One-Pot Synthesis and  In Vitro  Studies of Calix[4]-2-methylresorcinarene Derivatives as Antimalarial Agents Against  Plasmodium falciparum  Chloroquine-Resistant Strain FCR-3

Baiq Ike Nursofia; Yehezkiel Steven Kurniawan; Jumina Jumina; Harno Dwi Pranowo; Eti Nurwening Sholikhah; Jeffry Julianus; Susalit Setya Wibowo; Hana Anisa Fatimi; Yoga Priastomo; Krisfian Tata Aneka Priyangga

doi:10.22146/ijc.94885

One-Pot Synthesis and In Vitro Studies of Calix[4]-2-methylresorcinarene Derivatives as Antimalarial Agents Against Plasmodium falciparum Chloroquine-Resistant Strain FCR-3

https://doi.org/10.22146/ijc.94885

Baiq Ike Nursofia⁽¹⁾, Yehezkiel Steven Kurniawan⁽²⁾, Jumina Jumina^(3*), Harno Dwi Pranowo⁽⁴⁾, Eti Nurwening Sholikhah⁽⁵⁾, Jeffry Julianus⁽⁶⁾, Susalit Setya Wibowo⁽⁷⁾, Hana Anisa Fatimi⁽⁸⁾, Yoga Priastomo⁽⁹⁾, Krisfian Tata Aneka Priyangga⁽¹⁰⁾

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(3) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(5) Department of Pharmacology and Therapeutics, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(6) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Sanata Dharma, Yogyakarta 55282, Indonesia
(7) Research Center for Process and Manufacturing Industry Technology, National Research and Innovation Agency (BRIN), KST BJ Habibie, Banten 15314, Indonesia
(8) Pharmacy Study Program, Faculty of Mathematics and Natural Science, Universitas Sebelas Maret, Jl. Ir. Sutami 36A, Surakarta 57126, Indonesia
(9) Department of Chemical Education, Faculty of Mathematics and Natural Science, Universitas Negeri Yogyakarta, Jl. Colombo No. 1, Yogyakarta 55281, Indonesia
(10) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
(*) Corresponding Author

Abstract

Malaria is an endemic disease in Indonesia caused by infection from the Plasmodium parasite. Recently, antimalarial resistance significantly contributed to the decline in the cure rate of malaria sufferers. In this work, three calix[4]resorcinarenes have been synthesized from 2-methylresorcinol and different benzaldehyde derivatives, i.e., 4-chlorobenzaldehyde, 4-methoxybenzaldehyde, and 4-dimethylaminobenzaldehyde through the one-pot synthesis procedure. The calix[4]resorcinarenes synthesis was done through a cyclo-condensation reaction by using HCl 37% as the catalyst and ethanol as the solvent in an one-pot reaction. The structures of the synthesized products were confirmed using Fourier transform infrared, proton-nuclear magnetic resonance, and liquid chromatography-mass spectrometry techniques. The antimalarial activity assay was evaluated against the Plasmodium falciparum FCR-3 strain through an in vitro study. Three synthesized compounds, i.e., C-4-chlorophenylcalix[4]-2-methylresorcinarene, C-4-methoxyphenylcalix[4]-2-methylresorcinarene and C-4-dimethylaminophenylcalix[4]-2-methylresorcinarene have been successfully synthesized in up to 97% yield. The C-4-chlorophenylcalix[4]-2-methylresorcinerene exhibited the most potent antimalarial activity with a half-maximal inhibitory concentration (IC₅₀) value of 2.66 µM against P. falciparum FCR-3 while the C-4-methoxyphenylcalix[4]-2-methylresorcinarene and C-4-dimethylaminophenylcalix[4]-2-methylresorcinarene gave the IC₅₀ values of 23.63 and 13.82 µM, respectively. From the results, it could be concluded that the antimalarial activity of calix[4]-2-methylresorcinarenes was influenced by the type of substituent of aromatic rings at the para position.

