Sains Malaysiana 51(4)(2022): 1123-1130

http://doi.org/10.17576/jsm-2022-5104-14

Aktiviti Antimalaria secara in vitro Kompleks Logam Ligan Makrosiklik Tetraaza terhadap Strain Plasmodium falciparum K1

(in vitro Antimalarial Activity of Metal Complexes of Tetraazamacrocyclic Ligands against Plasmodium falciparum K1 Strain)

NUR AQILAH ZAHIRAH NORAZMI¹, NUR HAFIZAH MUKHTAR¹, AMATUL HAMIZAH ALI¹, NURUL HUDA ABD KARIM¹, SITI FAIRUS MOHD YUSOFF¹, HANI KARTINI AGUSTAR², MOHD RIDZUAN MOHD ABD RAZAK³ & NURUL IZZATY HASSAN^1*

¹Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor Darul Ehsan, Malaysia

²Department of Earth Science and Environment, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor Darul Ehsan, Malaysia

³Herbal Medicine Research Centre, Institute for Medical Research, National Institute of Health (NIH) Complex, Ministry of Health Malaysia, 40170 Shah Alam, Selangor Darul Ehsan, Malaysia

Received: 27 June 2021/Accepted: 19 August 2021

Abstrak

Malaria masih lagi kekal menjadi salah satu penyakit endemik yang boleh membawa maut dan rawatan yang digunakan kini untuk merawat malaria adalah terapi gabungan artemisinin. Namun begitu, akses kepada rawatan ini adalah sangat terhad dan memberi kesan besar kepada negara miskin disebabkan kos terapi yang tinggi. Penilaian aktiviti antimalaria bagi kompleks organologam berasaskan ligan makroksiklik tetraaza masih kurang meluas dijalankan. Ligan makrosiklik tetraaza 5,5,7,12,12,14- heksametil-1,4,8,11- tetraazasiklotetradeka-7,14-dienium bromida, dikomplekskan dengan empat logam peralihan iaitu Cu(II), Pb(II) dan Ni(II) dan Cd(II). Aktiviti antimalarial secara in vitro ke atas strain parasit Plasmodium falciparum yang rintang terhadap klorokuina, K1 ditentukan dan dibandingkan dengan aktiviti antiplasmodial sebatian klorokuina dan artemisinin. Kompleks [Cd(L)(OAc)]Br^- merencat pertumbuhan parasit dengan 50% kepekatan perencatan berkesan (EC₅₀) dalam julat aktiviti antiplasmodium yang poten (EC₅₀<1 μM) manakala Cu(L)(OAc)]Br^- menunjukkan kesan aktiviti antiplasmodium sederhana (20< EC₅₀<100 μM). Aktiviti kesitotoksikan terhadap sel mamalia Vero yang ditunjukkan oleh kompleks logam Cd(II) berada dalam julat sederhana toksik (10 μM <CC₅₀< 100 μM), manakala, Cu(II), Pb(II) dan Ni(II) berada dalam julat tidak toksik (CC₅₀>100 μM). Nilai indeks pemilihan yang tinggi turut ditunjukkan oleh kompleks Cd(II) iaitu 60.5 seterusnya menjadikan kompleks ini berpotensi untuk dibangunkan sebagai agen antimalaria.

Kata kunci: Antiplasmodium; in vitro; kesitotoksikan; makrosiklik tetraaza, Plasmodium falciparum K1

Abstract

Malaria remains one of the most lethal endemic diseases, and the treatment used today to treat malaria is artemisinin-based combination therapy. However, access to this treatment is minimal and has a huge impact on low-income countries due to the high cost of therapy. The evaluation of antimalarial activity for metal complexes based on tetraaza macrocyclic ligand is unlimited. The macrocyclic 5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradeca-7,14-dienium bromide is complexed with four transition metals, namely Cu(II), Pb(II) and Ni(II) and Cd(II). in vitro antimalarial activity on parasite strain Plasmodium falciparum resistant to chloroquine, K1 is determined and compared to the antiplasmodial activity of chloroquine and artemisinin compounds. Complex [Cd(L)(OAc)]Br^- inhibits the growth of parasites with 50% effective inhibition concentration (EC₅₀) within the potent range of antiplasmodial activity (EC₅₀<1 μM) while Cu(L)(OAc)]Br^- shows the effect of activity moderate antiplasmodial (20< EC₅₀<100 μM). The activities of the toxicity of Vero mammalian cells indicated by the metal complex, Cd(II) are within moderate toxicity range (10 μM <CC₅₀< 100 μM), while Cu(II), Pb(II) and Ni(II) are within the non-toxic range (CC₅₀>100 μM). The high selection index value is also indicated by the Cd(II) complex of 60.5, making this complex potentially to be developed as an antimalarial agent.

