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Medicinal Chemistry

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

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Research Article

A Series of Trifluoromethylisoxazolyl- and Trifluoromethylpyrazolyl- Substituted (Hetero)aromatic Sulfonamide Carbonic Anhydrase Inhibitors: Synthesis, and Convenient Prioritization Workflow for Further In Vivo Studies

Author(s): Nikolina Sibinčić, Stanislav Kalinin, Vladimir Sharoyko, Julia Efimova, Olga A. Gasilina, Mikhail Korsakov, Maxim Gureev and Mikhail Krasavin*

Volume 19, Issue 2, 2023

Published on: 27 September, 2022

Page: [193 - 210] Pages: 18

DOI: 10.2174/1573406418666220831112049

Price: $65

Abstract

Aims: To synthesize novel sulfonamide inhibitors of carbonic anhydrase and develop in vitro prioritization workflow to select compounds for in vivo evaluation.

Background: Carbonic anhydrase (CA) inhibitors gain significant attention in the context of drug discovery research for glaucoma, hypoxic malignancies, and bacterial infections. In previous works, we have successfully used direct sulfochlorination approach to develop diverse heterocyclic primary sulfonamides with remarkable activity and selectivity against therapeutically relevant CA isoforms.

Objective: Synthesis and investigation of the CA inhibitory properties of novel trifluoromethylisoxazolyl- and trifluoromethylpyrazolyl-substituted (hetero)aromatic sulfonamides.

Methods: Thirteen trifluoromethylisoxazolyl- and thirteen trifluoromethylpyrazolyl-substituted (hetero) aromatic sulfonamides were synthesized by direct sulfochlorination of hydroxyisoxazolines and pyrazoles followed by reaction with ammonia. The compound structures were confirmed by 1H and 13C NMR as well as element analysis. The obtained compounds were evaluated, using the CA esterase activity assay, for their potential to block the catalytic activity of bovine CA (bCA).

Results: Eight most potent compounds selected based on the esterase activity assay data were tested for direct affinity to the enzyme using the thermal shift assay (TSA). These compounds displayed Kd values (measured by TSA) in the double-digit nanomolar range, thus showing comparable activity to the reference drug acetazolamide.

Conclusion: Coupling the bCA esterase activity assay with thermal shift assay represents a streamlined and economical strategy for the prioritization of sulfonamide CA inhibitors for subsequent evaluation in vivo.

Keywords: Carbonic anhydrase, zinc-binding groups, sulfonamides, trifluoromethyl group, carbon dioxide, bicarbonate.

