Main Article Content
Aim: As part of ongoing studies in developing new anti-inflammatory agents, 2-thioxo-1,2,3,4-tetrahydropyrimidine derivative 1 was synthesized by direct Biginelli condensation and used for the synthesis of novel series of pyrimidin-2-thione derivatives (2a-d to 7a-b).
Materials and Methods: All compounds were examined for their anti-inflammatory activity using the carrageenan-induced rat paw edema assay in comparison to ibuprofen, as a reference drug. Molecular docking studies were carried out using SYBLYL-X v.2.1 software.
Study Design: A series of pyrimidine derivatives were synthesized by a simple and available method leads to a molecule of promising anti-inflammatory activity, the docking studies show good agreement with anti-inflammatory results. Future researches are recommended to assure the importance of these new derivatives for various applications.
Place and Duration of Study: Pharmaceutical Organic Chemistry Department and Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt, between February 2018 and March 2019.
Results: Compounds showed 61 to 86% anti-inflammatory activity where-as ibuprofen showed 69% activity. Compounds 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 7a, 7b induced strong anti-inflammatory activity, comparable with that of ibuprofen, they showed significantly difference at 4h post-carrageenan. Compound 3c (86%) showed the best result of edema inhibition in rats. Moreover, compounds 1, 2c and 3c were subjected to in vitro enzyme assay investigations against COX-1 and COX-2. All tested compounds showed higher potency towards COX-2 over COX-1. Compound 3c realized higher potency towards COX-2 (IC50= 0.046 μM) than compounds 1(IC50= 0.21 μM) and 2c (IC50=0.11 μM) as well as ibuprofen (IC50= 43.628 μM). Structure-activity relationship (SAR) has been discussed.
Conclusion: A series of pyrimidine derivatives were synthesized by a simple and available method gave a molecule of promising anti-inflammatory activity, the docking studies showed good agreement with anti-inflammatory results.
Maja SB, Ana R, Marijana J, Ljubica GO, Domagoj D, Silvana, RM, et al. Synthesis, cytostatic and antibacterial evaluations of novel 1,2,3 - triazolyl- tagged pyrimidine and furo [2,3- d] pyrimidine derivatives. Croat Chem Acta. 2017;90(2):197- 205.
Ruofeng S, Yunpeng Y, Chao Z, Yunxing F, Jianping L, Wanxia P. Antibacterial activity and pharmacokinetic profile of a promising antibacterial agent: 14- O-[(4-Amino-6-hydroxy-pyrimidine-2-yl) thio acetyl]mutilin. Pharma Research. 2018; 129:424-31.
Han-Bo L, Wei-Wei G, Vijai KRT, Cheng-He ZRG. Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation. Eur J Med Chem. 2018;143: 66-84.
Nagaraju M, Sunandamma Y, Manojit P. 1,2,3-Triazole fused with pyridine/ pyrimidine as new template for antimicrobial agents: Regioselective synthesis and identification of potent N -heteroarenes. Bioorg & Med Chem Lett. 2018;28:3302-6.
Mostafa S, Adel MKE, Mostafa A, Reda H. Design, synthesis and characterization of novel pyrimidines bearing indole as antimicrobial agents. J Chin Chem Soc. 2018;1-8.
Mahesh MP, Laxman UN, Manoj DP, Sujit GB, Jayant MG, Dhiman S, et al. Hybrids of thieno pyrimidinones and thiouracils as anti-tubercular agents: SAR and docking studies. Eur J Med Chem. 2017;127:459-69.
Guonan C, Jing J, Hualong C, Ran C, Xiaoguang C, Bailing X. Synthesis and biological evaluation of pyrimidine derivatives as novel human Pin1 inhibitors. Bioorg & Med Chem. 2018;26: 2186-97.
Wuji S, Shengquan H, Shubiao F, Hong Y. Design, synthesis and biological evaluation of pyrimidine-based derivatives as VEGFR-2 tyrosine kinase inhibitors. Bioorg Chem. 2018;78:393-405.
Kai JJ, Hong Y, Erik DC, Christophe P, Ge M, Fen EC. Discovery of biphenyl-sub stituted diarylpyrimidines as non-nucleoside reverse transcriptase inhibitors with high potency against wild-type and mutant HIV-1. Eur J Med Chem. 2018;145:726-34.
Kai JJ, Ya LS, Erik DC, Christophe P, Ge M. Design and synthesis of a novel series of non-nucleoside HIV-1 inhibitors bearing pyrimidine and N-substituted aromatic piperazine. Bioorg & Med Chem Lett. 2018;28:3491-95.
Joana F, Joao LS, Eunice C, Leena K, Jari Y, Vania MM, et al. Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents. Eur J Med Chem. 2018;143:829-42.
