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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Carbonic Anhydrase Inhibitory Potential of 1,2,4-triazole-3-thione Derivatives of Flurbiprofen, Ibuprofen and 4-tert-butylbenzoic Hydrazide: Design, Synthesis, Characterization, Biochemical Evaluation, Molecular Docking and Dynamic Simulation Studies

Author(s): Saghir Abbas, Sumera Zaib, Shafiq Ur Rahman, Saqib Ali*, Shahid Hameed*, Muhammad N. Tahir, Khurram S. Munawar, Farzana Shaheen, Syed M. Abbas and Jamshed Iqbal*

Volume 15, Issue 3, 2019

Page: [298 - 310] Pages: 13

DOI: 10.2174/1573406414666181012165156

Price: $65

Abstract

Background: The over-expression of the carbonic anhydrases results in some specific carcinomas including pancreatic, gastric and brain tumor. Tumors are distinguished under hypoxic conditions and various investigations are being carried out to target the known hypoxic areas of the tumors to increase the sensitivity towards standard therapeutic treatment.

Objective: Herein, we have designed and synthesized some biologically important esters, hydrazides, thiocarbamates, 1,2,4-triazole-3-thiones and Schiff bases. The purpose of the research was to evaluate the derivative against carbonic anhydrase and to assess the toxicity of the same compounds.

Method: The structures of all the compounds were characterized by FT-IR, mass spectrometry, elemental analysis, 1H and 13C NMR spectroscopy. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase II by in vitro assay. Double reciprocal plots for inhibition kinetics of the potent compounds were constructed and mode of inhibition was determined. Furthermore, to check the cytotoxicity, these derivatives were tested against human breast adenocarcinoma by MTT method.

Results: X-ray diffraction analysis of the compounds 10, 14 and 15 showed that they did not have any π-π or C-H…π interactions. The experimental results were validated by molecular docking and dynamic simulations of the potent compounds in the active pocket of enzyme. Important binding interactions of potent compounds with the key residues in the active site of the carbonic anhydrase enzyme were revealed. Drug likeness profile of the derivatives was evaluated to determine the physicochemical properties.

Conclusion: The proposed synthetic approach provides a suitable platform for the generation of a new library of compounds which could potentially be employed in the future testing and optimization of inhibitor potencies.

Keywords: 1, 2, 4-triazole-3-thione, chemotherapy, schiff base, X-ray crystallography, molecular docking, dynamic simulations.