Keywords

Antimalarial; calix[4]-2-methylresorcinarene; in vitro assay; one-pot synthesis; Plasmodium falciparum

Full Text:

Full Text PDF

References

[1] World Health Organization, 2023, Word Malaria Report 2021, World Health Organization, Geneva, Switzerland, https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2023/, accessed on 2 February 2024.

[2] Oluwafemi, T., and Azuaba, E., 2022, Impact of hygiene on malaria transmission dynamics: A mathematical model, J. Multidiscip. Appl. Nat. Sci., 2 (1), 1–9.

[3] Shibeshi, M.A., Kifle, Z.D., and Atnafie, S.A., 2020, Antimalarial drug resistance and novel targets for antimalarial drug discovery, Infect. Drug Resist., 13, 4047–4060.

[4] Balikagala, B., Fukuda, N., Ikeda, M., Katuro, O.T., Tachibana, S., Yamauchi, M., Opio, W., Emoto, S., Anywar, D.A., Kimura, E., Odongo-Aginya, E., Ogwang, M., Horii, T., and Mita, T., 2021, Evidence of artemisinin-resistant malaria in Africa, N. Engl. J. Med., 385 (13), 1163–1171.

[5] Chen, I., and Hsiang, M.S., 2022, Triple artemisinin-based combination therapies for malaria: A timely solution to counter antimalarial drug resistance, Lancet Infect. Dis., 22 (6), 751–753.

[6] Saunders, D.L., Vanachayangkul, P., and Lon, C., 2014, Dihydroartemisinin–piperaquine failure in Cambodia, N. Engl. J. Med., 371 (5), 484–485.

[7] Pei, W.Y., Yang, J., Wu, H., Zhou, W., Yang, Y.W., and Ma, J.F., 2020, A calix[4]resorcinarene-based giant coordination cage: Controlled assembly and iodine uptake, Chem. Commun., 56 (16), 2491–2494.

[8] Ohto, K., 2021, Review of adsorbents incorporating calixarene derivatives used for metals recovery and hazardous ions removal: The concept of adsorbent design and classification of adsorbents, J. Inclusion Phenom. Macrocyclic Chem., 101 (3), 175–194.

[9] Basílio, N., Garcia-Rio, L., and Martín-Pastor, M., 2012, Calixarene-based surfactants: Evidence of structural reorganization upon micellization, Langmuir, 28 (5), 2404–2414.

[10] Kurniawan, Y.S., Ryu, M., Sathuluri, R.R., Iwasaki, W., Morisada, S., Kawakita, H., Ohto, K., Maeki, M., Miyazaki, M., and Jumina, J., 2019, Separation of Pb(II) ion with tetraacetic acid derivative of calix[4]arene by using droplet-based microreactor system, Indones. J. Chem., 19 (2), 368–375.

[11] Memon, F.N., Memon, S., and Minhas, F.T., 2016, Calix[4]arene-mediated uphill transport of methyl red through bulk liquid membrane: Kinetics of operational variables, Desalin. Water Treat., 57 (18), 8358–8371.

[12] Priyangga, K.T.A., Kurniawan, Y.S., Ohto, K., and Jumina, J., 2022, A review on calixarene fluorescent chemosensor agents for various analytes, J. Multidiscip. Appl. Nat. Sci., 2 (1), 23-40.

[13] Naseer, M.M., Ahmed, M., and Hameed, S., 2017, Functionalized calix[4]arenes as potential therapeutic agents, Chem. Biol. Drug Des., 89 (2), 243–256.

[14] Du, D., Liu, Y., Lan, J., Hou, X., Liu, J., Shi, Q., Huang, Q., Xue, Y., Yan, C., and An, L., 2023, Novel biotin-linked amphiphilic calix[4]arene-based supramolecular micelles as doxorubicin carriers for boosted anticancer activity, Chem. Commun., 59 (83), 12487–12490.

[15] Ni, J., Lu, L., and Liu, Y., 2019, Antiradical and antioxidative activity of azocalix[4]arene derivatives: Combined experimental and theoretical study, Molecules, 24 (3), 485.

