{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T16:56:16Z","timestamp":1775667376071,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2012,1,16]],"date-time":"2012-01-16T00:00:00Z","timestamp":1326672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In this study, the antinociceptive properties of 3,4-dihydro-2,6-diaryl-4-oxo-pyrimidine-5-carbonitrile derivatives 5a\u2013i at doses of 25 and 50 mg\/kg were evaluated in mice, using the abdominal constriction test. Molecular modeling studies were also performed using density functional theory calculations. These data provided information about the electrostatic and ionization potentials and were used to compare the antinociceptive activity of the title compounds. The most active compounds were 3,4-dihydro-2-(4-chlorophenyl)-6-(4-methoxyphenyl)-4-oxo-pyrimidine-5-carbonitrile (5b) and 3,4-dihydro-2,6-diphenyl-4-oxo-pyrimidine-5-carbonitrile (5i), which inhibited the number of abdominal constrictions, at 50 mg\/kg dose, in 88.6% and 88% of the sample, respectively. A preliminary SAR study demonstrated that halogen replacement in the phenyl rings of the compounds under study reduces the antinociceptive activity. DFT calculations showed that there is a high correlation between the ionization potentials and the analgesic properties of the compounds. It was found that compounds with a positive ionization potential (compounds 5b and 5i) were found to be the best analgesic drugs in this series.<\/jats:p>","DOI":"10.3390\/molecules17010809","type":"journal-article","created":{"date-parts":[[2012,1,16]],"date-time":"2012-01-16T11:14:14Z","timestamp":1326712454000},"page":"809-819","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Comparative Computational Studies of 3,4-Dihydro-2,6-diaryl-4-oxo-pyrimidine-5-carbonitrile Derivatives as Potential Antinociceptive Agents"],"prefix":"10.3390","volume":"17","author":[{"given":"Jana\u00edna V. dos","family":"Anjos","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica Fundamental, Universidade Federal de Pernambuco, 50740-540, Recife, PE, Brazil"}]},{"given":"Rajendra M.","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Fundamental, Universidade Federal de Pernambuco, 50740-540, Recife, PE, Brazil"}]},{"given":"Jo\u00e3o H.","family":"Costa-Silva","sequence":"additional","affiliation":[{"name":"N\u00facleo de Educa\u00e7\u00e3o F\u00edsica e Ci\u00eancias do Esporte, Universidade Federal de Pernambuco, 55608-680, Vit\u00f3ria de Santo Ant\u00e3o, PE, Brazil"}]},{"given":"Luciana","family":"Scotti","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Tecnologia Farmac\u00eautica, Universidade Federal da Para\u00edba, Campus I, 50740-540, Jo\u00e3o Pessoa, PB, Brazil"}]},{"given":"Marcus T.","family":"Scotti","sequence":"additional","affiliation":[{"name":"Departamento de Engenharia e Meio Ambiente, Universidade Federal da Para\u00edba, Campus IV, 58297-000, Rio Tinto, PB, Brazil"}]},{"given":"Almir G.","family":"Wanderley","sequence":"additional","affiliation":[{"name":"Departamento de Fisiologia e Farmacologia, Universidade Federal de Pernambuco, 50670-901, Recife, PE, Brazil"}]},{"given":"Elisa Soares","family":"Leite","sequence":"additional","affiliation":[{"name":"Departamento de Engenharia Qu\u00edmica, Universidade Federal de Pernambuco, 50670-901, Recife, PE, Brazil"}]},{"given":"Sebasti\u00e3o J. de","family":"Melo","sequence":"additional","affiliation":[{"name":"Departamento de Antibi\u00f3ticos, Universidade Federal de Pernambuco, 50670-901, Recife, PE, Brazil"}]},{"given":"Francisco J. B. Mendon\u00e7a","family":"Junior","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancias Biol\u00f3gicas, Universidade Estadual da Para\u00edba, Campus V, 58058-420, Jo\u00e3o Pessoa, PB, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2012,1,16]]},"reference":[{"key":"ref_1","first-page":"57","article-title":"Pyrimidines and their benzoderivatives","volume":"Volume 3","author":"Katritzky","year":"1984","journal-title":"Comprehensive Heterocyclic Chemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/0039-9140(82)80027-1","article-title":"Analytical Reactions of Substituted Pyrimidines","volume":"29","author":"Singh","year":"1982","journal-title":"Talanta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0065-2571(81)90023-6","article-title":"Antineoplastic properties of pyrimidinone interferon inducers","volume":"19","author":"Stringfellow","year":"1981","journal-title":"Adv. Enzyme Regul."