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[1]
Waheed, A.; Sly, W.S. Carbonic anhydrase XII functions in health and disease. Gene, 2017, 623, 33-40.
[2]
van Kuijk, S.J.; Parvathaneni, N.K.; Niemans, R.; van Gisbergen, M.W.; Carta, F.; Vullo, D.; Pastorekova, S.; Yaromina, A.; Supuran, C.T.; Dubois, L.J.; Winum, J.Y.; Lambin, P. New approach of delivering cytotoxic drugs towards CAIX expressing cells: A concept of dual-target drugs. Eur. J. Med. Chem., 2017, 127, 691-702.
[3]
Smith, K.S.; Ferry, J.G. Prokaryotic carbonic anhydrases. FEMS Microbiol. Rev., 2000, 24, 335-366.
[4]
Temperini, C.; Innocenti, A.; Scozzafava, A.; Supuran, C.T. Carbonic anhydrase activators: Kinetic and X-ray crystallographic study for the interaction of d-and l-tryptophan with the mammalian isoforms I–XIV. Bioorg. Med. Chem., 2008, 16, 8373-8378.
[5]
Ghiasi, M.; Kamalinahad, S.; Arabieh, M.; Zahedi, M. Carbonic anhydrase inhibitors: A quantum mechanical study of interaction between some antiepileptic drugs with active center of carbonic anhydrase enzyme. Comput. Theor. Chem., 2012, 992, 59-69.
[6]
Gilmour, K.M. Perspectives on carbonic anhydrase. Comp. Biochem. Physiol.Part A Mol. Integr. Physiol., 2010, 157, 193-197.
[7]
Supuran, C.T. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov., 2008, 7, 168-181.
[8]
Kiwull-Schone, H.F.; Teppema, L.J.; Kiwull, P.J. Low-dose acetazolamide does affect respiratory muscle function in spontaneously breathing anesthetized rabbits. Am. J. Respir. Crit. Care Med., 2001, 163, 478-483.
[9]
Supuran, C.T.; Winum, J.Y. Designing carbonic anhydrase inhibitors for the treatment of breast cancer. Expert Opin. Drug Discov., 2015, 10, 591-597.
[10]
Sh Ali, A.A.; Al-Mashta, S.A. Cerebral calcification, osteopetrosis and renal tubular acidosis: is it carbonic anhydrase-II deficiency? Saudi J. Kidney Dis. Transpl., 2013, 24, 61-565.
[11]
Swenson, E.R.; Hughes, J.M. Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in men. J. Appl. Physiol., 1993, 74, 230-237.
[12]
Klein, M.; Krainz, K.; Redwan, I.N.; Dinér, P.; Grøtli, M. Synthesis of chiral 1,4-disubstituted-1,2,3-triazole derivatives from amino acids. Molecules, 2009, 14, 5124-5143.
[13]
Bayrak, H.; Demirbas, A.; Demirbas, N.; Karaoglu, S.A. Synthesis of some new 1,2,4-triazoles starting from isonicotinic acid hydrazide and evaluation of their antimicrobial activities. Eur. J. Med. Chem., 2009, 44, 4362-4366.
[14]
El-Sayed Ali, T.; El-Kaza, A.M. Synthesis and antimicrobial activity of some new 1,3-thiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and 1,3-thiazines incorporating acridine and 1,2,3,4-tetrahydroacridine moieties. Eur. J. Chem., 2010, 1, 6-11.
[15]
Tehranchian, S.; Akbarzadeh, T.; Fazeli, M.R.; Jamalifar, H.; Shafiee, A. Synthesis and antibacterial activity of 1- [1, 2, 4-triazol-3-yl] and 1- [1, 3, 4-thiadiazol-2-yl]-3-methylthio-6, 7-dihydrobenzo [c] thiophen-4 (5H) ones. Bioorg. Med. Chem. Lett., 2005, 15, 1023-1025.
[16]
Papadopoulou, M.V.; Bloomer, W.D.; Rosenzweig, H.S.; Chatelain, E.; Kaiser, M.; Wilkinson, S.R.; McKenzie, C.; Ioset, J.R. Novel 3-nitro-1H-1, 2, 4-triazole-based amides and sulfonamides as potential anti-trypanosomal agents. J. Med. Chem., 2012, 55, 5554-5565.