[16] Zarranz, B., Jaso, A., Aldana, I., Monge, A., Maurel, S., Deharo, E., Jullian, V., and Sauvain, M., 2005, Synthesis and antimalarial activity of new 3-arylquinoxaline-2-carbonitrile derivatives, Arzneimittelforschung, 55 (12), 754–761.

[17] Liu, M., Wilairat, P., Croft, S.L., Tan, A.L.C., and Go, M.L., 2003, Structure-activity relationships of antileishmanial and antimalarial chalcones, Bioorg. Med. Chem., 11 (13), 2729–2738.

[18] Syahri, J., Nasution, H., Nurohmah, B.A., Purwono, B., Yuanita, E., Zakaria, N.H., and Hassan, N.I., 2020, Design, synthesis and biological evaluation of aminoalkylated chalcones as antimalarial agent, Sains Malays., 49 (11), 2667–2677.

[19] Putri, R.R., Pranowo, H.D., Kurniawan, Y.S., Fatimi, H.A., and Jumina, J., 2023, Synthesis of calix[4]resorcinarene derivatives as antimalarial agents through heme polymerization inhibition assay, Indones. J. Chem., 23 (4), 1032–1041.

[20] Sari, D.K., Hidayat, D.N.W., Fatmawati, D.R., Triono, S., Kurniawan, Y.S., and Jumina, J., 2022, Synthesis and antimalarial activity assay of C-arylcalix[4]pyrogallolarenes using heme polymerization inhibition activity (HPIA) method, Mater. Sci. Forum, 1061, 187–193.

[21] Nisa, S.A., Jumina, J., Mardjan, M.I.D., and Kurniawan, Y.S., 2023, Synthesis, activity test and molecular docking of novel nitrophenylcalix[4]-2-methylresorcinarene derivatives as antimalarial agent, Molekul, 18 (3), 404–413.

[22] Jumina, J., Siswanta, D., Zulkarnaian, A.K., Triono, S., Priatmoko, P., Yuanita, E., Imawan, A.C., Fatmasari, N., and Nursalim, I., 2019, Development of C-arylcalix[4]resorcinarenes and C-arylcalix[4]pyrogallolarenes as antioxidant and UV-B protector, Indones. J. Chem., 19 (2), 273–284.

[23] Congpuong, K., Sirtichaisinthop, J., Tippawangkosol, P., Suprakrob, K., Na-Bangchang, K., Tan-ariya, P., and Karbwang, J., 1998, Incidence of antimalarial pretreatment and drug sensitivity in vitro in multidrug-resistant Plasmodium falciparum infection in Thailand, Trans. R. Soc. Trop. Med. Hyg., 92 (1), 84–86.

[24] Zakiah, M., Syarif, R.A., Mustofa, M., Jumina, J., Fatmasari, N., and Sholikhah, E.N., 2021, In vitro antiplasmodial, heme polymerization, and cytotoxicity of hydroxyxanthone derivatives, J. Trop. Med., 2021 (1), 8866681.

[25] Rajkumar, P., Buvaneswari, N., Vaheith, Z.A., Ahamed, A.F., Saraswathy, G., and Dayanandhan, R., 2021, Kinetic analysis of oxidation of α-hydroxy acids by Caro’s acid in micellar medium, Rasayan J. Chem., 14 (2), 785–793.

[26] Castillo-Aguirre, A., Rivera-Monroy, Z., and Maldonado, M., 2017, Selective O-alkylation of the crown conformer of tetra(4-hydroxyphenyl)calix[4]resorcinarene to the corresponding tetraalkyl ether, Molecules, 22 (10), 1660.

[27] Elidrisi, I., Bhatt, P.V., Govender, T., Kruger, H.G., and Maguire, G.E.M., 2015, Synthesis and NMR elucidation of novel octa-amino acid resorcin[4]arenes derivatives, S. Afr. J. Chem., 68, 27–38.

