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Synthesis of 3-chloro-1-substituted aryl pyrrolidine-2,5-dione derivatives: discovery of potent human carbonic anhydrase inhibitors

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Abstract

Carbonic anhydrase isoenzymes are important metalloenzymes that are involved in many physiologic processes, in which they catalyze the reversible hydration of carbon dioxide (CO2) to bicarbonate (HCO3 –) and protons (H+) via a metal hydroxide nucleophilic mechanism. Because of their known biological activities and potential as carbonic anhydrase inhibitors, the present study focused on developing of a convenient route to synthesize 3-chloro-1-aryl pyrrolidine-2,5-diones (2b). This synthetic route started with (Z)-4-oxo-4-(arylamino)but-2-enoic acid (3b) and sulfurous dichloride (SOCl2) and resulted in a ring closing reaction that produced a series of 3-chloro-N-aryl maleimide derivatives (20–29) in good yields. This is the first report of the syntheses of 3-chloro-1-aryl pyyrolidine-2,5-diones 20–23 and 27–29 by ring-closing reactions of (Z)-4-oxo-4-(arylamino)but-2-enoic acid. The structures of all of the products were determined by 1H-NMR, 13C-NMR and infrared spectroscopy. Their biological activities were studied against human carbonic anhydrase I, and II. The 3-chloro-1-aryl pyrrolidine-2,5-diones strongly inhibited the activity of human carbonic anhydrase I and II, with K i values in the low nanomolar range of 23.27–36.83 nmol/L against human carbonic anhydrase I and 10.64–31.86 nmol/L against human carbonic anhydrase II.

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References

  • Akbaba Y, Bastem E, Topal F, Gülçin İ, Maraş A, Göksu S (2014) Synthesis and carbonic anhydrase inhibitory effects of novel sulfamides derived from 1-aminoindanes and anilines. Arch Pharm 347:950–957

    Article  CAS  Google Scholar 

  • Akıncıoğlu A, Akbaba Y, Göçer H, Göksu S, Gülçin İ, Supuran CT (2013) Novel sulfamides as potential carbonic anhydrase isoenzymes inhibitors. Bioorg Med Chem 21:1379–1385

    Article  PubMed  Google Scholar 

  • Akıncıoğlu A, Akıncıoğlu H, Gülçin I, Durdağı S, Supuran CT, Göksu S (2015) Discovery of potent carbonic anhydrase and acetylcholine esterase inhibitors: novel sulfamoylcarbamates and sulfamides derived from acetophenones. Bioorg Med Chem 23:3592–3602

    Article  PubMed  Google Scholar 

  • Akıncıoğlu A, Topal M, Gülçin İ, Göksu S (2014) Novel sulfamides and sulfonamides incorporating tetralin scaffold as carbonic anhydrase and acetylcholine esterase inhibitors. Arch Pharm 347:68–76

    Article  Google Scholar 

  • Aksu K, Nar M, Tanç M, Vullo D, Gülçin İ, Göksu S, Tümer F, Supuran CT (2013) The synthesis of sulfamide analogues of dopamine-related compounds and their carbonic anhydrase inhibitory properties. Bioorg Med Chem 21:2925–2931

    Article  CAS  PubMed  Google Scholar 

  • Arabaci B, Gülçin İ, Alwasel S (2015) Capsaicin: a potent inhibitor of carbonic anhydrase isoenzymes. Molecules 19:10103–10114

    Article  Google Scholar 

  • Atasaver A, Özdemir H, Gülçin İ, Küfrevioğlu Öİ (2013) One-step purification of lactoperoxidase from bovine milk by affinity chromatography. Food Chem 136:864–870

    Article  Google Scholar 

  • Aydin B, Gülcin I, Alwasel SH (2015) Purification and characterization of polyphenol oxidase from Hemşin apple (Malus communis L.). Int J Food Prop 18:2735–2745

    Article  CAS  Google Scholar 

  • Boros M, Kosi JK, Vamos J, Kovesdi I, Noszal B (2007) Methods for syntheses of N-methyl-dl-aspartic acid derivatives. Amino Acids 33:709–717

    Article  CAS  PubMed  Google Scholar 

  • Boztaş M, Çetinkaya Y, Topal M, Gülçin İ, Menzek A, Şahin E, Tanc M, Supuran CT (2015) Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII inhibitory effects of dimethoxy-bromophenol derivatives incorporating cyclopropane moieties. J Med Chem 58:640–650