Keywords: Antiplasmodial; in vitro; cytotoxicity; Plasmodium  falciparum K1; tetraaza macrocyclic

REFERENCES

 Abiodun, B.J., Salami, A.T., Matthew, O.J. & Odedokun, S. 2013. Potential impacts of afforestation on climate change and extreme events in Nigeria. Climate Dynamics 41(2): 277-293.

Ali, A.H., Sudi, S., Shi-Jing, N., Hassan, W.R.M., Basir, R., Agustar, H.K., Embi, N., Sidek, H.M. & Latip, J. 2021. Dual anti-malarial and GSK3β-mediated cytokine-modulating activities of quercetin are requisite of its potential as a plant-derived therapeutic in malaria. Pharmaceuticals 14(3): 248.

Ali, A.H., Agustar, H.K., Hassan, N.I., Latip, J., Embi, N. & Sidek, H.M. 2020. Data on antiplasmodial and stage-specific inhibitory effects of Aromatic (Ar)-Turmerone against Plasmodium Falciparum 3D7. Data In Brief 33(2020): 106592.

Amoyaw, P.N.A., Pham, K., Cain, A.N., McClain, J.M., Hubin, T. & Faruk Khan, M.O. 2014. Synthesis of novel tetraazamacrocyclic bisquinoline derivatives as potential antimalarial agents. Current Organic Synthesis 11(6): 916-921.

Antony, H.A. & Parija, S.C. 2016. Antimalarial drug resistance: An overview. Tropical Parasitology 6: 30-41.

Bahl, D., Athar, F., Soares, M.B.P., de Sá, M.S., Moreira, D.R.M., Srivastava, R.M., Leite, A.C.L. & Azam, A. 2010. Structure-activity relationships of mononuclear metal-thiosemicarbazone complexes endowed with potent antiplasmodial and antiamoebic activities. Bioorganic and Medicinal Chemistry 18(18): 6857-6864.

Boudhar, A., Ng, X.W., Loh, C.Y., Chia, W.N., Tan, Z.M., Nosten, F., Dymock, B.W. & Tan, K.S. 2016. Overcoming chloroquine resistance in malaria: Design, synthesis, and structure-activity relationships of novel hybrid compounds. Antimicrobial Agents and Chemotherapy 60(5): 3076-3089.

Bueno, J.M., Manzano, P., García, M.C., Chicharro, J., Puente, M., Lorenzo, M., García, A., Ferrer, S., Gómez, R.M., Fraile, M.T. & Lavandera, J.L. 2011. Potent antimalarial 4-pyridones with improved physico-chemical properties. Bioorganic and Medicinal Chemistry Letters 21(18): 5214-5218.

Burger, A.M. & Fiebig, H.H. 2014. Preclinical Screening for New Anticancer Agents. Handbook of Anticancer Pharmacokinetics and Pharmacodynamics. New Jersey: Humana Press. pp. 23-38.

da Silva Filho, A.A., Resende, D.O., Fukui, M.J., Santos, F.F., Pauletti, P.M., Cunha, W.R., Silva, M.L.A., Gregório, L.E., Bastos, J.K. & Nanayakkara, N.P.D. 2009. In vitro antileishmanial, antiplasmodial and cytotoxic activities of phenolics and triterpenoids from Baccharis dracunculifolia DC (Asteraceae). Fitoterapia 80(8): 478-482.

Dar, O., Khan, M.S. & Adagu, I. 2008. The potential use of methotrexate in the treatment of falciparum malaria: in vitro assays against sensitive and multidrug-resistant Falciparum strains. Japanese Journal of Infectious Diseases 61(3): 210-211.

Fairhurst, R.M. & Dondorp, A.M. 2016. Artemisinin-resistant Plasmodium falciparum malaria. Microbiology Spectrum 4(3): 10.1128/microbiolspec.EI10-0013-2016

Fitch, C.D. 1998. Involvement of heme in the antimalarial action of chloroquine. Transactions of the American Clinical and Climatological Association 109: 97.

Ginsburg, H., Famin, O., Zhang, J. & Krugliak, M. 1998. Inhibition of glutathione-dependent degradation of heme by chloroquine and amodiaquine as a possible basis for their antimalarial mode of action. Biochemical Pharmacology 56(10): 1305-1313.

Hossain, M.F., Amoyaw, P.N.A., Saluja, H.S. & Khan, F.M.O. 2016. Evaluation of the physicochemical properties of a novel antimalarial drug lead, cyclen bisquinoline. Modern Chemistry and Applications 4(2): 1000181.