[28] Pineda-Castañeda, H., Maldonado-Villamil, M., Parra-Giraldo, C.M., Leal-Castro, A.L., Fierro-Medina, R., Rivera-Monroy, Z.J., and García-Castañeda, J.E., 2023, Peptide-resorcinarene conjugates obtained via click chemistry: Synthesis and antimicrobial activity, Antibiotics, 12 (4), 773.

[29] Galindres, D.M., Cifuentes, D., Tinoco, L.E., Murillo-Acevedo, Y., Rodrigo, M.M., Ribeiro, A.C.F., and Esteso, M.A., 2022, A review of the application of resorcinarenes and SBA-15 in drug delivery, Processes, 10 (4), 684.

[30] Pineda-Castañeda, H.M., Maldonado, M., and Rivera-Monroy, Z.J., 2023, Efficient separation of C-tetramethylcalix[4]resorcinarene conformers by means of reversed-phase solid-phase extraction, ACS Omega, 8 (1), 231–237.

[31] Shebitha, A.M., Sreejith, S.S., Sherly Mole, P.B., Mohan, N., Avudaiappan, G., Hiba, K., Priya, K.S., and Sreekumar, K., 2020, Facile synthesis, X-ray diffraction studies, photophysical properties and DFT-D based conformational analysis of octa and dodecacyanomethoxycalix[4]resorcinarenes, J. Mol. Struct., 1214, 128215.

[32] Taylor, D., Ling, I., Vilela, F., and Dalgarno, S.J., 2022, Intermolecular interactions drive the unusual co-crystallization of different calix[4]arene conformations, Crystals, 12 (2), 250.

[33] Liu, J.L., Zhang, P.Z., Jia, A.Q., Shi, H.T., and Zhang, Q.F., 2022, Supramolecular assemblies of sulfonatomethylated calix[4]resorcinarenes with aquated sodium(I), cesium(I), and aluminum(III) ions, ChemistrySelect, 7 (1), e202104118.

[34] Liu, J.L., Liu, X.L., Jia, A.Q., Shi, H.T., and Zhang, Q.F., 2020, Supramolecular structures and crystal stability of diisobutylaminomethylated calix[4]resorcinarenes, J. Inclusion Phenom. Macrocyclic Chem., 98 (1), 49–56.

[35] Eddaif, L., Trif, L., Telegdi, J., Egyed, O., and Shaban, A., 2019, Calix[4]resorcinarene macrocycles, J. Therm. Anal. Calorim., 137 (2), 529–541.

[36] Batista, R., De Jesus Silva Júnior, A., and De Oliveira, A.B., 2009, Plant-derived antimalarial agents: New leads and efficient phytomedicines. Part II. Non-alkaloidal natural products, Molecules, 14 (8), 3037–3072.

[37] Park, G.M., Park, H., Oh, S., and Lee, S., 2017, Antimalarial activity of C-10 substituted triazolyl artemisinin, Korean J. Parasitol., 55 (6), 661–665.

[38] Wicht, K.J., Mok, S., and Fidock, D.A., 2020, Molecular mechanisms of drug resistance in Plasmodium falciparum malaria, Annu. Rev. Microbiol., 74, 431–454.

[39] Shah, R.B., Valand, N.N., Sutariya, P.G., and Menon, S.K., 2016, Design, synthesis and characterization of quinoline-pyrimidine linked calix[4]arene scaffolds as anti-malarial agents, J. Inclusion Phenom. Macrocyclic Chem., 84 (1), 173–178.

[40] Kpotin, G.A., Bédé, A.L., Houngue-Kpota, A., Anatovi, W., Kuevi, U.A., Atohoun, G.S., Mensah, J.B., Gómez-Jeria, J.S., and Badawi, M., 2019, Relationship between electronic structures and antiplasmodial activities of xanthone derivatives: A 2D-QSAR approach, Struct. Chem., 30 (6), 2301–2310.

DOI: https://doi.org/10.22146/ijc.94885