plastic ruler and with paper towels. The mucosa is scraped off. About 100 g scrapings are divided into portions of 10 g and homogenized in 0.25 M sucrose with seven strokes in a Potter-Elvehjem Teflon-glass homogenizer. The total volume is 600 mL which is centrifuged at 20000×g for 40 min. The pellet is discarded. The supernatant is centrifuged at 75000×g for 1 h. The resulting microsomal pellet is homogenized in 30 mL 0.25 M sucrose. Aliquots of 15 mL are transferred to 100 mL centrifuge tubes and layered on top of step gradients, from the bottom comprising 25 mL 37% sucrose (w/v) and 45 mL 7.5% Ficoll (w/v) in 0.25 M sucrose. The tubes are centrifuged at 75 000×g for 1 h in a 6×100 mL ME angle rotor at 4°C. The gradient is then fractionated by pumping Fluoroinert 70 through narrow tubing in a fractionating cap down to the bottom of the tube. Fractions are collected from top through a center hole in the fractionating cap. The yield of vesicles in a typical preparation is about 50-75 mg protein. In order Table 1: Anti-ulcer activities of the tested compounds (1-9) Compound No. Ulcer index Free acid (mEq L G 1 ) Total acid (mEq L G 1 ) Control 4.50 3.28 11.14 Omeprazole 3.31 0.43 0.33 1 a 0.10 0.29 0.24 1 b 0.10 0.29 0.24 2 a 0.10 0.25 0.22 2 b 0.10 0.24 0.21 3 a 0.10 0.26 0.22 3 b 0.10 0.25 0.22 4 a 0.10 0.28 0.23 4 b 0.10 0.28 0.23 5 a 0.10 0.15 0.12 5 b 0.10 0.14 0.11 6 a 0.10 0.14 0.11 6 b 0.10 0.2 0.10 7 a 0.10 0.17 0.14 7 b 0.10 0.18 0.15 8 a 0.10 0.21 0.21 8 b 0.10 0.20 0.17 9 a 0.10 0.20 0.17 9 b 0.10 0.19 0.16 to maintain a stable vesicular structure for a long period of time, the vesicles are frozen at -70°C under nitrogen They can then be kept for several months without decrease of H+/K+-ATPase activity. The ATPase activity is measured at 37°C as the release of inorganic phosphate (Pi) from ATP. The test drug and the standard (omeprazole) are pre-incubated in concentrations of 0.01 to 100.0 μ M in enzyme containing buffers in parallel at pH 6.0 and 7.4 for 30 min at 37°C. Then, the medium of pH 6.0 is adjusted with HEPES/Tris buffer to pH 7.4. The enzyme reaction is started by addition of nigericin and Tris/ATP. The total reaction volume is 1 mL, containing 20 μ g vesicular protein, 4 mM MgCl 2, 10 mM KCl, 20 μ M nigericin, 2 mM Tris-ATP, 10 mM HEPES and additionally 2 mM Pipes for the pre-incubation medium at pH 6.0. After 4 min at 37°C, the reaction is stopped by the addition of 10 mL of 50% trichloroacetic acid. The denaturated protein is spun down and the Pi content is determined according to LeBel et al . (1978) based on the reduction of a phosphomolybdate complex by p-methyl-aminophenol sulfate in a copper acetate buffer or according to Carter and Karl (1982) based on the reaction of phosphomolybdate with the basic dye malachite green. IC 50 values are calculated by probit analysis, whereby 0% corresponds to 4 mM MgCl 2 +dependent and 100% to 4 mM MgCl 2 + plus 10 mM K+dependent ATP hydrolysis. The IC 50 values of the test compound at different pH values are compared with IC 50 values of the standard. Statistical differences (p<0.05) are calculated by Student’s t-test (Table 2) RESULTS AND DISCUSSION Chemistry: Herein a series of pyrimidothienopyridine heterocyclic derivatives (1-9) (Fig. 1 and 2) were synthesized 841 www.ansinet.com | Volume 11 | Issue 7 | 2015 |

