Summary
Thiourea derivatives have been shown to posses several biological activities. Therefore a series of N-substituted-N′-(3,5-di/1,3,5-trimethylpyrazole-4-yl)thioureas were synthesized and the antitubercular and anticonvulsant activities were studied. Among the new compounds, N-phenyl-N′-(3,5-dimethylpyrazole-4-yl)thiourea (S) was demonstrated to have remarkable anticonvulsant activity. In this study, S was selected as a model compound and thein vivo metabolic pathway in rats was investigated. The substrate was given intraperitoneally (50 mg/kg) and blood samples were collected at 0, 1, 2, 4, 8, 12, 24 and 48 h. The substrate and its potential metabolites were separated using HPLC on reverse phase system. The substrate was detected at all times with small quantity of metabolites.
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Todoulou O.G., Papadaki-Valiraki A.E., Filippatos E.C., Ikeda S., De Clerq E. (1994): Synthesis and anti-myxovirus activity of some novel N,N′-disubstituted thioureas. Eur. J. Med. Chem., 29, 127–131.
Riccieri F.M., Porcelli G.A., Pastaris M.C. (1967): Thiourea derivatives and their antitubercular activity. Farmaco Ed. Sci., 22 (21), 114–120.
Doub B.Y.L., Richardson L.M., Herbest D.R., Block M.L., Stevenson O.L., Bambas L.L., Youmans G.P., Youmans A.S. (1958): Some phenylthiourea derivatives and their antituberculous activity. J. Am. Chem. Soc., 80, 2205–2217.
Vajragupta O., Pathamsakul A., Matavatsuk C., Ruangreangyngyad L., Wongkrajang Y., Foye W.O. (1996): Synthesis and antihypertensive activity of N-(alkyl/alkenyl/aryl)-N′-heterocyclic ureas and thioureas. J. Pharm. Sci., 85 (3), 258–261.
Küçükgüzel I., Rollas S., Çevikbaş A. (1995): Synthesis and characterizations of certin thiourea derivatives starting from 1,2,4-triazoline-3-thiones as potential antibacterial and antifungal agents. Drug Metab. and Drug Interact., 12(2), 151–160.
Bell F.W., Cantrell A.S., Högberg M., Jaskinas S.R., Johansson N.G., Jordan L.C., Kinnick M.D., Morin J.M., Noreen R., Öberg B., Palkowitz J.A., Parrish C.A., Pranc P., Sahlberg C., Ternansky R.J., Vasileff R.T., Vrong L., West S.J., Zhang H., Zhou X.X. (1995): Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors, 1. Synthesis and basic structure-activity relationship studies of PETT analogs. J. Med. Chem., 38, 4929–4936.
Cantrell S.A., Engelhardt P., Högberg M., Jaskinas R.S., Johansson G.N., Jordan L.C., Kangasmetsa J., Kinnick D.M., Lind P., Morin M.J., Muesing M.A., Noréen N., Öberg B., Pranc P., Sahlberg C., Ternansky R.J., Vasileff R.T., Vrong L., West S.J., Zhang H. (1996): Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Sythesis and further structure activity relationship studies of PETT analogs. J. Med. Chem., 39, 4261–4274.
Desai N.C., Bhatt J.J., Shah R.R., Undavia N.K., Triverdi P.B. (1996): Sythesis of substituted quinazolone derivatives as potential anti-HIV agents. JL Farmaco, 51(5), 361–366.
Dong Y., Venkatachalam T.K., Narla R.K., Trieu V.N., Sudbeck E.A., Uçkun F.M. (2000): Antioxidant fuction of phenethyl-5-bromopyridyl thiourea compounds with potent anti-HIV activity. Bioorg. Med. Chem. Lett., 10, 87–90.
Uçkun F.M., Mao C., Pendergrass S., Maher D., Zhu D., Tuel-Ahlgren L., Venkatachalam T.K (1999): N-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-bromopyridyl)] thiourea and N′-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-chloropyridyl)] thiourea as a potent inhibitors of multidrug-resistant HIV-1. Bioorg. Med. Chem. Lett., 9, 2721–2726.
Uçkun F.M., Pendergrass S., Maher D., Zhu D., Tuel-Ahlgren L., Mao C., Venkatachalam T.K. (1999): N′-[2-(2-thiophene)ethyl]-N′-[2-(5-bromopyridyl)]thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant HIV-1. Bioorg. Med. Chem. Lett., 9, 3411–3416.
Jones A.R., Mashford P.M. (1983): The fat of N-methyl-N′-(hydroxymethyl)thiourea in the rat. Xenobiotica, 13(2), 73–79.
Debruyne D., Moulin M.A., Bricard H., Bigot M.C. (1985): Liquid chromatographic determination of noxytiolin and 1-methyl-2-thiourea in serum: application to pharmacokinetic studies in rabbits and humans. J. Pharm. Sci., 74(2), 224–226.
Hucker H.B., Stauffer S.C., White S.D., Arison B.H., Zacchei A.G. (1982): Physiologic dispotion and metabolism of an anti-ulcer agent, N-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyridyl)-N, N′-dimethylurea, in rats, dogs and monkeys. Drug Metab. Dispos., 10(1), 28–34.
Kaymakçioĝlu B., Rollas S., Körceĝez E., Ariciĝlu-Kartal F. (2001): Evolution of anticonvulsant activity of N-substituted-N′-(3,5-dimethyl/1,3,5-trimethylpyrazole-4-yl)thiourea derivatives. 3rd International Symposium on Pharmaceutical Chemistry, September 17–19, Istanbul, P-24.
Koçyiĝit Kaymakçioĝlu B., Rollas S. (2002): Synthesis, characterization and evaluation of antituberculosis activity of some hydrazones. IL Farmaco, 57, 595–599.
Oruç E.E., Rollas S., Kabasakal L., Uysal M.K. (1999): The in vivo metabolism of 5-(4-nitrophenyl)-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione in rats. Drug Metab. and Drug Interact., 15, 127–140.
Gülerman N.N., Oruç E.E., Kartal F., Rollas S. (2000): In vivo metabolism of 4-fluorobenzoic acid[(5-nitro-2-furanyl)methylene]hydrazide in rats. Eur. J. Drug Metab. Pharmacokinet., 25(2), 103–108.
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Kaymakçioĝlu, B.K., Rollas, S. & Kartal-Aricioglu, F. In vivo metabolism of N-phenyl-N′-(3,5-dimethylpyrazole-4-yl) thiourea in rats. European Journal of Drug Metabolism and Pharmacokinetics 28, 273–278 (2003). https://doi.org/10.1007/BF03220179
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DOI: https://doi.org/10.1007/BF03220179