Méndez-Arriaga JM, Oyarzabal I, Escolano G, Rodríguez-Diéguez A, Sánchez-Moreno M, Salas JM. In vitro leishmanicidal and trypanocidal evaluation and magnetic properties of 7-amino-1,2,4-triazolo[1,5-a ]pyrimidine Cu(II) complexes. J Inorg Biochem. 2018;180:26-32.
Alexandra MT, Hiba AA, Patrick GN, Caroll BH, Mark NP, Peter W, et al. Dihydropyrimidinones and -thiones with improved activity against human polyomavirus family members. Bioorg & Med Chem Lett. 2016;26:5087-91.
Song B, Shan L, Yunying Z, Qin W. Asymmetric synthesis and antiviral activity of novel chiral amino-pyrimidine derivatives. Tetrahedron Lett. 2018;59: 3179-83.
Adel AA, Abd-Allah SE, Ahmed ESA, Megied IFZ, El Sayed HE. Synthesis and antiviral evaluation of novel 2,3- dihydroxypropyl nucleosides from 2- and 4- Thiouracils. Nucleosides Nucleotides and Nucleic Acids. 2008;27:1257-71.
Hojung C, Chang YL, Eun-Young P, Kyoung ML, Dongyun S, Hee-Sook J. Design, synthesis and effects of novel phenylpyrimidines as glucagon receptor antagonists. Bioorg & Med Chem. 2018;26:5701-10.
Vibhu J, Kamlendra SB. Synthesis, pharmacolo gical evaluation and molecular docking studies of pyrimidine dione based DPP-4 inhibitors as antidiabetic agents. J Molecular Structure. 2018;1158:96-105.
Samir MA, Yasser MZ, Sahar AA, Shahenda M, Ahmed MS. Design, synthesis, molecular modeling and biological evaluation of novel thiouracil derivatives as potential antithyroid agents. Molecules. 2018;23:2913:1-14.
Meeta S, Nadeem S, Vidushi S, Sharad W. 5,6-Dihydropyrimidine-1(2 H )-carbothioamides: Synthesis, in vitro GABA-AT screening, anticonvulsant activity and molecular modelling study. Bioorg Chem. 2018;77:56-67.
Yi-Xiang X, Huan W, Xiao-Kang L, Sheng-Nan D, Wen-Wen L, Qi G, et al. Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer's disease. Eur J Med Chem. 2018;143:33-47.
Jain KS, Chitre TS, Miniyar PB, Kathiravan MK, Bendre VS, Veer VS, et al. Biological and medicinal significance of pyrimidines. Current Science. 2006;90(6):793-803.
Ahmad FE, Ahmed HE, Rehab FA, Ayman RB. Design, synthesis, in vivo anti-inflammatory, analgesic activities and molecular docking of some novel pyrazolone derivatives. Med Chem. 2015;5(10):458-466.
Priyanka TP, Poojali PW, Kirti TP, Santosh SU, Jamale DK, Vibhute SS, et al. Simple and efficient one-pot novel synthesis of pyrazolo[3,4-b][1,8]naphthyridine and pyrazolo[3,4-d]pyrimido[1,2-a]pyrimidine derivatives as anti-inflammatory agents. Res Chem Intermed. 2018;44:1119-30.
Mallu L, Indira VA, Dhakshanamurthy T. One pot multi-component synthesis of functionalized Spiro pyridine and pyrido [2,3- d]pyrimidine scaffolds and their potent in- vitro anti- inflammatory and anti- oxidant investigations. Chem Biol Drug Des. 2018;1-9.
Rania BB, Amany AA, Khaled RAA. Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of new 1-phenylpyrazolo[3,4- d ]pyrimidine derivatives. J Enzyme Inhib Med Chem. 2016;31(S2):6-12.
Gina NT, Salwa MF, Hayam MA, Mounir AK, Rasha AN, Ibrahim ML. Design, synthesis and evaluation of some pyrazolo[3,4-d]pyrimidines as anti-inflammatory agents. Bioorg Chem. 2018;78:358-71.
Thirumurugan K, Sivalingam L, Dharman GD, Sam DP, Ramalakshmi N, Arul AS. Design, synthesis and anti-inflammatory activity of pyrimidine scaffold benzamide derivatives as epidermal growth factor receptor tyrosine e kinase inhibitors. J Molecular Structure. 2018;1171:541-50.
Sushilkumar SB, Devanand BS. Synthesis and anti-inflammatory activity of some [4,6-(4-substituted aryl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-acetic acid derivatives. Bioorg & Med Chem Lett. 2004;14:1733-36.
Mohamed AA, Rania B. Bakr, Amany AA. Novel pyrimidine-pyridine hybrids: Synthesis, cyclooxygenase inhibition, anti-inflammatory activity and ulcerogenic liability. Bioorg Chemistry. 2018;77:339-48.
Prafulla BC, Swapnil DJ, Rakesh PD, Manish SB, Suhel SS, Kundan BI, et al. Development of pyrimidine derivatives as selective Cox-2 inhibitors. American-Eurasian. J Sci Res. 2012;7(2):69-76.
