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Synthesis and in vitro biological activities of ferrocenyl–chalcone amides

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Abstract

A series of aminoferrocenyl–chalcone amides 11–19 were synthesized through condensation of a carboxylic acid-functionalized chalcone 10 with ferrocenylamines, using 1,1′-carbonyldiimidazole as the coupling agent. The compounds were screened for their antiplasmodial activities against CQS 3D7 and CQR FCR3 strains of Plasmodium falciparum. All compounds were found to be active, with IC50 values ranging between 0.5–4.5 and 2.1–6.6 µM against 3D7 and FCR3, respectively. Amide 11, featuring a 2-aminoethylene linker, was the most active of all, with IC50 values of 2.6 and 2.1 µM against the 3D7 and FCR3 strains, respectively. In screens against a panel of three cancer cell lines, i.e., TK-10, UACC-62, and MCF-7, amide 19, with a piperazinyl linker, showed increased activity against all three cell lines, compared to the reference drug, parthenolide. Antimicrobial assays that had been performed on six different microorganisms revealed that most of the synthesized amides were inactive against all of these microorganisms. Compound 17, however, with an aminodi(ethyleneoxy) linker, displayed moderate bactericidal activity against the gram-negative microorganisms, with a MIC100 value of 128 µM. The outcomes of this study may hence significantly contribute toward malaria and cancer chemotherapy research, and more generally to the growing body of research that aims at illustrating the potential of employing organometallic compounds in medicinal chemistry programs.

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References

  • Acevedo-Morantes CY, Meléndez E, Singh SP, Ramírez-Vick JE (2012) Cytotoxicity and reactive oxygen species generated by ferrocenium and ferrocene on MCF7 and MCF10A Cell Lines. J Cancer Sci Ther 4:271–275

    CAS  Google Scholar 

  • Aly ASI, Matuschewski K (2005) A malarial cysteine protease is necessary for Plasmodium sporozoite egress from oocysts. J Exp Med 202:225–230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Attar S, O’Brien Z, Alhaddad H, Golden ML, Calderón-Urrea A (2011) Ferrocenyl chalcones versus organic chalcones: a comparative study of their nematocidal activity. Bioorg Med Chem 19:2055–2073

    Article  CAS  PubMed  Google Scholar 

  • Beagley P, Blackie MAL, Chibale K, Clarkson C, Meijboom R, Moss JR, Smith PJ, Su H (2003) Synthesis and antiplasmodial activity in vitro of new ferrocene-chloroquine analogues. Dalton Trans. doi:10.1039/B303335J

  • Chibale K, Moss JR, Blackie M, van Schalkwyk D, Smith PJ (2000) New amine and urea analogs of ferrochloroquine: synthesis, antimalarial activity in vitro and electrochemical studies. Tetrahedron Lett 41:6231–6235

    Article  CAS  Google Scholar 

  • CLSI (2009) Method for antifungal disk diffusion susceptibility testing of yeasts; approved guideline-second (ed). CLSI document M44-A2. Clinical and Laboratory Standards Institute, Wayne, PA

  • CLSI (2012a) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-ninth (ed). CLSI document M07-A9. Clinical and Laboratory Standards Institute, Wayne, PA

  • CLSI (2012a) Performance standards for antimicrobial susceptibility testing; twenty-second informational supplement. CLSI document M100-S24. Clinical and Laboratory Standards Institute, Wayne, PA

  • D’Alessandro S, Silvestrini F, Dechering K, Corbett Y, Parapini S, Timmerman M, Galastri L, Basilico N, Sauerwein R, Alano P, Taramelli D (2013) A Plasmodium falciparum screening assay for anti-gametocyte drugs based on parasite lactate dehydrogenase detection. J Antimicrob Chemother 68:2048–2058

    Article  PubMed  Google Scholar 

  • Ettari R, Bova F, Zappalà M, Grasso S, Micale N (2009) Falcipain-2 inhibitors. Med Res Rev 30:136–167

    Google Scholar 

  • Gimeno MC, Goitia H, Laguna A, Luque ME, Villacampa MD, Sepúlveda C, Meireles M (2011) Conjugates of ferrocene with biological compounds. Coordination to gold complexes and antitumoral properties. J Inorg Biochem 105:1373–1382

    Article  CAS  PubMed  Google Scholar 

  • Go M-L, Liu M, Wilairat P, Rosenthal PJ, Saliba KJ, Kirk K (2004) Antiplasmodial chalcones inhibit sorbitol-induced hemolysis of Plasmodium falciparum-infected erythrocytes. Antimicrob Agents Chemother 48:3241–3245