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Int. J. Pharmacol., 11 (7): 840-845, 2015 H C 3 N N Ar O S N N Ar N S O N N CH 3 1 a, b H C 3 N N H N 2 O S N N Ar Ar N S 2 a, b N N O CH 3 NH 2 H C 3 N N N S O S Ar N N N Ar N S N N CH 3 S O 3 a, b H C 3 N N N O O O S N N N Ar Ar N N N O O O S CH 3 4 a, b N N HN S O N N N S O NH N N Ar Ar 5 a, b a: Ar = Ph, b: Ar = 2-thienyl Fig. 1: Chemical structure for the tested compounds 1-5 Table 2: H+/K+-ATPase inhibition in membrane vesicles of stomach mucosa of the tested compounds (1-9) Compound No IC 50 (µM) Control Omeprazole 66 1 a 32.4±0.009 1 b 34.3±0.009 2 a 21.34±0.008 2 b 20.12±0.009 3 a 24.32±0.008 3 b 22.33±0.007 4 a 28.76±0.009 4 b 26.65±0.009 5 a 11.23±0.003 5 b 10.34±0.004 6 a 9.91±0.005 6 b 9.80±0.006 7 a 17.46±0.006 7 b 17.23±0.007 8 a 19.50±0.009 8 b 19.20±0.009 9 a 18.28±0.007 9 b 17.99±0.008 and illustrated by physical, chemical and spectroscopic evidences before and screened as analgesic, anticonvulsant and antiparkinsonian agents (Amr et al ., 2003). In this study, we report the activities of these compounds as antiulcerogenic agents Pharmacology: Pyrazolo, imidazolo and triazolopyrimidines were prepared and evaluated for cytoprotective antiulcer activity. Among them, 4-methoxy-6-methyl-2-(1 H-pyrazol-1- yl)pyrimidine showed potent inhibition of the HCl-ethanolinduced and water-immersion stress-induced ulcers in rats, as well as low acute toxicity (Ikeda et al ., 1996; Terashima et al ., 1995). Some of substituted quinazoline and pyrimidinethione derivatives were synthesized and tested for antiulcer activity against pylorus ligation-induced, aspirin induced and ethanol induced ulcer in rat model. The compounds were scrammed for their antiulcer activity: some of these compounds showed higher activity than omeprazole used as standard (Patil et al ., 2010; Kodhati et al ., 2013). A series of substituted 2-(pyrimidinylsulfinyl) benzamidazoles derivatives were evaluated against antiulcer and antisecretory activity as a inhibition of gastric H + /K + -ATPase by induction of gastric ulcerations experimentally in male Wister rats according to the 842 www.ansinet.com | Volume 11 | Issue 7 | 2015 |

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Int. J. Pharmacol., 11 (7): 840-845, 2015 a: Ar = Ph, b: Ar = 2=thienyl N N Ar O S N N Ar N S O N N CH 3 N N H C 3 6 a, b S H N N Ar O S N N Ar N S O N H N S 7 a, b H CS OOCH 3 N N Ar O S N N Ar N S O N N SCH COOH 2 9 a, b C H S 2 5 N N Ar O S N N Ar N S O N N SC 2 5 H 8 a, b Fig. 2: Chemical structure for the tested compounds 6-9 reported method (Khan and Asnani, 2011). Many of synthesized heterocyclic derivatives containing thiazole, thiophene, pyridine and pyran derivatives were evaluated as anti-ulcer agents (Mohareb et al ., 2015). On the other hand, some of arylthiomethylpyridine showed gastroprotective activity against 96% ethanol-induced gastric lesions greater than omeprazole. In addition, pyridine derivatives are known to possess antiulcers activities (Evangelista et al ., 1988; Cho et al ., 2001; Katsura et al ., 1992) From Table 1 and 2, all the tested compounds showed potent antiulcerogenic activities and in searching for their mechanism of action, it was founded that these compounds exerts their antiulcer activities via inhibiton of H + /K + -ATPase 2,6-bis-(2-methyl-4-oxo-3,9-diphenyl-3,4-dihydropyrido [3',2':4,5]-thieno[3,2-d]pyrimidin-7-yl)pyridine (1 a,) and 2,6- b i s ( 2 - m e t h y l - 4 - o x o - 3 - p h e n y l - 9 - ( 2 - t h i e n y l ) - 3 , 4 - dihydropyrido[3',2':4,5]thieno[3,2-d]-pyrimidin-7-yl)pyridine (1 b) showed anti-ulcerogenic activities but they still the least potent compounds, where replacing the N-phenyl radicles with N-amino greatly increases the antiulcerogenic activities as for compounds 2 b and 2 a Condensation of compounds 2 b and 2 a with thiophene aldehydes afforded the schiff’s bases 3 b and 3 a that were less active than their starting 2 b and 2 a, respectively as antiulcer agents. The same thing happened when condensed compounds 2 b and 2 a with phthalic anhydride afforded compounds 4 b and 4 a respectively that were less actives as antiulcerogenic agent than