    Article  PubMed  Google Scholar 

  • Bradford MM (1976) Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye 624 binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Carta F, Di Cesare Mannelli L, Pinard M, Ghelardini C, Scozzafava A, McKenna R, Supuran CT (2015) A class of sulfonamide carbonic anhydrase inhibitors with neuropathic pain modulating effects. Bioorg Med Chem 23:1828–1840

    Article  CAS  PubMed  Google Scholar 

  • Ceruso M, Vullo D, Scozzafava A, Supuran CT (2014) Sulfonamides incorporating fluorine and 1,3,5-triazine moieties are effective inhibitors of three β-class carbonic anhydrases from Mycobacterium tuberculosis. J Enzyme Inhib Med Chem 29:686–689

    Article  CAS  PubMed  Google Scholar 

  • Çetinkaya Y, Göçer H, Gülçin İ, Menzek A (2014) Synthesis and carbonic anhydrase isoenzymes inhibitory effects of brominated diphenylmethanone and its derivatives. Arch Pharm 347:354–359

    Article  Google Scholar 

  • Çoban TA, Beydemir Ş, Gülçin İ, Ekinci D (2008) The inhibitory effect of ethanol on carbonic anhydrase isoenzymes: in vivo and in vitro studies. J Enzyme Inhib Med Chem 23:266–270

    Article  PubMed  Google Scholar 

  • Çoban TA, Beydemir Ş, Gülçin İ, Ekinci D (2007) Morphine inhibits erythrocyte carbonic anhydrase in vitro and in vivo. Biol Pharm Bull 30:2257–2261

    Article  PubMed  Google Scholar 

  • Colquhoun HM, Zhu Z, Williams DJ (2003) Extreme complementarity in a macrocycle-tweezer complex. Org Lett 5:4353–4356

    Article  CAS  PubMed  Google Scholar 

  • El-Gaby MSA, Gaber AM, Atalla AA, Abd Al-Wahab KA (2002) Novel synthesis and antifungal activity of pyrrole and pyrrolo[2,3-d]pyrimidine derivatives containing sulfonamido moieties. II Farm 57:613–617

    Article  CAS  Google Scholar 

  • Faturacı Y, Coskun N (2012) Substituent effects on the regioselectivity of maleamic acid formation and hydrogen chloride addition to N-aryl maleimides. Turk J Chem 36:749–758

    Google Scholar 

  • Gaina C, Gaina V (2005) Alpha-chlorosuccinimides—a new source for maleimides and succinimides. Rev Roum de Chim 50:655–661

    CAS  Google Scholar 

  • Göçer H, Akıncıoğlu A, Göksu S, Gülçin İ, Supuran CT (2015) Carbonic anhydrase and acetylcholine esterase inhibitory effects of carbamates and sulfamoylcarbamates. J Enzyme Inhib Med Chem 30:316–320

    Article  PubMed  Google Scholar 

  • Göçer H, Akıncıoğlu A, Öztaşkın N, Göksu S, Gülçin İ (2013) Synthesis, antioxidant and antiacetylcholinesterase activities of sulfonamide derivatives of dopamine related compounds. Arch Pharm 346:783–792

    Article  Google Scholar 

  • Göksu S, Naderi A, Akbaba Y, Kalın P, Akıncıoğlu A, Gulcin İ, Durdaği S, Salmas RE (2014) Carbonic anhydrase inhibitory properties of novel benzylsulfamides using molecular modeling and experimental studies. Bioorg Chem 56:75–82

    Article  PubMed  Google Scholar 

  • Gülçin İ, Beydemir S (2013) Phenolic compounds as antioxidants: carbonic anhydrase isoenzymes inhibitors. Mini Rev Med Chem 13:408–430

    PubMed  Google Scholar 

  • Gülçin İ, Küfrevioğlu Öİ, Oktay M (2005) Purification and characterization of polyphenol oxidase from nettle (Urtica dioica L.) and inhibition effects of some chemicals on the enzyme activity. J Enzyme Inhib Med Chem 20:297–302

    Article  Google Scholar 

  • Güney M, Coşkun A, Topal F, Daştan A, Gülçin İ, Supuran CT (2014) Oxidation of cyanobenzocycloheptatrienes: synthesis, photooxygenation reaction and carbonic anhydrase isoenzymes inhibition properties of some new benzotropone derivatives. Bioorg Med Chem 22:3537–3543

    Article  PubMed  Google Scholar 

  • Haval KP, Mhaske SB, Argade NP (2006) Cyanuric chloride: decent dehydrating agent for an exclusive and efficient synthesis of kinetically controlled isomaleimides. Tetrahedron 62:937–942