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[1]
Pastorekova, S.; Parkkila, S.; Pastorek, J.; Supuran, C.T. Carbonic anhydrases: Current state of the art, therapeutic applications and future prospects. J. Enzyme Inhib. Med. Chem., 2004, 19(3), 199-229.
[http://dx.doi.org/10.1080/14756360410001689540] [PMID: 15499993]
[2]
Alterio, V.; Di Fiore, A.; D’Ambrosio, K.; Supuran, C.T.; De Simone, G. Multiple binding modes of inhibitors to carbonic anhydrases: How to design specific drugs targeting 15 different isoforms? Chem. Rev., 2012, 112(8), 4421-4468.
[http://dx.doi.org/10.1021/cr200176r] [PMID: 22607219]
[3]
Supuran, C.T. Structure-based drug discovery of carbonic anhydrase inhibitors. J. Enzyme Inhib. Med. Chem., 2012, 27(6), 759-772.
[http://dx.doi.org/10.3109/14756366.2012.672983] [PMID: 22468747]
[4]
Scozzafava, A.; Supuran, C.T. Glaucoma and the applications of carbonic anhydrase inhibitors. Subcell. Biochem., 2014, 75, 349-359.
[http://dx.doi.org/10.1007/978-94-007-7359-2_17] [PMID: 24146387]
[5]
Supuran, C.T. Acetazolamide for the treatment of idiopathic intracranial hypertension. Expert Rev. Neurother., 2015, 15(8), 851-856.
[http://dx.doi.org/10.1586/14737175.2015.1066675] [PMID: 26154918]
[6]
Swenson, E.R. Carbonic anhydrase inhibitors and high altitude illnesses. Subcell. Biochem., 2014, 75, 361-386.
[http://dx.doi.org/10.1007/978-94-007-7359-2_18] [PMID: 24146388]
[7]
Wongboonsin, J.; Thongprayoon, C.; Bathini, T.; Ungprasert, P.; Aeddula, N.; Mao, M.; Cheungpasitporn, W. Acetazolamide therapy in patients with heart failure: A meta-analysis. J. Clin. Med., 2019, 8(3), 349.
[http://dx.doi.org/10.3390/jcm8030349] [PMID: 30871038]
[8]
Buzás, G.M.; Supuran, C.T. The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puşcaş (1932–2015). J. Enzyme Inhib. Med. Chem., 2016, 31(4), 527-533.
[http://dx.doi.org/10.3109/14756366.2015.1051042] [PMID: 26108882]
[9]
Ciccone, L.; Cerri, C.; Nencetti, S.; Orlandini, E. Carbonic anhydrase inhibitors and epilepsy: State of the art and future perspectives. Molecules, 2021, 26(21), 6380.
[http://dx.doi.org/10.3390/molecules26216380] [PMID: 34770789]
[10]
Mboge, M.Y.; McKenna, R.; Frost, S.C. Advances in anti-cancer drug development targeting carbonic anhydrase IX and XII. Top. Anticancer. Res., 2015, 5, 3-42.
[PMID: 30272043]
[11]
Ward, C.; Meehan, J.; Gray, M.E.; Murray, A.F.; Argyle, D.J.; Kunkler, I.H.; Langdon, S.P. The impact of tumour pH on cancer progression: Strategies for clinical intervention. Exploration of Targeted Anti-tumor Therapy, 2020, 1(2), 71-100.
[http://dx.doi.org/10.37349/etat.2020.00005]
[12]
Carta, F.; Vullo, D.; Osman, S.M.; AlOthman, Z.; Supuran, C.T. Synthesis and carbonic anhydrase inhibition of a series of SLC-0111 analogs. Bioorg. Med. Chem., 2017, 25(9), 2569-2576.
[http://dx.doi.org/10.1016/j.bmc.2017.03.027] [PMID: 28347633]
[13]
McDonald, P.C.; Chia, S.; Bedard, P.L.; Chu, Q.; Lyle, M.; Tang, L.; Singh, M.; Zhang, Z.; Supuran, C.T.; Renouf, D.J.; Dedhar, S. A phase 1 study of SLC-0111, a novel inhibitor of carbonic anhydrase IX, in patients with advanced solid tumors. Am. J. Clin. Oncol., 2020, 43(7), 484-490.
[http://dx.doi.org/10.1097/COC.0000000000000691] [PMID: 32251122]
[14]
Assi, R.; Kantarjian, H.M.; Kadia, T.M.; Pemmaraju, N.; Jabbour, E.; Jain, N.; Daver, N.; Estrov, Z.; Uehara, T.; Owa, T.; Cortes, J.E.; Borthakur, G. Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome. Cancer, 2018, 124(13), 2758-2765.
[http://dx.doi.org/10.1002/cncr.31398] [PMID: 29660836]
[15]