compounds 2 b and 2 a. Due to stearic hindered factors compounds 4 a,b were less active than compounds 3 b,a. Replacing the pyrimidine moieties of derivatives 2 b and 2 a with triazinone ones as in compounds 5 b and 5 a greatly increases the antiulcerogenic activities which probably could attributed to the more basic centers that could undergoes efficient strong hydrogen bonding with H+/K+-ATPase. The later concept confirmed via methylation of derivatives 5 b and 5 a that afforded the more potent antiulcer N-methyl analogues 6 b and 6 a The pyrimidinethiones 7 b and 7 a where more active than their congeneers containing no sulfur (derivatives 1-4) due to their increasing abilities to form hydrogen bonding with the H+/K+-ATPase. Involvement of the thione in a such structure that decreasing their abilities to form hydrogen bonding with the H+/K+-ATPase decreasing their binding forces leads to decreasing the antiulcerogenic activities as in derivatives 8 a,b and 9 a,b but still derivatives 9 a,b more active than derivatives 8 a,b because it contains carboxy group for binding to H+/K+- ATPase All the tested compounds have a proton pump inhibitor activities and its was worth mentioned that these compounds were more active than positive control 843 www.ansinet.com | Volume 11 | Issue 7 | 2015 |

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Int. J. Pharmacol., 11 (7): 840-845, 2015 CONCLUSION All the tested compounds showed potent antiulcerogenic activities and the potency descending order was 6 b, 6 a, 5 b, 5 a, 7 b, 7 a, 9 b, 9 a, 8 b, 8 a, 2 b, 2 a, 3 b, 3 a, 4 b, 4 a, 1 b and 1 a. The tested agents exert their antiulcerogenic activities via a proton pump inhibitor activities Studying the structural activities relationship of the tested agents calumniated on the following assumptions: C Triazine polycyclic provides the highest activities C In triazine polycyclic the free amino ones is the most active ones C The pyrimidones were less active than the triazine polycyclic C In the pyrimidones the thiones more active than the thioacetic acid and the later more active than the ethyl thiol C Thienyl substituents provides more activity than the phenyl one C N-N bond increases the activity, where the free amino group has higher activities than that involved in aliphatic bond and the later more active than that involved in cyclic ring structure C Dihydropyrido provides more activity than the oxazine ones C Amide increases the activity more than the ethyl ester C Thiones increases the activity more than the ketonic ones ACKNOWLEDGMENT The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-172 REFERENCES Abdalla, M.M., A.G.E. Amr, M.G. Assy and Z.M. Ramadan, 2014. Calcium channel blocking and anti-arrhythmic activities of some thienopyrimidine with benzoxazine, quinazoline and azole moieties. J. Pure Applied Microbiol., 8: 3773-3780 Amr, A.G.E., M.I. Hegab, A.A. Ibrahiem and M.M. Abdulla, 2003. Synthesis and reactions of some fused oxazinone, pyrimidinone, thiopyrimidinone and triazinone derivatives with a thiophene ring as analgesic, anticonvulsant and antiparkinsonian agents. Chem. Monthly, 134: 1395-1409 Amr, A.G.E., M.H. Sherif, M.G. Assy, M.A. Al-Omar and I. Ragab, 2010. Antiarrhythmic, serotonin antagonist and antianxiety activities of novel substituted thiophene derivatives synthesized from 2-amino-4,5,6,7-tetrahydro- N -phenylbenzo[b]thiophene-3-carboxamide. Eur. J. Med Chem., 45: 5935-5942 Assy, M.G., M.H. Sherif, A.E.E. Amr, O.I. Abdelsalam, M.A. Al-Omar, M.M. Abdalla and I. Ragab, 2013. Synthesis and reactions of some heterocyclic candidates based on 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene moiety as anti-arrhythmic agents. J. Heterocyc. Chem., 50: 766-773 Carter, S.G. and