TY - JOUR T1 - Tiyoürelerin tüberküloz tedavisinde kullanımı TT - The use of thioureas in the treatment of tuberculosis AU - Kalem, Esra AU - Ağar, Erbil PY - 2022 DA - November DO - 10.17932/IAU.ABMYOD.2006.005abmyod_v16i64001 JF - Anadolu Bil Meslek Yüksekokulu Dergisi JO - ABMYO Dergisi PB - Istanbul Aydin University WT - DergiPark SN - 1306-3375 SP - 239 EP - 262 VL - 16 IS - 64 LA - tr AB - İnsan sağlığı için tüberküloz prevalansı, özellikle immün yetmezlik virüsü enfeksiyonu ve AIDS oldukça ciddi sorunlardandır. Aynı derecede ciddi bir halk sağlığı sorunu çoklu ilaca karşı direncin tüberküloz oranınını artırmasıdır. Çoklu ilaca dirençli tüberküloz hastaları arasındaki oranlar incelendiğinde şu anda sadece birkaç alternatif kemoterapötik rejim mevcut olup düşük terapötik sonuçlar ve yüksek ölüm oranı ile sonuçlanmaktadır. Tüberkülozun tedavisinde kullanılan birinci kuşak ilaçlar izoniazid, etambutol, pirazinamid ve rifampindir. Tüberküloz basili ilaç direnci kazanmaktadır. Buna karşın ikinci kuşak ilaçlar olarak tiyoüre türevlerinden etiyonamid (ETA), protiyonamid (PTA), tiasetazon (TAZ) ve izoksil (ISO), flurokinolonlar, amikasin, kanamisin, kapreomisin ve benzeri ilaçlar kullanılmaktadır. Ancak bu ilaçlara da direnç gelişimi gözlemlenmektedir. Bunlardan farklı bakterisidal mekanizmalara sahip yeni, etkili antitüberküloz ilaçları geliştirmeye acil ihtiyaç duyulmaktadır. Tiyoüreler, olağanüstü biyolojik uygulamalara sahip çok yönlü kimyasallardır. Tiyoürelerin en belirgin biyolojik uygulamaları enfeksiyon tedavisidir. Antioksidan, karınca alerjenleri, anti bakteriyel ajanlar, anti-inflamatuar, anti-tiroid ilaçları, anti-epileptik ilaçlar, anti-hipertansif, rodentisit, kanser önleyici ilaç, DNA bağlayıcı ve üreaz inhibitörleri olarak kullanılmaktadırlar. Bu ligandlar, oksijen, nitrojen ve kükürt atomları aracılığıyla bir dizi metal merkezini koordine etme konusunda belirgin bir yetenek göstermektedir. Bu türevler, nötral tek dişli (S), monobazik iki dişli (O,S) ve iki dişli (N,S) gibi çeşitli bağlanma modlarına sahiptir. Sert ve yumuşak donör bölgelerinin varlığından dolayı seçici bağlayıcılar olarak iyi bilinmektedir. Çalışmalar, bu bileşiklerin mikrobiyal enfeksiyonlar, tüberküloz, karsinomlar, sıtma, üreaz inhibitörleri ve anti-inflamatuar gibi insan hastalıklarını tedavi etmek için ilaç olarak kullanılabileceğini göstermiştir. KW - tiyoüre KW - tiyoüre kompleksleri KW - tüberküloz KW - mycrobacterium tüberküloz N2 - The prevalence of tuberculosis, especially immunodeficiency virus infection and AIDS, are serious problems for human health. An equally serious public health concern is that multidrug resistance increases the rate of tuberculosis. Examining the proportions among multidrug-resistant tuberculosis patients, only a few alternative chemotherapeutic regimens are currently available, resulting in low therapeutic outcomes and high mortality. First generation drugs used in the treatment of tuberculosis are isoniazid, ethambutol, pyrazinamide and rifampin. Tuberculosis bacillus is gaining drug resistance. On the other hand, thiourea