    Article  CAS  Google Scholar 

  • Hiran BL, Paliwal SN, Chaudhary J, Meena S (2007) Preparation polymerization and characterization of some new maleimides. J Indian Chem Soc 84:385–388

    CAS  Google Scholar 

  • Isobe Y, Onimura K, Tsutsumi H, Oishi T (2001) Asymmetric polymerization of N-1-naphthylmaleimide with chiral anionic initiator: preparation of highly optically active poly(N-1-naphthylmaleimide). Macromolecules 34:7617–7623

    Article  CAS  Google Scholar 

  • Kaur A, Singh B, Singh Jaggi AS (2013) Synthesis and evaluation of novel 2,3,5-triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-diones for advanced glycation end product formation inhibitory activity. Bioorg Med Chem Lett 23:797–801

    Article  CAS  PubMed  Google Scholar 

  • Khattab MK, Ragab F, Galal SA, El Diwani HI (2012) Synthesis of 4-(1H-benzo[d]imidazol-2-yl)aniline derivatives of expected anti-HCV activity. Int J Res Pharm Chem 2:937–946

    CAS  Google Scholar 

  • Köksal E, Ağgül AG, Bursal E, Gülçin İ (2012) Purification and characterization of peroxidase from sweet gourd (Cucurbita Moschata Lam. Poiret). Int J Food Prop 15:1110–1119

    Article  Google Scholar 

  • Köksal E, Gülçin İ (2008) Purification and characterization of peroxidase from cauliflower (Brassica oleracea L.) buds. Protein Pept Lett 15:320–326

    Article  PubMed  Google Scholar 

  • Kumar B, Verma RK, Singh H (1986) Esterification of maleanilic acids: intramolecular esterification through imidate ester. Indian J Chem 25B:692–696

    CAS  Google Scholar 

  • Kumar PP, Devi BR, Dubey PK (2013) A facile and green synthesis of N-substituted imides. Indian J Chem 62:1166–1171

    Google Scholar 

  • Lanier M, Schade D, Willems E, Tsuda Spiering MS, Kalisiak J, Mercola M, Cashman JR (2012) Wnt inhibition correlates with human embryonic stem cell cardiomyogenesis: a structure–activity relationship study based on inhibitors for the Wnt response. J Med Chem 55:697–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li K, Yuan C, Zhang S, Fang Q (2012) A facile and economical procedure for the synthesis of maleimide derivatives using an acidic ionic liquid as a catalyst. Tetrahedron Lett 53:4245–4247

    Article  CAS  Google Scholar 

  • Lineweaver H, Burk D (1934) The determination of enzyme dissociation constants. J Am Chem Soc 56:658–666

    Article  CAS  Google Scholar 

  • Mohammed IA, Mustapha A (2010) Synthesis of new azo compounds based on N-(4-hydroxypheneyl)maleimide and N-(4-methylpheneyl)maleimide. Molecules 15:7498–7508

    Article  CAS  PubMed  Google Scholar 

  • Molla MR, Ghosh S (2012) Exploring versatile sulfhydryl chemistry in the chain end of a synthetic polylactide. Macromolecules 45:8561–8570

    Article  CAS  Google Scholar 

  • Nar M, Çetinkaya Y, Gülçin İ, Menzek A (2013) (3,4-Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives as carbonic anhydrase isoenzymes inhibitors. J Enzyme Inhib Med Chem 28:402–406

    Article  PubMed  Google Scholar 

  • Neri D, Supuran CT (2011) Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov 10:767–777

    Article  CAS  PubMed  Google Scholar 

  • Oktay K, Polat Köse L, Şendil K, Gültekin MS, Gülçin İ, Supuran CT (2016) The synthesis of (Z)-4-Oxo-4-(arylamino)but-2-enoic acids derivatives and determination of theirs inhibition properties against human carbonic anhydrase I, and II isoenzymes. J Enzyme Inhib Med Chem 31:904–910

    Article  Google Scholar 

  • Ol’shevskaya A, Luzgina VN, Kurakina YA, Makarenkov AV, Petrovskii PV, Kononova EG, Mironov AF, Shtil AA, Kalinin VN (2012) Synthesis and antitumor properties of carborane conjugates of 5-(4-aminophenyl)-10,15,20-triphenylporphyrin. Dokl Chem 443:91–96