[17]
Küçükgüzel, S.G.; Küçükgüzel, I.; Tatar, E.; Rollas, S.; Sahin, F.; Gulluce, M.; De Clercq, E.; Kabasakal, L. Synthesis of some novel heterocyclic compounds derived from diflunisal hydrazide as potential anti-infective and anti-inflammatory agents. Eur. J. Med. Chem., 2007, 42, 893-901.
[18]
Amir, M.; Kumar, H.; Javed, S.A. Synthesis and pharmacological evaluation of condensed heterocyclic 6-substituted-1, 2, 4-triazolo [3, 4-b]-1, 3, 4-thiadiazole derivatives of naproxen. Bioorg. Med. Chem. Lett., 2007, 17, 4504-4508.
[19]
Lango, K.I.; Valentina, P. Facile synthesis and cytotoxic activity of 3, 6-disubstituted 1, 2, 4-triazolo- [3, 4-b]-1, 3, 4-thiadiazoles. Eur. J. Chem., 2010, 1, 50-53.
[20]
Bijul Lakshman, A.; Gupta, R.L.; Prasad, D. Quantitative structure activity relationships for the nematicidal activity of 4-amino-5-substituted aryl-3-mercapto-(4H)-1,2,4-triazoles. Indian J. Chem. Sect. B, 2010, 12, 1657-1661.
[21]
Bijul Lakshman, A.; Gupta, R.L. Fungitoxicity and QSAR of 4-amino-5-substituted aryl-3-mercapto-(4H)-1,2,4-triazoles. Indian J. Chem. Sect. B, 2010, 9, 1235-1242.
[22]
Gui-fa, S.; Yi-ming, Z.; Jiang-ke, Q.; Ye-cheng, D.; Ming, Z.; Zhong-chang, W.; Xi, Y.H. Synthesis, characterization and antibacterial activity of 3-substituted-6-(4′-decarboxydehydroabietyl)-1,2,4-triazolo [3,4-b]-1,3,4-thiadiazole derivatives. Chin. J. Appl. Chem., 2010, 27(6), 651-657.
[23]
Bijul Lakshman, A.; Gupta, R.L. Microwave assisted synthesis of some 4-amino-5-substituted aryl-3-mercapto-(4H)-1,2,4-triazoles. Asian J. Chem., 2009, 1, 86-92.
[24]
Krasovskii, A.N.; Bulgakov, A.K.; Andrushko, A.P.; Krasovskii, I.A.; Dyachenko, A.M.; Bokun, A.A.; Kravchenko, N.A.; Demchenko, A.M. Antimicrobial and tuberculostatic activity of 5-aryl (hetaryl)-1, 3, 4-oxadiazole-2-thiones and their derivatives. Pharm. Chem. J., 2000, 34, 115-117.
[25]
Bijev, A.T.; Prodanova, P. Derivatives of 4-amino-4H-1, 2, 4-triazole-3-thiols linked to the pyrrole cycle and some products of their S-alkylation. Chem. Heterocycl. Compd., 2007, 43, 306-313.
[26]
El-Khawass, S.M.; Habib, N.S. Synthesis of 1, 2, 4‐triazole, 1, 2, 4‐triazolo [3, 4‐b] [1, 3, 4] thiadiazole and 1, 2, 4‐triazolo [3, 4‐b] [1, 3, 4] thiadiazine derivatives of benzotriazole. J. Heterocycl. Chem., 1989, 26, 177-181.
[27]
Bua, S.; Di Cesare, M.L.; Vullo, D.; Ghelardini, C.; Bartolucci, G.; Scozzafava, A.; Suparan, C.T.; Carta, F. Design and synthesis of novel nonsteroidal anti-inflammatory drugs and carbonic anhydrase inhibitors hybrids (NSAIDs–CAIs) for the treatment of rheumatoid arthritis. J. Med. Chem., 2017, 60, 1159-1170.
[28]
Tidewell, T.T.; Schiff, H. (ugo). Schiff bases and a century of b-lactam synthesis. Angew. Chem. Ed, 2008, 47, 1016-1020.
[29]
Mirkhani, V.; Kia, R.; Vartooni, A.R.; Fun, H.K. New Re(I) tricarbonyl-diimine complexes with N, N0-bis (substituted benzaldehyde)-1,2-diiminoethane Schiff base ligands: synthesis, spectroscopic and electrochemical studies and crystal structures. Polyhedron, 2010, 29, 1600-1606.
[30]
Sirajuddin, M.; Uddin, N.; Ali, S.; Tahir, M.N. Potential bioactive Schiff base compounds: synthesis, characterization, X-ray structures, biological screenings and interaction with Salmon sperm DNA. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2013, 116, 111-121.
