Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Inhibitory Efficacy of Thiosemicarbazones for Carbonic Anhydrase II (Bovine and Human) as a Target of Calcification and Tumorigenicity

Author(s): Majid Khan, Sobia Ahsan Halim, Zahid Shafiq, Muhammad Islam, Muhammad Tariq Shehzad, Aliya Ibrar, Farhan A. Khan, Najat Marraiki, Jalal Uddin, Ajmal Khan* and Ahmed Al-Harrasi*

Volume 28, Issue 36, 2022

Published on: 25 August, 2022

Page: [3010 - 3022] Pages: 13

DOI: 10.2174/1381612828666220729105849

Price: $65

conference banner
Abstract

Background: Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma.

Objective: In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized.

Methods: This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out.

Results: In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety plays a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetic studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki).

Conclusion: Subsequently, (3e, 3f, 3l and 3p) were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 μM, while (3d) as a noncompetitive inhibitor of bCA-II (Ki = 2.5 ± 0.015 μM), however, (3g) demonstrated competitive inhibition of hCA-II with a Ki value of 5.95 ± 0.002 μM. The selectivity index reflects that compound (3g) is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.

Keywords: Thiosemicarbazone, carbonic anhydrase II, bovine, human, kinetics studies, molecular docking.

« Previous Next »
[1]
Smith KS, Ferry JG. Prokaryotic carbonic anhydrases. FEMS Microbiol Rev 2000; 24(4): 335-66.
[http://dx.doi.org/10.1111/j.1574-6976.2000.tb00546.x] [PMID: 10978542]
[2]
Aksu K, Özgeriş B, Taslimi P, Naderi A, Gülçin İ, Göksu S. Antioxidant activity, acetylcholinesterase, and carbonic anhydrase inhibitory properties of novel ureas derived from phenethylamines. Arch Pharm (Weinheim) 2016; 349(12): 944-54.
[http://dx.doi.org/10.1002/ardp.201600183] [PMID: 27862205]
[3]
Gul HI, Tugrak M, Sakagami H, Taslimi P, Gulcin I, Supuran CT. Synthesis and bioactivity studies on new 4-(3-(4-Substitutedphenyl)-3a,4-dihydro-3 H -indeno[1,2-c]pyrazol-2-yl) benzenesulfonamides. J Enzyme Inhib Med Chem 2016; 31(6): 1619-24.
[http://dx.doi.org/10.3109/14756366.2016.1160077] [PMID: 27028783]
[4]
Liljas A, Kannan KK, Bergstén PC, et al. Crystal structure of human carbonic anhydrase C. Nat New Biol 1972; 235(57): 131-7.
[http://dx.doi.org/10.1038/newbio235131a0] [PMID: 4621826]
[5]
Topal F, Nar M, Gocer H, et al. Antioxidant activity of taxifolin: An activity-structure relationship. J Enzyme Inhib Med Chem 2016; 31(4): 674-83.
[http://dx.doi.org/10.3109/14756366.2015.1057723] [PMID: 26147349]
[6]
Camadan Y, Özdemir H, Gulcin İ. Purification and characterization of dihydropyrimidine dehydrogenase enzyme from sheep liver and determination of the effects of some anaesthetic and antidepressant drugs on the enzyme activity. J Enzyme Inhib Med Chem 2016; 31(6): 1335-41.
[http://dx.doi.org/10.3109/14756366.2015.1132710] [PMID: 26758717]
[7]
Liljas A, Håkansson K, Jonsson BH, Xue Y. Inhibition and catalysis of carbonic anhydrase. Recent crystallographic analyses. Eur J Biochem 1994; 219(1-2): 1-10.
[http://dx.doi.org/10.1111/j.1432-1033.1994.tb19909.x] [PMID: 8306976]
[8]
Lane TW, Morel FMM. A biological function for cadmium in marine diatoms. Proc Natl Acad Sci USA 2000; 97(9): 4627-31.
[http://dx.doi.org/10.1073/pnas.090091397] [PMID: 10781068]
[9]
Hilvo M, Tolvanen M, Clark A, et al. Characterization of CA XV, a new GPI-anchored form of carbonic anhydrase. Biochem J 2005; 392(1): 83-92.
[http://dx.doi.org/10.1042/BJ20051102] [PMID: 16083424]
[10]
Aksu K, Nar M, Tanç M, et al. The synthesis of sulfamide analogues of dopamine related compounds and their carbonic anhydrase inhibitory properties. Bioorg Med Chem 2013; 21: 2925-31.