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1089\/jir.1988.8.319","article-title":"Combined treatment of colon adenocarcinoma in rats with tumor necrosis factor and the interferon inducer ABPP","volume":"8","author":"Marquet","year":"1988","journal-title":"J. Interferon Res."},{"key":"ref_5","first-page":"44","article-title":"Antitumor activity of pyrimidinones, a class of small-molecule biological response modifiers","volume":"6","author":"Li","year":"1987","journal-title":"J. Biol. Response Mod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/BF01741709","article-title":"The antitumor activity of the interferon inducer bropirimine is partially mediated by endogenous tumor necrosis factor \u03b1","volume":"32","author":"Scheringa","year":"1990","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1097\/00001813-199502000-00019","article-title":"In vitro and in vivo antitumor activity of the interferon inducer bropirimine","volume":"6","author":"Shimizu","year":"1995","journal-title":"Anticancer Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/S0192-0561(99)00040-5","article-title":"Pharmacokinetic properties, induction of interferon, and efficacy of selected 5-halo-6-phenyl pyrimidinones, bropirimine analogues, in a model of severe experimental autoimmune encephalomyelitis","volume":"21","author":"Vroegop","year":"1999","journal-title":"Int. J. Immunopharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1016\/S0968-0896(02)00077-9","article-title":"A new and efficient synthesis of substituted 6-[(2\u2032-dialkylamino)ethyl] pyrimidine and 4-N,N-dialkyl-6-vinyl-cytosine derivatives and evaluation of their anti-rubella activity","volume":"10","author":"Saladino","year":"2002","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1021\/jm9803626","article-title":"Stereospecific synthesis, structure-activity relationship, and oral bioavailability of tetrahydropyrimidin-2-one HIV protease inhibitors","volume":"42","author":"Liang","year":"1999","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0960-894X(01)81139-2","article-title":"Cyclopentanespiro-3H-dihydro-pyrimidinones as Angiotensin II AT1 receptor antagonists","volume":"4","author":"Bernhart","year":"1994","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4806","DOI":"10.1021\/jm00024a008","article-title":"N-3-substituted pyrimidinones as potent, orally active, AT1 selective angiotensin II receptor antagonists","volume":"38","author":"Salimbeni","year":"1995","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2671","DOI":"10.1016\/S0968-0896(02)00107-4","article-title":"Synthesis and biological activity of novel pyrimidinone containing thiazolidinedione derivatives","volume":"10","author":"Madhavan","year":"2002","journal-title":"Bioorg. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.jinorgbio.2005.11.010","article-title":"Syntheses of vanadyl and zinc(II) complexes of 1-hydroxy-4,5,6-substituted 2(1H)-pyrimidinones and their insulin-mimetic activities","volume":"100","author":"Yamaguchi","year":"2006","journal-title":"J. Inorg. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5711","DOI":"10.1016\/j.bmc.2004.07.068","article-title":"Synthesis and anticonvulsant evaluation of some new 2-substituted-3-arylpyrido[2,3-d]pyrimidinones","volume":"12","author":"White","year":"2004","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1021\/jm00191a009","article-title":"Synthesis of 3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-2-carboxylates, a new series of orally active antiallergy agents","volume":"22","author":"Temple","year":"1979","journal-title":"J. Med. Chem."