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Guantai EM, Ncokazi K, Egan TJ, Gut J, Rosenthal PJ, Smith PJ, Chibale K (2010) Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds. Bioorg Med Chem 18:8243–8256

    Article  CAS  PubMed  Google Scholar 

  • Guo C, McMartin KE (2005) The cytotoxicity of oxalate, metabolite of ethylene glycol, is due to calcium oxalate monohydrate formation. Toxicology 208:347–355

    Article  CAS  PubMed  Google Scholar 

  • Hartung T (2013) Food for thought look back in anger—what clinical studies tell us about preclinical work. ALTEX 30:275–291

    Article  PubMed Central  PubMed  Google Scholar 

  • Haslam G, Wyatt D, Kitos PA (2000) Estimating the number of viable animal cells in multi-well cultures based on their lactate dehydrogenase activities. Cytotechnology 32:63–75

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jayasinghe L, Balasooriya B, Padmini WC, Hara N, Fujimoto Y (2004) Geranyl chalcone derivatives with antifungal and radical scavenging properties from the leaves of Artocarpus nobilis. Phytochemistry 65:1287–1290

    Article  CAS  PubMed  Google Scholar 

  • Kanzian T, Nigst T, Maier A, Pichl S, Mayr H (2009) Nucleophilic reactivities of primary and secondary amines in acetonitrile. Eur J Org Chem. doi:10.1002/ejoc.200900925

  • Kaur K, Jain M, Reddy RP, Jain R (2010) Quinolines and structurally related heterocycles as antimalarials. Eur J Med Chem 45:3245–3264

    Article  CAS  PubMed  Google Scholar 

  • Kohjimoto Y, Kennington L, Scheid CR, Honeyman TW (1999) Role of phospholipase A2 in the cytotoxic effects of oxalate in cultured renal epithelial cells. Kidney Int 56:1432–1441

    Article  CAS  PubMed  Google Scholar 

  • Kumar R, Mohanakrishnan D, Sharma A, Kaushik NK, Kalia K, Sinha AK, Sahal D (2010) Reinvestigation of structure-activity relationship of methoxylated chalcones as antimalarials: synthesis and evaluation of 2,4,5-trimethoxy substituted patterns as lead candidates derived from abundantly available natural β-asarone. Eur J Med Chem 45:5292–5301

    Article  CAS  PubMed  Google Scholar 

  • Larsen M, Kromann H, Kharazmi A, Nielsen SF (2005) Conformationally restricted anti-plasmodial chalcones. Bioorg Med Chem Lett 15:4858–4861

    Article  CAS  PubMed  Google Scholar 

  • Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25

    Article  CAS  Google Scholar 

  • Lombard MC, N’Da DD, Breytenbach JC, Smith PJ, Lategan CA (2011) Synthesis, in vitro antimalarial and cytotoxicity of artemisinin-aminoquinoline hybrids. Bioorg Med Chem Lett 21:1683–1686

    Article  CAS  PubMed  Google Scholar 

  • Mathiyalagan K, Gopal S, Ramasamy E, Vennila T (2008) In-vitro antimicrobial screening of ferrocene derived compounds. Inter J ChemTech Res 4:1775–1781

    Google Scholar 

  • Mishra N, Arora P, Kumar B, Mishra LC, Bhattacharya A, Awasthi SK, Bhasin VK (2008) Synthesis of novel substituted 1,3-diaryl propenone derivatives and their antimalarial activity in vitro. Eur J Med Chem 43:1530–1535

    Article  CAS  PubMed  Google Scholar 

  • Monserrat J-P, Chabot GG, Hamon L, Quentin L, Scherman D, Jaouen G, Hillard EA (2010) Synthesis of cytotoxic ferrocenyl flavones via a ferricenium-mediated 1,6-oxidative cyclization. Chem Commun 46:5145–5147

    Article  CAS  Google Scholar 

  • Muller TJ, Conradie J, Erasmus E (2012) A spectroscopic, electrochemical and DFT study of para-substituted ferrocene-containing chalcone derivatives: structure of FcCOCHCH(p-tBuC6H4). Polyhedron 33:257–266

    Article  CAS  Google Scholar 

  • Nabi G, Liu Z-Q (2011) Radical-scavenging properties of ferrocenyl chalcones. Bioorg Med Chem Lett 21:944–946

    Article  CAS  PubMed  Google Scholar 

  • N’Da DD, Breytenbach JC, Smith PJ, Lategan C (2010) Synthesis, cytotoxicity and antimalarial activity of ferrocenyl amides of 4-aminoquinolines. Arzneimittelforschung 60:627–635

    PubMed  Google Scholar 

  • Nzila A, Mwai L (2010) In vitro selection of Plasmodium falciparum drug-resistant parasite lines. J Antimicrob Chemother 65:390–398