[http://dx.doi.org/10.1016/j.bmc.2013.03.077] [PMID: 23623256]
[11]
Ozgun DO, Yamali C, Gul HI, et al. Inhibitory effects of isatin Mannich bases on carbonic anhydrases, acetylcholinesterase, and butyrylcholinesterase. J Enzyme Inhib Med Chem 2016; 31(6): 1498-501.
[http://dx.doi.org/10.3109/14756366.2016.1149479] [PMID: 26928426]
[12]
Turan B, Şendil K, Şengül E, et al. The synthesis of some β-lactams and investigation of their metal-chelating activity, carbonic anhydrase and acetylcholinesterase inhibition profiles. J Enzyme Inhib Med Chem 2016; 31 (sup1): 79-88.
[http://dx.doi.org/10.3109/14756366.2016.1170014] [PMID: 27075164]
[13]
Kucuk M, Gulcin İ. Purification and characterization of the carbonic anhydrase enzyme from Black Sea trout (Salmo trutta Labrax Coruhensis) kidney and inhibition effects of some metal ions on enzyme activity. Environ Toxicol Pharmacol 2016; 44: 134-9.
[http://dx.doi.org/10.1016/j.etap.2016.04.011] [PMID: 27175889]
[14]
Öztaşkın N, Çetinkaya Y, Taslimi P, Göksu S, Gülçin İ. Antioxidant and acetylcholinesterase inhibition properties of novel bromophenol derivatives. Bioorg Chem 2015; 60: 49-57.
[http://dx.doi.org/10.1016/j.bioorg.2015.04.006] [PMID: 25956827]
[15]
Göçer H, Akıncıoğlu A, Öztaşkın N, Göksu S, Gülçin İ. Synthesis, antioxidant, and antiacetylcholinesterase activities of sulfonamide derivatives of dopamine-related compounds. Arch Pharm (Weinheim) 2013; 346(11): 783-92.
[http://dx.doi.org/10.1002/ardp.201300228] [PMID: 24591156]
[16]
Topal M, Gülçin İ. Rosmarinic acid: A potent carbonic anhydrase isoenzymes inhibitor. Turk J Chem 2014; 38: 894-902.
[http://dx.doi.org/10.3906/kim-1403-5]
[17]
Güney M, Coşkun A, Topal F, Daştan A, Gülçin İ, Supuran CT. Oxidation of cyanobenzocycloheptatrienes: Synthesis, photooxygenation reaction and carbonic anhydrase isoenzymes inhibition properties of some new benzotropone derivatives. Bioorg Med Chem 2014; 22(13): 3537-43.
[http://dx.doi.org/10.1016/j.bmc.2014.04.007] [PMID: 24856184]
[18]
Temperini C, Scozzafava A, Vullo D, Supuran CT. Carbonic anhydrase activators. Activation of isozymes I, II, IV, VA, VII, and XIV with l- and d-histidine and crystallographic analysis of their adducts with isoform II: Engineering proton-transfer processes within the active site of an enzyme. Chemistry 2006; 12(27): 7057-66.
[http://dx.doi.org/10.1002/chem.200600159] [PMID: 16807956]
[19]
Taslimi P, Sujayev A, Mamedova S, et al. Synthesis and bioactivity of several new hetaryl sulfonamides. J Enzyme Inhib Med Chem 2017; 32(1): 137-45.
[http://dx.doi.org/10.1080/14756366.2016.1238367] [PMID: 28100082]
[20]
Finch RA, Liu MC, Grill SP, et al. Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem Pharmacol 2000; 59(8): 983-91.
[http://dx.doi.org/10.1016/S0006-2952(99)00419-0] [PMID: 10692563]
[21]
Finch RA, Liu MC, Cory AH, Cory JG, Sartorelli AC. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): An inhibitor of ribonucleotide reductase with antineoplastic activity. Adv Enzyme Regul 1999; 39(1): 3-12.
[http://dx.doi.org/10.1016/S0065-2571(98)00017-X] [PMID: 10470363]
[22]
Kune GA. To-day’s Drugs: Methisazone. BMJ 1964; 2(5409): 621-1.
[http://dx.doi.org/10.1136/bmj.2.5409.621] [PMID: 14171075]
[23]
Heiner GG, Fatima N, Russell PK, et al. Field trials of methisazone as a prophylactic agent against smallpox. Am J Epidemiol 1971; 94(5): 435-49.
[http://dx.doi.org/10.1093/oxfordjournals.aje.a121340] [PMID: 4941154]
[24]
Singhal S, Arora S, Agarwal S, Sharma R, Singhal N. A review on potential biological activities of thiosemicarbazides. World J Pharm Pharm Sci 2013; 2: 4661-81.
[25]