derivatives such as ethionamide (ETA), prothionamide (PTA), thiacetazone (TAZ) and isoxyl (ISO), fluoroquinolones, amikacin, kanamycin, capreomycin and similar drugs are used as second generation drugs. However, resistance to these drugs is also observed. There is an urgent need to develop new, effective antituberculosis drugs with different bactericidal mechanisms than these. Thioureas are versatile chemicals with extraordinary biological applications. The most prominent biological applications of thioureas are the treatment of infections. They are used as antioxidants, ant allergens, antibacterial agents, anti-inflammatory, anti-thyroid drugs, anti-epileptic drugs, anti-hypertensive, rodenticide, anti-cancer drug, DNA binding and urease inhibitors. These ligands determine a particular ability to target metal centers with a range of lightning, nitrogen and sulfur atoms. These derivatives have modes that can pass neutral single digits (S), monobasic two digits (O,S), and two digits (N,S). They are well known as custom made for garments of hard and cloth donors. These students' microbials can be used as medicine to sicken human diseases such as practice, urea inoperable and anti-inflammatory. CR - Beyer, L., Hoyer, H., Hennig, H., Kirmse, R., Hartmann, J., Liebscher. J., 1975, “Synthese und Charakterisierung Neuartiger Übergangsmetall-chelate von 1,1-dialkyl-3- benzoyl-thioharnstoffen”, J. Prakt. Chem., 317(5), 829-839 CR - Beyer, L., Hoyer, E., Liebscher, J., Hartmann, H., 1981, “Formation of complexes with Nacylthioureas”, Z. Chem., 21(3), 81-91 CR - Beyer, L., Widera, R., 1982, “Reactions of metal-coordinated N-acylthioureas with acidchlorides - a simple path to new thiourea derivatives”, Z. Chem., 22(9), 345-346 CR - Buu-Hoi,P., Xuong, D., Nam, H., 1955, N,N -Diarylthioureas and related compounds of potential biological interest, J. Chem. Soc., 1573–1581 CR - Crowther, A.F., Curd, F. H. S., Richardson, (Miss)D. N. and Rose, F. L., 1948, 333. Synthetic antimalarials. Part XXIX. The preparation of some N1-aryl-N2-alkyl-N5-alkyl- and -dialkyl-diguanides, Journal of The Chemical Society CR - Doub, L., Richardson, L. M., Herbst, D. R., Black, 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 CR - Huang, Y.-B.; Yi, W.-B.; Cai, C., 2012, Thiourea based fluorous organocatalyst. Fluorous Chemistry: Springer;,191-212 Karakus¸ S., Rollas, S., 2002, Synthesis and antituberculosis activity of new N-phenylN -[4-(5-alkyl/arylamino-1,3,4-thiadiazole-2-yl)phenyl]thioureas, Il Farmaco, 57, 577–581 CR - Koch, K. R., Miller, J., Sieldemann, O., 2002, “Determination of the nucleophilic reactivity constants for a series of N-(N-propyl)-N′-(para-R-benzoyl)thioureas towards transPt(pyridine)2Cl2]”, Inorg. Chim. Acta, 331, 136-142 CR - Koketsu, M.; Kobayashi, C.; Ishihara, H. 2003, Heteroatom Chemistry. 