Supuran, C.T.; Capasso, C. Antibacterial carbonic anhydrase inhibitors: An update on the recent literature. Expert Opin. Ther. Pat., 2020, 30(12), 963-982.
[http://dx.doi.org/10.1080/13543776.2020.1811853] [PMID: 32806966]
[16]
De Vita, D.; Angeli, A.; Pandolfi, F.; Bortolami, M.; Costi, R.; Di Santo, R.; Suffredini, E.; Ceruso, M.; Del Prete, S.; Capasso, C.; Scipione, L.; Supuran, C.T. Inhibition of the α-carbonic anhydrase from Vibrio cholerae with amides and sulfonamides incorporating imidazole moieties. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 798-804.
[http://dx.doi.org/10.1080/14756366.2017.1327522] [PMID: 28569564]
[17]
Rasti, B.; Mazraedoost, S.; Panahi, H.; Falahati, M.; Attar, F. New insights into the selective inhibition of the β-carbonic anhydrases of pathogenic bacteria Burkholderia pseudomallei and Francisella tularensis: A proteochemometrics study. Mol. Divers., 2019, 23(2), 263-273.
[http://dx.doi.org/10.1007/s11030-018-9869-5] [PMID: 30120657]
[18]
Aspatwar, A.; Winum, J.Y.; Carta, F.; Supuran, C.; Hammaren, M.; Parikka, M.; Parkkila, S. Carbonic anhydrase inhibitors as novel drugs against mycobacterial β-carbonic anhydrases: An update on in vitro and in vivo studies. Molecules, 2018, 23(11), 2911.
[http://dx.doi.org/10.3390/molecules23112911] [PMID: 30413024]
[19]
Nishimori, I.; Minakuchi, T.; Vullo, D.; Scozzafava, A.; Supuran, C.T. Inhibition studies of the β-carbonic anhydrases from the bacterial pathogen Salmonella enterica serovar Typhimurium with sulfonamides and sulfamates. Bioorg. Med. Chem., 2011, 19(16), 5023-5030.
[http://dx.doi.org/10.1016/j.bmc.2011.06.038] [PMID: 21757360]
[20]
Grande, R.; Carradori, S.; Puca, V.; Vitale, I.; Angeli, A.; Nocentini, A.; Bonardi, A.; Gratteri, P.; Lanuti, P.; Bologna, G.; Simeone, P.; Capasso, C.; De Luca, V.; Supuran, C.T. Selective inhibition of Helicobacter pylori carbonic anhydrases by carvacrol and thymol could impair biofilm production and the release of outer membrane vesicles. Int. J. Mol. Sci., 2021, 22(21), 11583.
[http://dx.doi.org/10.3390/ijms222111583] [PMID: 34769015]
[21]
Del Prete, S.; De Luca, V.; Bua, S.; Nocentini, A.; Carginale, V.; Supuran, C.T.; Capasso, C. The Effect of substituted benzene-sulfonamides and clinically licensed drugs on the catalytic activity of cynt2, a carbonic anhydrase crucial for Escherichia coli life cycle. Int. J. Mol. Sci., 2020, 21(11), 4175.
[http://dx.doi.org/10.3390/ijms21114175] [PMID: 32545297]
[22]
Krasavin, M.; Korsakov, M.; Dorogov, M.; Tuccinardi, T.; Dedeoglu, N.; Supuran, C.T. Probing the ‘bipolar’ nature of the carbonic anhydrase active site: Aromatic sulfonamides containing 1,3-oxazol-5-yl moiety as picomolar inhibitors of cytosolic CA I and CA II isoforms. Eur. J. Med. Chem., 2015, 101, 334-347.
[http://dx.doi.org/10.1016/j.ejmech.2015.06.022] [PMID: 26160114]
[23]
Ferraroni, M.; Lucarini, L.; Masini, E.; Korsakov, M.; Scozzafava, A.; Supuran, C.T.; Krasavin, M. 1,3-Oxazole-based selective picomolar inhibitors of cytosolic human carbonic anhydrase II alleviate ocular hypertension in rabbits: Potency is supported by X-ray crystallography of two leads. Bioorg. Med. Chem., 2017, 25(17), 4560-4565.
[http://dx.doi.org/10.1016/j.bmc.2017.06.054] [PMID: 28728897]
[24]
Krasavin, M.; Korsakov, M.; Ronzhina, O.; Tuccinardi, T.; Kalinin, S.; Tanç, M.; Supuran, C.T. Primary mono- and bis-sulfonamides obtained via regiospecific sulfochlorination of N-arylpyrazoles: Inhibition profile against a panel of human carbonic anhydrases. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 920-934.