Kalinowski DS, Yu Y, Sharpe PC, et al. Design, synthesis, and characterization of novel iron chelators: Structure-activity relationships of the 2-benzoylpyridine thiosemicarbazone series and their 3-nitrobenzoyl analogues as potent antitumor agents. J Med Chem 2007; 50(15): 3716-29.
[http://dx.doi.org/10.1021/jm070445z] [PMID: 17602603]
[26]
Abid M, Azam A. Synthesis and antiamoebic activities of 1-N-substituted cyclised pyrazoline analogues of thiosemicarbazones. Bioorg Med Chem 2005; 13(6): 2213-20.
[http://dx.doi.org/10.1016/j.bmc.2004.12.050] [PMID: 15727873]
[27]
Hamre D, Brownlee KA, Donovick R. Studies on the chemotherapy of vaccinia virus. II. The activity of some thiosemicarbazones. J Immunol 1951; 67(4): 305-12.
[PMID: 14888894]
[28]
Hameed A, Khan KM, Zehra ST, et al. Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors. Bioorg Chem 2015; 61: 51-7.
[http://dx.doi.org/10.1016/j.bioorg.2015.06.004] [PMID: 26119990]
[29]
Hameed A, Yaqub M, Hussain M, et al. Coumarin-based thiosemicarbazones as potent urease inhibitors: Synthesis, solid state self-assembly and molecular docking. RSC Advances 2016; 6(68): 63886-94.
[http://dx.doi.org/10.1039/C6RA12827K]
[30]
Hameed A, Shafiq Z, Yaqub M, et al. Me 3 N-promoted synthesis of 2,3,4,4a-tetrahydroxanthen-1-one: Preparation of thiosemicarbazone derivatives, their solid state self-assembly and antimicrobial properties. New J Chem 2015; 39(12): 9351-7.
[http://dx.doi.org/10.1039/C5NJ01879J]
[31]
Shehzad MT, Imran A, Njateng GSS, et al. Benzoxazinone-thiosemicarbazones as antidiabetic leads via aldose reductase inhibition: Synthesis, biological screening and molecular docking study. Bioorg Chem 2019; 87: 857-66.
[http://dx.doi.org/10.1016/j.bioorg.2018.12.006] [PMID: 30551808]
[32]
Borges F, Roleira F, Milhazes N, Santana L, Uriarte E. Simple coumarins and analogues in medicinal chemistry: Occurrence, synthesis and biological activity. Curr Med Chem 2005; 12(8): 887-916.
[http://dx.doi.org/10.2174/0929867053507315] [PMID: 15853704]
[33]
Kontogiorgis C, Detsi A, Hadjipavlou-Litina D. Coumarin-based drugs: A patent review (2008 – present). Expert Opin Ther Pat 2012; 22(4): 437-54.
[http://dx.doi.org/10.1517/13543776.2012.678835] [PMID: 22475457]
[34]
Patel RV, Kumari P, Rajani DP, Chikhalia KH. Synthesis of coumarin-based 1,3,4-oxadiazol-2ylthio-N-phenyl/benzothiazolyl acetamides as antimicrobial and antituberculosis agents. Med Chem Res 2013; 22(1): 195-210.
[http://dx.doi.org/10.1007/s00044-012-0026-x]
[35]
Turner S, Myers M, Gadie B, et al. Antihypertensive thiadiazoles. 1. Synthesis of some 2-aryl-5-hydrazino-1,3,4-thiadiazoles with vasodilator activity. J Med Chem 1988; 31(5): 902-6.
[http://dx.doi.org/10.1021/jm00400a003] [PMID: 3361578]
[36]
Hanna MA, Girges MM, Rasala D, Gawinecki R. Synthesis and pharmacological evaluation of some novel 5-(pyrazol-3-yl)thiadiazole and oxadiazole derivatives as potential hypoglycemic agents. Arzneimittelforschung 1995; 45(10): 1074-8.
[PMID: 8595062]
[37]
Thakur A, Singla R, Jaitak V. Coumarins as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Eur J Med Chem 2015; 101: 476-95.
[http://dx.doi.org/10.1016/j.ejmech.2015.07.010] [PMID: 26188907]
[38]
Emami S, Dadashpour S. Current developments of coumarin-based anti-cancer agents in medicinal chemistry. Eur J Med Chem 2015; 102: 611-30.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.033] [PMID: 26318068]
[39]
Sandhu S, Bansal Y, Silakari O, Bansal G. Coumarin hybrids as novel therapeutic agents. Bioorg Med Chem 2014; 22(15): 3806-14.
[http://dx.doi.org/10.1016/j.bmc.2014.05.032] [PMID: 24934993]
[40]
Zhang H, Qiu S, Tamez P, et al. Antimalarial agents from plants II. Decursivine, a new antimalarial indole alkaloid from Rhaphidophora decursiva. Pharm Biol 2002; 40(3): 221-4.