[31]
Hearn, M.J.; Cynamon, M.H.; Chen, M.F.; Coppins, R.; Davis, J.; Joo-On Kang, H.; Noble, A.; Tu-Sekine, B.; Terrot, M.S.; Trombino, D. Thai, M.; Webster, E.R.; Wilson, R. Preparation and antitubercular activities in vitro and in vivo of novel Schiff bases of isoniazid. Eur. J. Med. Chem., 2009, 44, 4169-4178.
[32]
El-Faham, A.; Farooq, M.; Khattab, S.N.; Elkayal, A.M.; Ibrahim, M.F.; Abutaha, N.; Wadaan, M.A.; Hameed, E.A. Synthesis and biological activity of Schiff base series of valproyl, N-valproyl glycinyl and N-valproyl-4-aminobenzoyl hydrazide derivatives. Chem. Pharm. Bull., 2014, 6, 591-599.
[33]
Gaur, S. Physico-chemical and biological properties of Mn (II), Co (II), Ni (II) and Cu (II) chelates of Schiff bases. Asian J. Chem., 2003, 15, 250-254.
[34]
Zaheer, M.; Zia-ur-Rehman, M.; Jamil, N.; Arshad, M.N.; Siddiqui, S.Z.; Asiri, A.M. Efficient green synthesis of N′-benzylidene-2-(2-fluorobiphenyl) propanehydrazides: crystal structure and anti-oxidant potential. J. Chem. Res., 2015, 11, 668-673.
[35]
MOE (The Molecular Operating Environment) Version 2010.10. Chemical Computing Group Inc, (CCG). http://www. chemcomp.com/
[36]
Stenberg, P.; Norinder, U.; Luthman, K.; Artursson, P. Experimental and computational screening models for the prediction of intestinal drug absorption. J. Med. Chem., 2001, 44, 1927-1937.
[37]
Armarego, W.L.F.; Chai, C.L.L. Purification of Organic Chemicals Chapter 5; , 2009, p. 6.
[38]
Saeed, A.; Khan, S.U.; Mahesar, P.A.; Channar, P.A.; Shabir, G.; Iqbal, J. Substituted (E)-2-(2-benzylidenehydrazinyl)-4-methylthia-zole-5-carboxylates as dual inhibitors of 15-lipoxygenase & carbonic anhydrase II: synthesis, biochemical evaluation and docking studies. Biochem. Biophys. Res. Commun., 2017, 482, 176-181.
[39]
Sheldrick, G.M. SHELXS-97, Program for X-ray Crystal Structure Solution; Göttingen University: Göttingen, 1997.
[40]
Sheldrick, G.M. SHELXS-97, Program for X-ray Crystal Structure Refinement; Göttingen University: Göttingen, 1997.
[41]
Parkkila, A.K.; Herva, R.; Parkkila, S.; Rajaniemi, H. Immuno-histochemical demonstration of human carbonic anhydrase iso-enzyme II in brain tumours. Histochem. J., 1995, 27, 974-982.
[42]
Frazier, M.L.; Lilly, B.J.; Wu, E.F.; Ota, T.; Hewett-Emmett, D. Carbonic anhydrase II gene expression in cell lines from human pancreatic adenocarcinoma. Pancreas, 1990, 5, 507-514.
[43]
Kivelä, A.; Parkkila, S.; Saarnio, J.; Karttunen, T.J.; Kivelä, J.; Parkkila, A.K.; Waheed, A.; Sly, W.S.; Grubb, J.H.; Shah, G.; Tureci, O.; Rajaniemi, H. Expression of a novel transmembrane carbonic anhydrase isozyme XII in normal human gut and colorectal tumors. Am. J. Pathol., 2000, 156, 577-584.
[44]
Chegwidden, W.; Spencer, I. Sulphonamide inhlbitors of carbonic anhydrase inhibit the growth of human lymphoma cells in culture. Inflammopharmacology, 1995, 3, 231-239.
[45]
Walloch, J.; Frankel, S.; Hrisinko, M.A.; Weil, S.C. Carbonic anhydrase: a marker for the erythroid phenotype in acute nonlymphocytic leukemia. Blood, 1986, 68, 304-306.

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