D.W. Karl, 1982. Inorganic phosphate assay with malachite green: An improvement and evaluation. J. Biochem. Biophys. Methods, 7: 7-13 Cho, S.Y., S.K. Kang, S.S. Kim, H.G. Cheon, J.K. Choi and E.K. Yum, 2001. Synthesis and SAR of benzimidazole derivatives containing oxycyclic pyridine as a gastric H + /K + -ATPase inhibitors. Bull. Korean Chem. Soc., 22: 1217-1223 Evangelista, S., M. Ghelardoni, A. Meli, V. Pestellini and G. Viti, 1988. [Synthesis and anti-ulcer activity of some new compounds with arylthiomethyl-pyridine structure]. Farmaco Sci., 43: 901-908, (In Italian) Ghorab, M.M. and M.S. Al-Said, 2012. Antitumor activity of novel pyridine, thiophene and thiazole derivatives. Arch. Pharm. Res., 35: 965-973 Hossan, A.S., H. Abu-Melha, M.A. Al-Omar and A.E.E. Amr, 2012. Synthesis and antimicrobial activity of some new pyrimidinone and oxazinone derivatives fused with thiophene rings using 2-chloro-6-ethoxy-4-acetylpyridine as starting material. Molecules, 17: 13642-13655 Ikeda, M., K. Maruyama, Y. Nobuhara, T. Yamada and S. Okabe, 1996. Synthesis and cytoprotective antiulcer activity of 2- or 4-(1 H-pyrazol-1-yl)pyrimidine derivatives related to mepirizole and dulcerozine. Chem. Pharm. Bull. (Tokyo), 44: 1700-1706 Kam, P.C.A. and C.M. Nethery, 2003. The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments. Anaesthesia, 58: 28-35 Katsura, Y., S. Nishino, Y. Inowe, M. Tomoi and H. Takasugi, 1992. Studies on antiulcer drugs. II. Synthesis and antiulcer activities of imidazo[1,2-alpha]pyridinyl-2- alkylaminobenzoxazoles and 5,6,7,8-tetrahydroimidazo [1,2-alpha]pyridinyl derivatives. Chem. Pharm. Bull. (Tokyo), 40: 371-380 Khan, F.R. and A.J. Asnani, 2011. Synthesis and antiulcer, anti-secretory activity of some new substituted 2-(pyrimidinylsulfinyl) benzamidazoles derivatives. Int. J. Res. Pharmaceut. Biomed. Sci., 2: 695-700 Kodhati, V., M.R. Vanga and N.R. Yellu, 2013. Synthesis and anti bacterial and anti-ulcer evaluation of new S-mannich bases of 4,6-diaryl-3,4-dihydropyrimidin-2(1 H)-thiones. J. Korean Chem. Soc., 57: 234-240 Kulkarni, S.K., 1999. Hand Book of Experimental Pharmacology. 3 rd Edn., Vallabh Prakashan, New Delhi LeBel, D., G.G. Poirier and A.R. Beaudoin, 1978 A convenient method for the ATPase assay. Anal. Biochem., 85: 86-89 844 www.ansinet.com | Volume 11 | Issue 7 | 2015 |

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Binding force, Anti-inflammatory, Ulcer index, Test drug, ANOVA, Antitumor activity, Mechanism of action, Analgesic activities, Student's t test, Total acidity, Positive control, IC50 value, Hydrogen bonding, Pyloric ligation, Free acidity, Normal saline, One-way analysis of variance, Dunnett's test, Chemical structure, Cytotoxicity, Antiulcer activity, Biological evaluation, Proton Pump Inhibitor, Statistical difference, Gastroprotective Activity, Gastric mucosa, Antiulcer agent, Gastric ulceration, King Saud University, Anti-inflammatory and analgesic activities, Sucrose, Sodium hydroxide, One-way analysis of variance (ANOVA), Schiff's base, Heterocyclic system, Aspirin-induced ulcer, Thienopyridines, Pyridine derivatives, Heterocyclic Derivatives, Pyrimidine derivatives, Probit analysis, Active metabolite, Pyridine, Antisecretory activity, Inorganic phosphate, Omeprazole, Thioacetic acid, Stomach mucosa, Ethanol induced ulcer, Ethyl ester, Amino Group, Proton pump inhibition, Phthalic anhydride, ATP hydrolysis, Antiulcer activities, ATPase activity, Proton pump, Basic center, Enzyme reaction, Anti-ulcer agent, Gastric content, Carboxy group, Free amino group, AMIDE, One-way analysis, Cell debris, Gastric lesion, Membrane vesicles, Aspirin induced, Aliphatic bond, Vesicular structure, Stable vesicular structure, Reaction volume, Structural activities.