14, 374-8 CR - Kordulákova, J., Janin, Y. L., Liav, A., Barilone, N., Vultos, T. D., Rauzier, J., Brennan, P. J., Gicquel, B., Jackson, M., 2007, Isoxyl activation is required for bacteriostatic activity against Mycobacterium tuberculosis, Antimicrob. Agents Chemother., 51, 3824–3829 CR - König, K. H., Schuster, M., Steinbrech, B., Schneeweis, G., Schlodder, R., 1985, “N,NDialkyl-N′-benzoylthioharnstoffe als selektive Extraktionsmittel zur Abtrennung und Anreicherung von Platinmetallen”, Fresenius Z. Anal. Chem., 321(5), 457-460 CR - Kurnakow, N., 1895, “Ueber complex metallbasen. Erste abhandlung”, J. Prakt. Chem., 51, 234 CR - Küçükgüzel, I., Küçükgüzel, S.G., Rollas, S., Kiraz, M., 2001, Some 3-thioxo/alkylthio-1, 2, 4-triazoles with a substituted thiourea moiety as possible antimycobacterials, Bioorganic & Medicinal Chemistry Letters, Volume 11, Issue 13, Pages 1703-1707 CR - Larik, F.A., Saeed, A., Faisal, M., Channar, P.A., Azam, S.S., Ismail, H., Dilshad, E., Mirza, B., 2018, “Synthesis, Molecular Docking and Comparative Efficacy of Various Alkyl/Aryl Thioureas as Antibacterial, Antifungal and α-Amylase Inhibitors”, Computational Biology and Chemistry, 77, 193–198 CR - Maddani, M.R.,A, Kandikere, R. P., 2010, A concise Synthesis of Substituted Thiourea Derivatives in Aqueous Medium, J. Org. Chem., 75, 7, 2327–2332 CR - Mansuroğlu, D. S., 2007, “Yeni tiyoüre türevi ligand ve metal komplekslerinin sentezlenmesi ve karakterizasyonu”, Mersin Üniversitesi Sağlık Bilimleri Enstitüsü, Yüksek Lisans Tezi, Mersin CR - Mishra, B., Hassan, P.A., Priyadarsini, K.L., Mohan, H., 2005, “Reactions of Biological Oxidants with Selenourea: Formation of Redox Active Nanoselenium”, Journal of Physical Chemistry B, 109 (26), 12718–12723 CR - Miyabe, H.; Takemoto, Y. 2008, Bulletin of the Chemical Society of Japan. 81, 785-95 CR - Moro, A. C., Mauro, A. E., Netto, A. V. G., Ananias, S. R., Quilles, M. B., Carlos, I. Z., Pavan, F. R., Leite, C. Q. F., Hörnerd, M., 2009, Antitumor and antimycobacterial activities of cyclopalladated complexes: X-ray structure of [Pd(C2,N-dmba)(Br)(tu)] (dmba = N,N-dimethylbenzylamine, tu = thiourea), European Journal of Medicinal Chemistry, Volume 44, Issue 11, Pages 4611-4615 CR - Mühl, P., Gloe, K., Dietze, F., Hoyer, E., Beyer, L., 1986, “N‐Acyl‐thioharnstoffe – effektive Extraktionsmittel für die Flüssig‐Flüssig‐Extraktion von Metallionen”, Z. Chem., 26(3), 81-94 CR - Neucki, E., 1873, Zur Kenntniss des Sulfoharnstoffs. Ber. Dtsch. Chem. Ges., 6, 598-600 CR - Nishida, C. R., Montellano, P. R. O., 2011, Chemico-Biological Interactions, Bioactivation of antituberculosis thioamide and thiourea prodrugs by bacterial and mammalian flavin monooxygenases, 192, 21-25 CR - O'Reilly, B.,Plutín, A.M., Pérez, H., Calderón, O., Ramos, R., Martínez, R., Toscano, R. A., Duque, J., Rodríguez-Solla, H., Martínez-Alvarez, R., Suárez, M., Martín, N., 2012, Synthesis and structural characterization of cobalt(II) and copper(II) complexes with N,N-disubstituted-N’-acylthioureas, Polyhedron, 36, pp. 133-140 CR - Phetsuksiri, B., Baulard, A., Cooper, A. M., Minnikin, D. E., Douglas, J. D., Besra, G. S., and Brennan, P. J., 1999, Antimicrob. Agents Chemother, 43, 1042–1051 CR - Plutín, A. M., Alvarez, A., Mocelo, R., Ramos, R., Castellano, E. E., Silva, M. M., Villarreal, W., Pavan, F. R., Meira, C. S., Filho, J. S. H. R., Moreira, D. R. M., Soares, M. M. P., Batista, A. A., 