},{"key":"ref_17","first-page":"551","article-title":"5-Substituted 2,3-dihydro-6-mercapto-1,3-diphenyl-2-thioxo-4(3H)-pyrimidinones and their 6-(acylthio) derivatives with platelet antiaggregating, antiinflammatory, antiarrhythmic, antihyperlipidemic and other activities","volume":"49","author":"Ranise","year":"1994","journal-title":"Farmaco"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/0223-5234(94)90097-3","article-title":"Research on heterocyclic compounds. XXXII. Synthesis and cyclooxygenase-independent antiinflammatory and analgesic activity of imidazo[1,2-a]pyrimidine derivatives","volume":"29","author":"Abignente","year":"1994","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","first-page":"343","article-title":"Estudo Preliminar da Toxicidade e das Atividades Anti-edematog\u00eanica e Anti-nociceptiva da 3,4-diidro-2-fenil-6-para-fl\u00faor-fenil-4-oxo-pirimidina-5-carbonitrila","volume":"27","year":"2008","journal-title":"Lat. Am. J. Pharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1021\/jm00158a030","article-title":"Pyrimidinones. 3. N-substituted 6-phenylpyrimidinones and pyrimidinediones with diuretic\/hypotensive and antiinflammatory activity","volume":"29","author":"Skulnick","year":"1986","journal-title":"J. Med. Chem."},{"key":"ref_21","first-page":"547","article-title":"Synthesis of 6-thiosubstituted 5-ethoxycarbonyl-1,3-diphenyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones, 6-substituted 5-hydroxy-1,3-diphenyl-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-ones and their esters with local anesthetic, antiarrhythmic, antiinflammatory and analgesic activities","volume":"52","author":"Ranise","year":"1997","journal-title":"Farmaco"},{"key":"ref_22","first-page":"500","article-title":"Synthesis of new [1,3,4]thiadiazolo[3,2-a]thieno[2,3-d]pyrimidinone derivatives with antiinflammatory activity","volume":"55","author":"Modica","year":"2000","journal-title":"Pharmazie"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/s00706-007-0651-0","article-title":"Synthesis, Reactions, and Anti-inflammatory activity of heterocyclic systems fused to a thiophene moiety using citrazinic acid as synthon","volume":"138","author":"Amr","year":"2007","journal-title":"Monatsh. Chem."},{"key":"ref_24","first-page":"479","article-title":"A simple approach for the synthesis of 2,6-diaryl-4-oxo-3,4-dihydropyrimidine-5-carbonitriles","volume":"11","author":"Yamamoto","year":"2005","journal-title":"Heterocycl. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0163-7258(85)90048-8","article-title":"Antiviral and other bioactivities of pyrimidinones","volume":"30","author":"Wierenga","year":"1985","journal-title":"Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/S0223-5234(00)01189-2","article-title":"Biologically active dihydropyrimidones of the Biginelli-type\u2014A literature survey","volume":"35","author":"Kappe","year":"2000","journal-title":"Eur. J. Med. Chem."},{"key":"ref_27","first-page":"39","article-title":"5-Fluoro (3H) pyrimidine-4-ones: synthesis, reactivity and pharmacological properties","volume":"50","author":"Thomasson","year":"1992","journal-title":"Ann. Pharm. Fr."},{"key":"ref_28","unstructured":"Agarwal, S.K., Tadiparthi, R., Aggarwal, P., Shivakumar, S., Dey, D., and Nag, B. (2003). New diaryl pyrimidinone derivatives are tumor necrosis factor alpha inhibitors, useful for the treatement of rheumatoid arthritis, osteoporosis, multiple myeloma and ischemic heart disease. (WO\/2003\/084935), International Patent."},{"key":"ref_29","unstructured":"Devadas, B., Hartmann, S.J., Heier, R.F., Jerome, K.D., Kolodziej, S.A., Mathias, J.P., Norton, M.B., Promo, M.A., Rucker, P.V., and Selness, S.R. (2007). New substituted pyridinone pyrazole urea and pyrimidinone pyrazole urea compounds useful for treating e.g. astma, inflammation and rheumatoid arthritis. (WO\/2007\/091176), International Patent."