    Article  Google Scholar 

  • Pacchiano F, Carta F, McDonald PC, Lou Y, Vullo D, Scozzafava A, Dedhar S, Supuran CT (2011) Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem 54:1896–1902

    Article  CAS  PubMed  Google Scholar 

  • Saedi H (2013) Solvent-free preparation of N-substituted maleanilic acid. Bull Chem Soc Ethiop 27:137–141

    CAS  Google Scholar 

  • Scozzafava A, Kalın P, Supuran CT, Gülçin İ, Alwasel S (2015a) The impact of hydroquinone on acetylcholine esterase and certain human carbonic anhydrase isoenzymes (hCA I, II, IX, and XII). J Enzyme Inhib Med Chem 30:941–946

    Article  CAS  PubMed  Google Scholar 

  • Scozzafava A, Passaponti M, Supuran CT, Gülçin İ (2015b) Carbonic anhydrase inhibitors: guaiacol and catechol derivatives effectively inhibit certain human carbonic anhydrase isoenzymes (hCA I, II, IX, and XII). J Enzyme Inhib Med Chem 30:586–591

    Article  CAS  PubMed  Google Scholar 

  • Şentürk M, Gülçin İ, Beydemir Ş, Küfrevioğlu Öİ, Supuran CT (2011) In vitro inhibition of human carbonic anhydrase I and II isozymes with natural phenolic compounds. Chem Biol Drug Des 77:494–499

    Article  PubMed  Google Scholar 

  • Şentürk M, Gülçin İ, Çiftci M, Küfrevioğlu Öİ (2008) Dantrolene inhibits human erythrocyte glutathione reductase. Biol Pharm Bull 31:2036–2039

    Article  PubMed  Google Scholar 

  • Şişecioğlu M, Gülçin İ, Çankaya M, Atasever A, Özdemir H (2010) The effects of norepinephrine on lactoperoxidase enzyme (LPO). Sci Res Essays 5:1351–1356

    Google Scholar 

  • Şişecioğlu M, Gülçin İ, Çankaya M, Özdemir H (2012) The inhibitory effects of l-Adrenaline on lactoperoxidase enzyme (LPO) purified from buffalo milk. Int J Food Prop 15:1182–1189

    Article  Google Scholar 

  • Supuran CT, Scozzafava A (2002) Applications of carbonic anhydrase inhibitors and activators in therapy. Expert Opin Ther Pat 12:217–242

    Article  CAS  Google Scholar 

  • Supuran CT (2013) Carbonic anhydrases: from biomedical applications of the inhibitors and activators to biotechnological use for CO2 capture. J Enzyme Inhib Med Chem 28:229–230

    Article  PubMed  Google Scholar 

  • Supuran CT (2008) Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7:168–181

    Article  CAS  PubMed  Google Scholar 

  • Topal M, Gülçin İ (2014) Rosmarinic acid: a potent carbonic anhydrase isoenzymes inhibitor. Turk J Chem 38:894–902

    Article  CAS  Google Scholar 

  • Verpoorte JA, Mehta S, Edsall JT (1967) Esterase activities of human carbonic anhydrases B and C. J Biol Chem 242:4221–4229

    CAS  PubMed  Google Scholar 

  • Yıldırım A, Atmaca U, Keskin A, Topal M, Çelik M, Gülçin İ, Supuran CT (2015) N-Acylsulfonamides strongly inhibit human carbonic anhydrase isoenzymes I and II. Bioorg Med Chem 23:2598–2605

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Faculty of Science, Department of Chemistry, Ataturk University, Erzurum, 25240, Turkey

    Koray Oktay, Leyla Polat Kose, Mehmet Serdar Gültekin & İlhami Gülçın

  2. Faculty of Science and Arts, Department of Chemistry, Kafkas University, Kars, 36100, Turkey

    Kıvılcım Şendil

  3. College of Science, Department of Zoology, King Saud University, Riyadh, Saudi Arabia

    İlhami Gülçın

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  1. Koray Oktay
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  2. Leyla Polat Kose
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  3. Kıvılcım Şendil
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  4. Mehmet Serdar Gültekin
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  5. İlhami Gülçın
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Correspondence to Mehmet Serdar Gültekin or İlhami Gülçın.

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Oktay, K., Polat Kose, L., Şendil, K. et al. Synthesis of 3-chloro-1-substituted aryl pyrrolidine-2,5-dione derivatives: discovery of potent human carbonic anhydrase inhibitors. Med Chem Res 26, 1619–1627 (2017). https://doi.org/10.1007/s00044-017-1865-2

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