2017, Palladium(II)/N,N-disubstituted-N′-acylthioureas complexes as anti-Mycobacterium tuberculosis and anti-Trypanosoma cruzi agents, Polyhedron, Volume 132, Pages 70-77 CR - Ramadas, K., Srinivasan, N., Janarthanan, N., 1993, A facile conversion of symmetrical to unsymmetrical thioureas, Tetrahedron Letters, Volume 34, Issue 40, 6447-6450 CR - Riccieri, F.M., Parcelli, G. A., Castellani, P., 1967, Thiourea derivatives and their antitubercular activity, Farmaco Ed. Sci., 22, 114–120 CR - Rigaudy, J.; Klesney, S.; Rigaudy, J., 1979, Nomenclature of Organic Chemistry: Sections A, B, C, D, E, F and H: Pergamon Press Oxford CR - Rollas, S. ve Koçyiğit-Kaymakçıoğlu, B., 2003, “Biological Activity Of Disubstituted Thiourea Derivatives”, Current Topics İn Med. Chem., 3, 121- 134 CR - Ruswanto, Miftah, A.M., Tjahjono, D.H., Siswandono, 2013, “Synthesis and in Vitro Cytotoxicity of 1-Benzoyl-3-Methyl Thiourea Derivatives”, Procedia Chemistry, 17, 157–161 CR - Scarim, C. B., Farias, R.L., Netto, A. V. G., Chin, C. M., Santos, J. L., Pavana, F. R., 2021, Recent advances in drug discovery against Mycobacterium tuberculosis: Metal-based complexes, European Journal of Medicinal Chemistry, Volume 214 CR - Shakeel, A., Altaf, A.A., Qureshi, A.M., Badshah, A., 2016, Thiourea Derivatives in Drug Design and Medicinal Chemistry, Journal of Drug Design and Medicinal Chemistry; 2(1): 10-20 CR - Sharma, S. K., Mohan, A., 2006, Multidrug-resistant tuberculosis. A menace that threatens to destabilize tuberculosis control, Chest., 136, 261–272 CR - Vest, P., Schuster, M., König, K. H., 1991, “Solvent extraction of gold with N-substituted benzoylthioureas”, Fresenius Z. Anal. Chem., 341(9), 566-568 CR - Winder, F. G., and Collins, P. B., 1970, J. Gen. Microbiol., 63, 41–48 CR - Winder, F. G., Collins, P. B., and Whelan, D., 1971, J. Gen. Microbiol., 66, 379–380 CR - Winkelmann, V. E., Wagner, W. H., Hilmer, H., 1969, Tuberkulostatisch wirksame N,N -diaryl-thioharnstoffe, Arzneim.-Forsch., 12, 543–558 CR - Wisterowicz, K., Foks, H., Janowiec, M., Zwolska-Kwiek, Z., 1989, Studies on pyrazine derivatives. XXVI. Synthesis and tuberculostatic activity of N-pyrazinylthiourea, Acta Pol. Pharm., 46, 101–113. CR - World Health Organization, 2020, "World Health Organization Global Tuberculosis Report 2020." World Health Organization , 232 CR - World Health Organization, 2020. WHO consolidated guidelines on tuberculosis. Module 4: treatment-drug-resistant tuberculosis treatment. CR - Zhao, M.M., Dong,X.Y., Li, G., Yang, Y.H., Zhang, Y.J., Yang, X.Q., 2013 “Antituberculosis and Antifungal Activities of Synthesized, Benzoylthiourea Derivatives”, Asian Journal of Chemistry, 25 (13), 7548–7550 CR - Zhoua, W., Lua, J., Zhanga, Z., Zhanga, Y., Caoa, Y., Lub, L.,Yang, X., 2004, “Structure and vibration spectra of N-4-chlorobenzoyl–N0-4- methoxylphenylthiourea”, Vib. Spectrosc., 34, 199–204 UR - https://doi.org/10.17932/IAU.ABMYOD.2006.005abmyod_v16i64001 L1 - https://dergipark.org.tr/en/download/article-file/2183254 ER -