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ornelas C (2011) Application of ferrocene and its derivatives in cancer research. New J Chem 35:1973–1985

    Article  CAS  Google Scholar 

  • Owens J (2003) Chris Lipinski discusses life and chemistry after the Rule of Five. Drug Discov Today 8:12–16

    Article  Google Scholar 

  • Reddy MVB, Su C-R, Chiou W-F, Liu Y-N, Chen RY-H, Bastow KF, Lee K-H, Wu T-S (2008) Design, synthesis, and biological evaluation of Mannich bases of heterocyclic chalcone analogs as cytotoxic agents. Bioorg Med Chem 16:7358–7370

    Article  CAS  PubMed  Google Scholar 

  • Rosenthal PJ (2004) Cysteine proteases of malaria parasites. Int J Parasitol 34:1489–1499

    Article  CAS  PubMed  Google Scholar 

  • Silverstein RM, Webster FX, Kiemle DJ (2005) Spectrometric identification of organic compounds. Wiley, New York

    Google Scholar 

  • Singh SS (2006) Preclinical pharmacokinetics: an approach towards safer and efficacious drugs. Curr Drug Metab 7:165–182

    Article  CAS  PubMed  Google Scholar 

  • Sinha S, Medhi B, Sehgal R (2013) Chalcones as an emerging lead molecule for antimalarial therapy: a review. J Mod Med Chem 1:64–77

    Google Scholar 

  • Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug Screening. J Natl Cancer Inst 82:1107–1112

    Article  CAS  PubMed  Google Scholar 

  • Smit FJ, N’Da DD (2014) Synthesis, in vitro antimalarial activity and cytotoxicity of novel 4-aminoquinolinyl-chalcone amides. Bioorg Med Chem 22:1128–1138

    Article  CAS  PubMed  Google Scholar 

  • Smit FJ, van Biljon RA, Birkholtz L-M, N’Da DD (2015) Synthesis and in vitro biological evaluation of dihydroartemisinyl-chalcone esters. Eur J Med Chem 90:33–44

    Article  CAS  PubMed  Google Scholar 

  • van de Waterbeemd H, Gifford E (2003) ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov 2:192–204

    Article  PubMed  Google Scholar 

  • Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1:1112–1116

    Article  CAS  PubMed  Google Scholar 

  • WHO (2014a) World malaria report. http://www.who.int/malaria/publications/world_malaria_report_2014/en/. Accessed 8 March 2014

  • WHO (2014) Cancer fact sheet no 297. http://www.who.int/iris/bitstream/10665/97008/10661/9789241564694_eng.pdf. Accessed 20 April 2014

  • Wu X, Wilairat P, Go M-L (2002) Antimalarial activity of ferrocenyl chalcones. Bioorg Med Chem Lett 12:2299–2302

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Tiekink ERT, Kostetski I, Kocherginsky N, Tan ALC, Khoo SB, Wilairat P, Go M-L (2006) Antiplasmodial activity of ferrocenyl chalcones: investigations into the role of ferrocene. Eur J Pharm Sci 27:175–187

    Article  CAS  PubMed  Google Scholar 

  • Zheng C-J, Jiang S-M, Chen Z-H, Ye B-J, Piao H-R (2011) Synthesis and anti-bacterial activity of some heterocyclic chalcone derivatives bearing thiofuran, furan and quinoline moieties. Arch Pharm Chem Life Sci 344:689–695

    Article  CAS  Google Scholar 

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Acknowledgments

This study was based upon research financially supported by the National Research Foundation (NRF) and the North-West University, Potchefstroom Campus. The authors wish to thank Dr. D Mancama from the CSIR for the biological activity screening, Dr. JHL Jordaan for the MS analysis, Mr. A Joubert for the NMR analysis, and Dr. JR Kriek and Dr. V Lates for their assistance with the electrochemical determinations.

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Authors and Affiliations

  1. Drug Design, Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, 2520, South Africa

    Frans J. Smit & David D. N’Da

  2. School of Biological Sciences, Subject Group Microbiology, Faculty of Natural Sciences, North-West University, Potchefstroom, South Africa

    Jaco J. Bezuidenhout & Carlos C. Bezuidenhout

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  1. Frans J. Smit
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  2. Jaco J. Bezuidenhout
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  3. Carlos C. Bezuidenhout
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  4. David D. N’Da
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Correspondence to David D. N’Da.

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Smit, F.J., Bezuidenhout, J.J., Bezuidenhout, C.C. et al. Synthesis and in vitro biological activities of ferrocenyl–chalcone amides. Med Chem Res 25, 568–584 (2016). https://doi.org/10.1007/s00044-016-1509-y

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