[http://dx.doi.org/10.1080/14756366.2017.1344236] [PMID: 28718328]
[25]
Yale, H.L. The trifluoromethyl group in medicinal chemistry. J. Med. Pharm. Chem., 1959, 1(2), 121-133.
[http://dx.doi.org/10.1021/jm50003a001] [PMID: 13665284]
[26]
Knudsen, J.F.; Carlsson, U.; Hammarström, P.; Sokol, G.H.; Cantilena, L.R. The cyclooxygenase-2 inhibitor celecoxib is a potent inhibitor of human carbonic anhydrase II. Inflammation, 2004, 28(5), 285-290.
[http://dx.doi.org/10.1007/s10753-004-6052-1] [PMID: 16134002]
[27]
Uda, N.R.; Seibert, V.; Stenner-Liewen, F.; Müller, P.; Herzig, P.; Gondi, G.; Zeidler, R.; van Dijk, M.; Zippelius, A.; Renner, C. Esterase activity of carbonic anhydrases serves as surrogate for selecting antibodies blocking hydratase activity. J. Enzyme Inhib. Med. Chem., 2015, 30(6), 955-960.
[http://dx.doi.org/10.3109/14756366.2014.1001754] [PMID: 25775095]
[28]
Kumar, V.; Aggarwal, R.; Singh, S.P. The reaction of hydroxylamine with aryl trifluoromethyl-β-diketones: Synthesis of 5-hydroxy-5-trifluoromethyl-Δ2-isoxazolines and their dehydration to 5-trifluoromethylisoxazoles. J. Fluor. Chem., 2006, 127(7), 880-888.
[http://dx.doi.org/10.1016/j.jfluchem.2006.03.009]
[29]
Martins, M.A.P.; Siqueira, G.M.; Bastos, G.P.; Bonacorso, H.G.; Zanatta, N. Haloacetylated enol ethers. 7. Synthesis of 3-aryl-5-trihalomethylisoxazoles and 3-aryl-5-hydroxy-5-trihalomethyl-4,5-dihydroisoxazoles. J. Heterocycl. Chem., 1996, 33(6), 1619-1622.
[http://dx.doi.org/10.1002/jhet.5570330612]
[30]
Flores, A.; Brondani, S.; Pizzuti, L.; Martins, M.; Zanatta, N.; Bonacorso, H.; Flores, D. Haloacetylated Enol Ethers, 19: Synthesis of 3-(2-Thienyl)- and 3-(2-Furyl)-5-trihalomethyl Substituted Azoles. Synthesis, 2005, 2005(16), 2744-2750.
[http://dx.doi.org/10.1055/s-2005-872140]
[31]
Reid, J.C.; Calvin, M. Some new β-diketones containing the trifluoromethyl group. J. Am. Chem. Soc., 1950, 72(7), 2948-2952.
[http://dx.doi.org/10.1021/ja01163a038]
[32]
Tashian, R.E.; Douglas, D.P.; Yu, Y.S.L. Esterase and hydrase activity of carbonic anhydrase-I from primate erythrocytes. Biochem. Biophys. Res. Commun., 1964, 14(3), 256-261.
[http://dx.doi.org/10.1016/0006-291X(64)90445-0] [PMID: 4953741]
[33]
Iyer, R.; Barrese, A.A., III; Parakh, S.; Parker, C.N.; Tripp, B.C. Inhibition profiling of human carbonic anhydrase II by high-throughput screening of structurally diverse, biologically active compounds. SLAS Discov., 2006, 11(7), 782-791.
[http://dx.doi.org/10.1177/1087057106289403] [PMID: 16858005]
[34]
Verpoorte, J.A.; Mehta, S.; Edsall, J.T. Esterase activities of human carbonic anhydrases B and C. J. Biol. Chem., 1967, 242(18), 4221-4229.
[http://dx.doi.org/10.1016/S0021-9258(18)95800-X] [PMID: 4964830]
[35]
Madhavi Sastry, G.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des., 2013, 27(3), 221-234.
[http://dx.doi.org/10.1007/s10822-013-9644-8] [PMID: 23579614]
[36]
Repasky, M.P.; Shelley, M.; Friesner, R.A. Flexible ligand docking with Glide; Curr. Protoc. Bioinformatics, 2007.
[http://dx.doi.org/10.1002/0471250953.bi0812s18]
[37]
Lu, C.; Wu, C.; Ghoreishi, D.; Chen, W.; Wang, L.; Damm, W.; Ross, G.A.; Dahlgren, M.K.; Russell, E.; Von Bargen, C.D.; Abel, R.; Friesner, R.A.; Harder, E.D. OPLS4: Improving force field accuracy on challenging regimes of chemical space. J. Chem. Theory Comput., 2021, 17(7), 4291-4300.
[http://dx.doi.org/10.1021/acs.jctc.1c00302] [PMID: 34096718]

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