},{"key":"ref_30","unstructured":"Liang, C., and Koenig, M. (2007). New pyrimidinones derivatives for treating disordes related to abnormal protein kinase activities e.g., cancer and inflammation. (WO\/2007\/081901), International Patent."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11714","DOI":"10.1016\/j.tet.2006.09.047","article-title":"An efficient one-pot construction of substituted pyrimidinones","volume":"62","author":"Lu","year":"2006","journal-title":"Tetrahedron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.tips.2007.04.008","article-title":"Novel strategies for inhibition of the p38 MAPK pathway","volume":"28","author":"Zhang","year":"2007","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_33","first-page":"216","article-title":"Synthesis of new 4-amino-2,6-diarylpyrimidine-5-carbonitriles","volume":"5","author":"Srivastava","year":"2002","journal-title":"J. Chem. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.ejmech.2005.09.009","article-title":"Synthesis and antiinflammatory activity of 4-amino-2-aryl-5-cyano-6-{3- and 4-(N-phthalimidophenyl)} pyrimidines","volume":"41","author":"Srivastava","year":"2006","journal-title":"Eur. J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1590\/S0103-50532008000200021","article-title":"Quantitative Structure Activity Relationships (QSAR) of 4-Amino-2,6-Diarylpyrimidine-5-Carbonitriles Having Anti-inflammatory Activity","volume":"19","author":"Ramos","year":"2008","journal-title":"J. Braz. Chem. Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1590\/1808-1657v69n4p0492002","article-title":"Atividades farmacol\u00f3gicas das folhas de Sesbania virgata (CAV.) PERS","volume":"69","author":"Braggio","year":"2002","journal-title":"Arq. Inst. Biol. (Sao Paulo)"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0223-5234(01)01197-7","article-title":"Cyclooxygenase inhibitors-current status and future prospects","volume":"36","author":"Dannhardt","year":"2001","journal-title":"Eur. J. Med. Chem."},{"key":"ref_38","first-page":"412","article-title":"Acetic acid for analgesic screening","volume":"18","author":"Koster","year":"1959","journal-title":"Fed. Proc."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kruger, L. (2001). Methods in Pain Research, CRC Press.","DOI":"10.1201\/9781420042566"},{"key":"ref_40","unstructured":"(2009). Hyperchem Program Release 8.0 for Windows, Hybercube, Inc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8127","DOI":"10.1021\/ja00467a001","article-title":"A hydrocarbon force-field utilizing V1 and V2 torsional terms","volume":"99","author":"Allinger","year":"1977","journal-title":"J. Am. Chem. Soc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3902","DOI":"10.1021\/ja00299a024","article-title":"AM1: A new general purpose quantum mechanical molecular model","volume":"107","author":"Dewar","year":"1985","journal-title":"J. Am. Chem. Soc."},{"key":"ref_43","unstructured":"Cohen, N.C. (1996). Guidebook on Molecular Modeling in Drug Design, Academic Press."},{"key":"ref_44","unstructured":"Leach, A.R. (2001). Molecular Modeling: Principles and Applications, Prentice Hall."},{"key":"ref_45","unstructured":"(2009). SpartanModel, Wavefunction, Inc.. Available online: http:\/\/www.wavefun.com\/products\/windows\/SpartanModel\/win_model.html."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/17\/1\/809\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:48:29Z","timestamp":1760219309000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/17\/1\/809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,1,16]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2012,1]]}},"alternative-id":["molecules17010809"],"URL":"https:\/\/doi.org\/10.3390\/molecules17010809","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,1,16]]}}}