Some N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-[(3-substituted) ureido/thioureido]benzenesulfonamides as carbonic anhydrase I and II inhibitors

Abstract

In the present study, N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-[(3-substitue)ureido] benzenesulfonamide (1-9) and N-(5-methyl-1,3,4-thiadiazol-2-yl)-4-[(3-substitue) thioureido]benzenesulfonamide (10-14) derivatives were synthesized from 4-amino-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (Sulfamethizole). All new compounds were characterized by elemental analysis and various spectroscopic methods (FTIR, ¹H-NMR and MS). These new sulfonamide derivatives were investigated as inhibitors of carbonic anhydrase especially human carbonic anhydrase I and II. The new compounds showed higher activity against the human cytosolic CA I (IC₅₀ values 0.095-15.65 nM) and CA II            (IC₅₀ values 0.057-17.95 nM) in comparison with the clinically used CAI inhibitor acetazolamide.

Keywords

• Carbonic anhydrase inhibitors,sulfonamide,sulfamethizole,urea and thiourea

Karbonik anhidraz I ve II inhibitörü olan bazı N-(5-metil- 1,3,4-tiyadiazol-2-il)-4-[(3-sübstitüe)üreido/tiyoüreido] benzensülfonamitler

Abstract

Bu çalışmada N-(5-metil-1,3,4-tiyadiazol-2-il)-4-[(3-sübstitüe)  üreido]benzensülfonamit ve N-(5-metil-1,3,4-tiyadiazol-2-  il)-4-[(3-sübstitüe)tiyoüreido]benzensülfonamit türevleri  4-amino-N-(5-metil-1,3,4-tiyadiazol-2-il)benzensülfonamitten  (sülfametizol) hareketle sentez edildi. Bütün yeni bileşiklerin  yapıları elemental analiz ve çeşitli spektroskopik yöntemler  (FTIR, 1H-NMR ve MS) yardımıyla aydınlatıldı. Bu yeni  sülfonamit türevlerinin, özellikle insan karbonik anhidraz  I ve II olmak üzere, karbonik anhidraz inhibitor etkileri  incelendi. Bileşiklerin klinikte kullanılan asetazolamide kıyasla  insan sitozolik CA I (IC50 değerleri 0.144-15.65 nM) ve CA II  (IC50 değerleri 0.109-17.95 nM) inhibisyon değerleri ile daha  yüksek aktivite gösterdikleri tespit edildi.  

Keywords

• Karbonik anhidraz inhibitörleri,sülfonamit,sülfametizol,üre ve tiyoüre

References

1. Leppialmi M, Koistinen P, Savolainen ER, Hannuksela J, Parkkila AK, Niemelä O, Pastoreková S, Pastorek J, Waheed A, Sly WS, Parkkila S, Rajaniemi H. The expression of carbonic anhydrase II in hematological malignancies. Clin Cancer Res 2002; 8: 2240-5.
2. Demir Y, Demir N, Yıldırm S, Nadaroğlu H, Karaosmanoğlu M, Bakan E. The Activities of Carbonic Anhydrase and Alkaline Phosphatase In Ancient Human Bones. Purification and Characterization of Outer Peripheral, Cytosolic, Inner Peripheral, and Integral CA. Prep Biochem Biotech 2001; 31: 291-304.
3. Demir N, Demir Y, Nadaroğlu H. Carbonic Anhydrase from Bovine Bone. Prep Biochem Biotech 2001; 31: 33-48.
4. Shah GN, Emmett DH, Grubb JH, Migas MC, Fleming RE, Waheed A, Sly WS. Mitochondrial carbonic anydrase CA VB: Differences in tissue distribution and pattern of evolution from those of CA VA suggest distinct physiological roles. Proc Natl Acad Sci USA 2000; 97: 1677-82.
5. Demir Y, Nadaroğlu H, Demir N. Purification and Characterization of Carbonic Anhydrase From Bovine Stomach And Inhibitory Effects Of Some Chemical Substances On Enzyme Activities. J Enzym Inhib Med Chem 2005; 20: 75-80.
6. Supuran CT. Structure-based drug discovery of carbonic anhydrase inhibitors. J Enzyme Inhib Med Chem 2012; 27: 759-72.
7. Supuran CT. Carbonic anhydrases - an overview. Curr Pharm Des 2008; 14: 603-14.
8. Supuran CT. Carbonic anydrase inhibitors. Bioorg Med Chem Lett 2010; 20: 3467-74.

9. Supuran CT, Scozzafava A. Carbonic anhydrases as targets for medicinal chemistry. Bioorg Med Chem 2007; 15: 4336-50.
10. Hilvo M, Tolvanen M, Clark A, Shen BR, Shah GN, Waheed A, Halmi P, Hanninen M, Hamalainen JM, Vihinen M, Sly WS, Parkkila S. Characterization of CA XV, a new GPI-anchored form of carbonic anydrase. Biochem J 2005; 392: 83-92.
11. Supuran CT. Carbonic anydrases: Novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 2008; 7: 168-81.
12. Supuran CT. Diuretics: From classical carbonic anhydrase inhibitors to novel applications of the sulfonamides. Curr Pharm Design 2008; 14: 641-48.
13. Zolnowska B, Slawinski J, Pogorzelska A, Chojnacki J, Vullo D, Supuran CT. Carbonic anhydrase inhibitors: synthesis, and molecular structure of novel series N-substituted-N'-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)guanidines and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII. Eur J Med Chem 2014; 71: 135-47.
14. Arslan A, Demir H, Arslan H. Investigating catalase and carbonic anhydrase enzyme activities and levels of certain trace elements and heavy metals in patients with primary and metastatic hepatic carcinoma. J Cancer Ther 2013; 4: 1373-81.
15. Haapasalo J, Nordfords K, Järvelä S, Bragge H,Rantala I, Parkkila AK, Haapasalo H, Parkkila S. Carbonic anhydrase II in the endothelium of glial tumors: A potential target for therapy. Neuro Oncol 2007; 9: 308-13.
16. Ibrahim DA, Lasheen DS, Zaky MY, Ibrahim AW, Vullo D, Ceruso M, Supuran CT, Ella DA. Design and synthesis of benzothiazole-6-sulfonamides acting as highly potent inhibitors of carbonic anhydrase isoforms I, II, IX and XII. Bioorg Med Chem 2015; 23: 4989-99.
17. Supuran CT, Scozzafava A. Carbonic anhydrae inhibitors: Aromatic sulfonamides and disulfonamides act as efficient tumor growth inhibitors. Eur J Med Chem 2000; 35: 867-74.