Yuan Z, Lu L, Chao H, Handeng L, Di C, Guoliang S, et al. Design, synthesis and biological activity of tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine derivatives as anti-inflammatory agents. Molecules. 2017;22:1960;1-21.
Mahmoud A, Muhammad AQ, Abdul Hameed MI, Muhammad M. Screening of curcumin-derived isoxazole, pyrazoles, and pyrimidines for their anti- inflammatory, antinociceptive and cyclooxygenase-2 inhibition. Chem Biol Drug Des. 2018;9:338-43.
Bacchi S, Palumbo P, Sponta A, Coppolino M. Clinical pharmacology of non-steroidal anti-inflammatory drugs: A review, Anti-inflamm. anti-allergy agents. Med Chem. (Formerly Current Med Chem-Anti-Inflammatory Anti-Allergy Agents. 2012;11(1): 52-64.
Dannhardt G, Kiefer W. Cyclooxygenase inhibitors--current status and future prospects. Eur J Med Chem. 2001;36:109-26.
Zarghi A, Arfaei S. Selective COX-2 inhibitors: A review of their structure-activity relationships. Iran J Pharm Res. 2011;10:655-83.
Peesa JP, Yalavarthi PR, Rasheed A, Mandava VBR. A perspective review on role of novel NSAID prodrugs in the management of acute inflammation. J Acute Dis. 2016;5:364-81.
Krishna RN, Surendra BMS, Basaveswara RMV, Nageswara R. Tentu, Karri A, Kumar GA. Novel synthesis and characterization of 1,2,3,4-tetrahydropyrimidine-2(1H)-thiones. Asian J Chemistry. 2017;9(4):882-4.
Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for anti-iflammatory drugs. Proc Soc Exp Biol Med. 1962;111: 544-47.
Heba AA, Mohamad M, Wissam HF, Wassim NS, Costantine FD, Hayam MAA, et al. Synthesis of new pyrazolo [3,4-d]pyrimidine derivatives and evaluation of their anti- inflammatory and anticancer activities. Chem Biol Drug Des. 2017;90: 83-96.
Shivapura V, Dinesh, Gundibasappa, Karikannar N, Prasanna S, Guru B, et al. One pot synthesis of thiazolo [2,3-b]dihydropyrimidinone possessing pyrazole moiety and evaluation of their anti-in flammatory and antimicrobial activities. Med Chem Res; 2017.
Andriy RV, Yuriy IH, Roman ZL, Alexandra IL, Vasyl K, Fedor IZ, et al. 5-Aryl-2-furaldehydes in the synthesis of tetrahydropyrimidinones by Biginelli reaction. Chem Hetero Comp. 2018;54(5): 545-49.
Ashraf SH, Gaber OM, Ahmed AA, Ahmed MN, Mohamed AA. Synthesis and antibacterial evaluation of fused pyrazoles and Schiff bases. Synth Comm. 2018;48(21):2761-72.
Khalid MHH, Dalia HS, Esmat BAS, Rakia AA. Synthesis and molecular modeling study of novel pyrrole Schiff bases as anti-HSV-1 agents. Life Sci J. 2012;9(2):736-745.
Kalpesh SP, Sandip PV. Synthesis and microbial studies of some novel Schiff base containing pyrimidine. IJPSR. 2012;3(9):3425-27.
Lalit Kumar, Amit S, Nand L, Ashish J, Sumit K, Kiran KST, et al. Design and synthesis of 3-(azol-1- yl)phenylpropanes as microbicidal spermicides for prophylactic contraception .Bioorg & Med. Chem Lett. 2011;21:176-81.
Nagarajaiah H, Imtiyaz AM, Noor SB. Synthesis of some new derivatives of thiazolopyrimidines and hydrolysis of its arylidene derivative. J Chem Sci. 2015;127(3):67-79.
Navin BP, Minesh DP. Synthesis and evaluation of antibacterial and antifungal activities of 4-thiazolidinones and 2-azetidinones derivatives from chalcone. Med Chem Res; 2017.
Mosaad SM, Naglaa M. Ahmed. Synthesis, characterization and study of antimicrobial activity of some novel 5-cyano-2-thiouracil derivatives. Inter J Pharma Sci. 2014;4(3): 591-600.
Waleed MH, Samar SF, Zainab MM, Ross PM, Gerhard S, David LO, et al. Synthesis and kinetic testing of tetrahydropyrimidine-2-thione and pyrrole derivatives as inhibitors of the metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. Chem Biol Drug Des. 2012; 80:500-15.
Anelia TM, Stefan D, Denitsa Y, Miroslav R, Diana W, Jordan AT. Synthesis, anticancer activity and photo stability of novel 3-ethyl-2-mercapto-thieno[2,3-d] pyrimidin-4(3H)-ones. Eur J Med Chem. 2016;123:69-79.