Synthesis and Molecular Modeling of 1,2,4 Triazole-Based Sulfanilamide Derivatives Using Dual Tail Strategy as Possible CAIs with their Cytotoxic Evaluation
DOI:
https://doi.org/10.22317/jcms.v11i1.1711Keywords:
carbonic anhydrases inhibitors, triazole-based derivatives, dual tail approach, sulfanilamide.Abstract
Objective: The aim of the study was to design and synthesize a novel series of 1,2,4 triazole-based sulfanilamide derivatives targeting carbonic anhydrase IX (CA IX), a promising therapeutic target in cancer, using dual tail approach, and to assess their cytotoxic effect against breast and colon cancer cell lines.
Methods: The final compounds P1-P6 were synthesized starting from sulfanilamide. Characterization of their structure was performed using FT-IR, NMR and ESI-MS spectroscopies. Cytotoxic evaluation of the six derivatives was performed against breast and colon cancer cell lines compared to acetazolamide (AZM). In addition, molecular docking was conducted with CA II, CA IX and CA XII to compare fitting of the derivatives with zinc ion.
Results: This study showed that compound P5 had a potential cytotoxic effect against cancerous cell lines. Performing molecular docking revealed that P5 had good zinc binding interaction with CA IX compared with CA II and CAXII, indicating possible selectivity for CA IX.
Conclusion: According to the molecular docking and cytotoxic evaluation, compound P5 could be a promising CA IX inhibitor using the dual tail approach to improve selectivity against this isoform.
References
Said MF, George RF, Petreni A, Supuran CT, Mohamed NM. Synthesis, molecular modelling and QSAR study of new N-phenylacetamide-2-oxoindole benzensulfonamide conjugates as carbonic anhydrase inhibitors with antiproliferative activity. J. Enzyme Inhib. Med. Chem. 2022 Dec 31; 37 (1):701-17.
Wu S, Zhou X, Li F, Sun W, Zheng Q, Liang D. Novel Anthraquinone-Based Benzenesulfonamide Derivatives and Their Analogues as Potent Human Carbonic Anhydrase Inhibitors with Antitumor Activity: Synthesis, Biological Evaluation, and In Silico Analysis. Int. J. Mol. Sci. 2024 Mar 15; 25 (6): 3348.
Hou Z, Lin B, Bao Y, Yan HN, Zhang M, Chang XW, Zhang XX, Wang ZJ, Wei GF, Cheng MS, Liu Y. Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site. Eur. J. Med. Chem. 2017 May 26; 132: 1-0.
Cuffaro D, Nuti E, Rossello A. An overview of carbohydrate-based carbonic anhydrase inhibitors. J. Enzyme Inhib. Med. Chem. 2020 Jan 1; 35 (1):1906-22.
Abdelrahman MA, Eldehna WM, Nocentini A, Ibrahim HS, Almahli H, Abdel-Aziz HA, Abou-Seri SM, Supuran CT. Novel benzofuran-based sulphonamides as selective carbonic anhydrases IX and XII inhibitors: synthesis and in vitro biological evaluation. J. Enzyme Inhib. Med. Chem. 2020 Jan 1;35(1):298-305.
Tanpure RP, Ren B, Peat TS, Bornaghi LF, Vullo D, Supuran CT, Poulsen SA. Carbonic anhydrase inhibitors with dual-tail moieties to match the hydrophobic and hydrophilic halves of the carbonic anhydrase active site. J. Med. Chem. 2015 Feb 12; 58 (3):1494-501.
Tawfik HO, Petreni A, Supuran CT, El-Hamamsy MH. Discovery of new carbonic anhydrase IX inhibitors as anticancer agents by toning the hydrophobic and hydrophilic rims of the active site to encounter the dual-tail approach. Eur. J. Med. Chem. 2022 Mar 15; 232:114190.
Alsughayer A, Elassar AZ, Mustafa S, Al Sagheer F. Synthesis, structure analysis and antibacterial activity of new potent sulfonamide derivatives. JBNB. 2011 Apr 29; 2(02):144-149.
Sabzi NA, Al-Mudhafar MM. Synthesis, characterization, and antimicrobial evaluation of new Schiff bases derived from vanillic acid conjugated to heterocyclic 4H-1, 2, 4-triazole-3-thiol. Pharmacia. 2023 Aug 18; 70: 657-63.
Rutkauskas K, Zubrienė A, Tumosienė I, Kantminienė K, Kažemėkaitė M, Smirnov A, Kazokaitė J, Morkūnaitė V, Čapkauskaitė E, Manakova E, Gražulis S. 4-amino-substituted benzenesulfonamides as inhibitors of human carbonic anhydrases. Molecules. 2014 Oct 28; 19(11):17356-80.