[http://dx.doi.org/10.1076/phbi.40.3.221.5832]
[41]
Farooq U, Naz S, Shams A, et al. Isolation of dihydrobenzofuran derivatives from ethnomedicinal species Polygonum barbatum as anti-cancer compounds. Biol Res 2019; 52(1): 1.
[http://dx.doi.org/10.1186/s40659-018-0209-0] [PMID: 30612577]
[42]
Ferreira-Júnior JC, Conserva LM, Lyra Lemos RP, de Omena-Neta GC, Cavalcante-Neto A, Barreto E. Isolation of a dihydrobenzofuran lignan, icariside E4, with an antinociceptive effect from Tabebuia roseo-alba (Ridley) Sandwith (Bignoniaceae) bark. Arch Pharm Res 2015; 38(6): 950-6.
[http://dx.doi.org/10.1007/s12272-014-0468-4] [PMID: 25138119]
[43]
Corrêa MF, Barbosa ÁJR, Teixeira LB, et al. Pharmacological characterization of 5-substituted 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines: Novel antagonists for the histamine H3 and H4 receptors with anti-inflammatory potential. Front Pharmacol 2017; 8: 825.
[http://dx.doi.org/10.3389/fphar.2017.00825] [PMID: 29184503]
[44]
Dias HJ, Patrocínio AB, Pagotti MC, et al. Schistosomicidal activity of dihydrobenzofuran neolignans. Chem Biodivers 2018; 15(7)e1800134
[http://dx.doi.org/10.1002/cbdv.201800134] [PMID: 29754441]
[45]
Fukui MJ, Dias HJ, Severiano ME, et al. Antimicrobial and cytotoxic activity of dihydrobenzofuran neolignans. ChemistrySelect 2018; 3(6): 1836-9.
[http://dx.doi.org/10.1002/slct.201703024]
[46]
Wan L, Zihui Y, Aixi H, et al. Synthesis and fungicidal activities of 2-{[(2-(1H-1, 2, 4-triazol-1-yl)-ethylidene) amino] oxy} alkana-mides containing dihydrobenzofuran. Heterocycl Commun 2018; 24: 339-44.
[http://dx.doi.org/10.1515/hc-2017-0245]
[47]
Amole KL, Bello IA, Oyewale AO. Synthesis, characterization and antibacterial activities of new fluorinated chalcones. Chemistry Africa 2019; 2(1): 47-55.
[http://dx.doi.org/10.1007/s42250-019-00043-4]
[48]
Islam M, Khan A, Shehzad MT, et al. Synthesis and characterization of new thiosemicarbazones, as potent urease inhibitors: In vitro and in silico studies. Bioorg Chem 2019; 87: 155-62.
[http://dx.doi.org/10.1016/j.bioorg.2019.03.008] [PMID: 30884309]
[49]
Shehzad MT, Khan A, Islam M, et al. Synthesis, characterization and molecular docking of some novel hydrazonothiazolines as urease inhibitors. Bioorg Chem 2020; 94103404
[http://dx.doi.org/10.1016/j.bioorg.2019.103404] [PMID: 31699392]
[50]
Pocker Y, Meany JE. The catalytic versatility of erythrocyte carbonic anhydrase. II. Kinetic studies of the enzyme-catalyzed hydration of pyridine aldehydes. Biochemistry 1967; 6(1): 239-46.
[http://dx.doi.org/10.1021/bi00853a037] [PMID: 4961820]
[51]
Saito R, Sato T, Ikai A, Tanaka N. Structure of bovine carbonic anhydrase II at 1.95 Å resolution. Acta Crystallogr D Biol Crystallogr 2004; 60(4): 792-5.
[http://dx.doi.org/10.1107/S0907444904003166] [PMID: 15039588]
[52]
Boriack-Sjodin PA, Zeitlin S, Christianson DW, et al. Structural analysis of inhibitor binding to human carbonic anhydrase II. Protein Sci 1998; 7(12): 2483-9.
[http://dx.doi.org/10.1002/pro.5560071201] [PMID: 9865942]
[53]
Nepali K, Sharma S, Sharma M, Bedi PMS, Dhar KL. Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids. Eur J Med Chem 2014; 77: 422-87.
[http://dx.doi.org/10.1016/j.ejmech.2014.03.018] [PMID: 24685980]
[54]
Avula SK, Rehman NU, Khan M, et al. New synthetic 1H-1,2,3-triazole derivatives of 3-O-acetyl-β-boswellic acid and 3-O-acetyl-11-keto-β-boswellic acid from Boswellia sacra inhibit carbonic anhydrase II in vitro. Med Chem Res 2021; 30(6): 1185-98.
[http://dx.doi.org/10.1007/s00044-021-02723-8]

Rights & Permissions Print Cite
Article Metrics
31
3
Wayfinder Image
World Suicide Prevention Day
© 2024 Bentham Science Publishers | Privacy Policy