Tiyoürelerin tüberküloz tedavisinde kullanımı

Yıl 2021, Cilt: 16 Sayı: 64, 239 - 262, 28.11.2022

Esra Kalem , Erbil Ağar

https://doi.org/10.17932/IAU.ABMYOD.2006.005abmyod_v16i64001

Öz

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.

Anahtar Kelimeler

tiyoüre, tiyoüre kompleksleri, tüberküloz, mycrobacterium tüberküloz

The use of thioureas in the treatment of tuberculosis

Öz

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.

Anahtar Kelimeler

thiourea, thiourea derivative complexes, tuberculosis, mycobacterium tuberculosis

Kaynakça

• 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
• Beyer, L., Hoyer, E., Liebscher, J., Hartmann, H., 1981, “Formation of complexes with Nacylthioureas”, Z. Chem., 21(3), 81-91
• 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
• Buu-Hoi,P., Xuong, D., Nam, H., 1955, N,N -Diarylthioureas and related compounds of potential biological interest, J. Chem. Soc., 1573–1581
• 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
• 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
• 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
• 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
• Koketsu, M.; Kobayashi, C.; Ishihara, H. 2003, Heteroatom Chemistry. 14, 374-8
• 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
• 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
• Kurnakow, N., 1895, “Ueber complex metallbasen. Erste abhandlung”, J. Prakt. Chem., 51, 234
• 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
• 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
• 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
• Mansuroğlu, D. S., 2007, “Yeni tiyoüre türevi ligand ve metal komplekslerinin sentezlenmesi ve karakterizasyonu”, Mersin Üniversitesi Sağlık Bilimleri Enstitüsü, Yüksek Lisans Tezi, Mersin
• 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
• Miyabe, H.; Takemoto, Y. 2008, Bulletin of the Chemical Society of Japan. 81, 785-95
• 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
• 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
• Neucki, E., 1873, Zur Kenntniss des Sulfoharnstoffs. Ber. Dtsch. Chem. Ges., 6, 598-600
• 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
• 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
• 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
• 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
• Ramadas, K., Srinivasan, N., Janarthanan, N., 1993, A facile conversion of symmetrical to unsymmetrical thioureas, Tetrahedron Letters, Volume 34, Issue 40, 6447-6450
• Riccieri, F.M., Parcelli, G. A., Castellani, P., 1967, Thiourea derivatives and their antitubercular activity, Farmaco Ed. Sci., 22, 114–120
• Rigaudy, J.; Klesney, S.; Rigaudy, J., 1979, Nomenclature of Organic Chemistry: Sections A, B, C, D, E, F and H: Pergamon Press Oxford
• Rollas, S. ve Koçyiğit-Kaymakçıoğlu, B., 2003, “Biological Activity Of Disubstituted Thiourea Derivatives”, Current Topics İn Med. Chem., 3, 121- 134
• 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
• 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
• 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
• Sharma, S. K., Mohan, A., 2006, Multidrug-resistant tuberculosis. A menace that threatens to destabilize tuberculosis control, Chest., 136, 261–272
• Vest, P., Schuster, M., König, K. H., 1991, “Solvent extraction of gold with N-substituted benzoylthioureas”, Fresenius Z. Anal. Chem., 341(9), 566-568
• Winder, F. G., and Collins, P. B., 1970, J. Gen. Microbiol., 63, 41–48
• Winder, F. G., Collins, P. B., and Whelan, D., 1971, J. Gen. Microbiol., 66, 379–380
• Winkelmann, V. E., Wagner, W. H., Hilmer, H., 1969, Tuberkulostatisch wirksame N,N -diaryl-thioharnstoffe, Arzneim.-Forsch., 12, 543–558
• 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.
• World Health Organization, 2020, "World Health Organization Global Tuberculosis Report 2020." World Health Organization , 232
• World Health Organization, 2020. WHO consolidated guidelines on tuberculosis. Module 4: treatment-drug-resistant tuberculosis treatment.
• 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
• 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