Yaseen Y, Kubba A, Shihab W, Tahtamouni L. Synthesis, docking study, and structure-activity relationship of novel niflumic acid derivatives acting as anticancer agents by inhibiting VEGFR or EGFR tyrosine kinase activities. Pharmacia. 2022 Jul 5; 69:595-614.
Heriz MH, Mahmood AA, Yasin SR, Saleh KM, AlSakhen MF, Kanaan SI, Himsawi N, Saleh AM, Tahtamouni LH. Synthesis, docking study, and antitumor evaluation of benzamides and oxadiazole derivatives of 3‐phenoxybenzoic acid as VEGFR‐2 inhibitors. Drug Dev. Res. 2024 May; 85(3):e22186.
Al-Amily DH, Hassan Mohammed M. Design, synthesis, and docking study of acyl thiourea derivatives as possible histone deacetylase inhibitors with a novel zinc binding group. Sci. Pharm. 2019;87(4):28.
Alibeg AA, Mohammed MH. Molecular docking, synthesis, characteristics and preliminary cytotoxic study of new coumarin-sulfonamide derivatives as histone deacetylase inhibitors. Pol. Med. J. 2024 Jan 1;77(3):514-25.
Saeed AM, Al-Hamashi AA. Molecular Docking, ADMET Study, Synthesis, Characterization and Preliminary Antiproliferative Activity of Potential Histone Deacetylase Inhibitors with Isoxazole as New Zinc Binding Group. Iraqi J. Pharm. Sci. 2023 Nov 3;32:188-203.
Angeli A, Kartsev V, Petrou A, Pinteala M, Vydzhak RM, Panchishin SY, Brovarets V, De Luca V, Capasso C, Geronikaki A, Supuran CT. New sulfanilamide derivatives incorporating heterocyclic carboxamide moieties as carbonic anhydrase inhibitors. Pharmaceuticals. 2021 Aug 23;14(8):828.
Leitans J, Kazaks A, Balode A, Ivanova J, Zalubovskis R, Supuran CT, Tars K. Efficient expression and crystallization system of cancer-associated carbonic anhydrase isoform IX. J. Med. Chem. 2015 Nov 25;58(22):9004-9.
Ivanova J, Nocentini A, Tars K, Leita̅ns J, Dvinskis E, Kazaks A, Domraceva I, Supuran CT, Zalubovskis R. Atropo/Tropo flexibility: a tool for design and synthesis of self-adaptable inhibitors of carbonic anhydrases and their antiproliferative effect. J. Med. Chem. 2023 Apr 6;66(8):5703-18.
Mosleh AA, Dakhel ZA. Molecular docking, microwave-assisted synthesis, characterization, and preliminary evaluation of the anti-microbial activity of new sulfonamide derivatives of the 1, 2, 4-triazole-3-thiol ring system. Pharmacia. 2024 Sep 3;71:1-9.
Mohammed ZM, Al-Hamashi AA. Molecular Docking, ADMET and Molecular Dynamics Simulation Studies for Molecules with Expected HDACInhibition Activity. Gomal J Med Sci. 2024 July 22(2):164-72.
Al-Musawi MH, Al-Mudhafar MM. Synthesis, Characterization, Molecular Docking, ADMET Study, and Antimicrobial Evaluation of New Mannich Bases of Isatin–Thiazole Imine Bases. AJMS. 2024 Jun 28;6(2):201-8.
Bondock S, Albarqi T, Nasr T, Mohamed NM, Abdou MM. Design, synthesis, cytotoxic evaluation and molecular docking of novel 1, 3, 4-thiadiazole sulfonamides with azene and coumarin moieties as carbonic anhydrase inhibitors. Arab. J. Chem. 2023 Aug 1;16(8):104956.
Zhang ZP, Zhong Y, Han ZB, Zhou L, Su HS, Wang J, Liu Y, Cheng MS. Synthesis, molecular docking analysis and biological evaluations of saccharide-modified thiadiazole sulfonamide derivatives. Int. J. Mol. Sci. 2021 May 22;22(11):5482.
Shriner RL, Hermann CKF, Morrill TC CD and FRC 7: Infrared Spectrometry, in: The systemic Identification of Organic Compounds, 8thedition, John Wiley & Sons, Inc., USA. :194-227.
J. M. Organic chemistry. In: Organic Chemistry. 7th ed. canada: David Harris; 2008;445.
Silverstein RM WF and KD". Ch. 2: Infrared Spectrometry", in: ―Spectrometric Identification of Organic Compounds‖, 7th edition, John Wiley & Sons, Inc., USA, p.72-126.
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