Hubin, T.J., Walker, A.N., Davilla, D.J., Freeman, T.N.C., Epley, B.M., Hasley, T.R., Amoyaw, P.N., Jain, S., Archibald, S.J., Prior, T.J. & Krause, J.A. 2019. Tetraazamacrocyclic derivatives and their metal complexes as antileishmanial leads. Polyhedron 163: 42-53.

Hubin, T.J., Amoyaw, P.N.A., Roewe, K.D., Simpson, N.C., Maples, R.D., Freeman, T.N.C., Cain, A.N., Le, J.G., Archibald, S.J., Khan, S.I. & Tekwani, B.L. 2014. Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands. Bioorganic and Medicinal Chemistry 22(13): 3239-3244.

Hussin, N., Lim, Y.A.L., Goh, P.P., William, T., Jelip, J. & Mudin, R.N. 2020. Updates on malaria incidence and profile in Malaysia from 2013 to 2017. Malaria Journal 19(1): 55.

Kapishnikov, S., Weiner, A., Shimoni, E., Guttmann, P., Schneider, G., Dahan-Pasternak, N., Dzikowski, R., Leiserowitz, L. & Elbaum, M. 2012. Oriented nucleation of hemozoin at the digestive vacuole membrane in Plasmodium falciparum. Proceedings of the National Academy of Sciences 109(28): 11188-11193.

Ke, H., Sigala, P.A., Miura, K., Morrisey, J.M., Mather, M.W., Crowley, J.R., Henderson, J.P., Goldberg, D.E., Long, C.A. & Vaidya, A.B. 2014. The heme biosynthesis pathway is essential for Plasmodium falciparum development in mosquito stage but not in blood stages. Journal of Biological Chemistry 289(50): 34827-34837.

Kiremire, E.M.R., Chibale, K., Rosenthal, P.J., Daniel, L.S., Negonga, A.M. & Munyolo, F.M. 2007. Metal complexes with high biological activity against chloroquine resistant strain of Plasmodium falciparum parasite. Biosciences Biotechnology Research Asia 4: 399-402.

Kumar, N., Khan, S.I., Sharma, M., Atheaya, H. & Rawat, D.S. 2009. Iodine-catalyzed one-pot synthesis and antimalarial activity evaluation of symmetrically and asymmetrically substituted 3, 6-diphenyl [1, 2, 4, 5] tetraoxanes. Bioorganic and Medicinal Chemistry Letters 19(6): 1675-1677.

Kumar Sharma, G., Yogi, A., Gaur, K. & Dashora, A. 2015. A review on antimalarial drug. International Journal of Basic Clinical Pharmacy and Research 1(1): 1-15.

McCarthy, J.S., Rückle, T., Djeriou, E., Cantalloube, C., Ter-Minassian, D., Baker, M., O’Rourke, P., Griffin, P., Marquart, L., van Huijsduijnen, R.H. & Möhrle, J.J. 2016. A phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study. Malaria Journal 15(1): 1-9.

Monti, D., Vodopivec, B., Basilico, N., Olliaro, P. & Taramelli, D. 1999. A novel endogenous antimalarial: Fe (II)-protoporphyrin IXα (heme) inhibits hematin polymerization to β-hematin (malaria pigment) and kills malaria parasites. Biochemistry 38(28): 8858-8863.

Mosmann, T. 1983. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods 65(1): 55-63.

Radfar, A., Méndez, D., Moneriz, C., Linares, M., Marín-García, P., Puyet, A., Diez, A. & Bautista, J.M. 2009. Synchronous culture of Plasmodium falciparum at high parasitemia levels. Nature Protocols 4(12): 1899-1915.

Sarr, S.O., Perrotey, S., Fall, I., Ennahar, S., Zhao, M., Diop, Y.M., Candolfi, E. & Marchioni, E. 2011. Icacina senegalensis (Icacinaceae), traditionally used for the treatment of malaria, inhibits in vitro Plasmodium falciparum growth without host cell toxicity. Malaria Journal 10: 85.

Stringer, T., Quintero, M.A.S., Wiesner, L., Smith, G.S. & Nordlander, E. 2019. Evaluation of PTA-derived ruthenium (II) and iridium (III) quinoline complexes against chloroquine-sensitive and resistant strains of the Plasmodium falciparum malaria parasite. Journal of Inorganic Biochemistry 191: 164-173.

Wiji Prasetyaningrum, P., Bahtiar, A. & Hayun, H. 2018. Synthesis and cytotoxicity evaluation of novel asymmetrical mono-carbonyl analogs of curcumin (AMACs) against Vero, HeLa, and MCF7 Cell Lines. Scientia Pharmaceutica 86(2): 25.

Yamin, B.M., Kadir, A. & Yusoff, S.F. 2015. Complexation of 5, 5, 7, 12, 12, 14-hexamethyl-1, 4, 8, 11-tetraazayclotetradeca-7, 14-dienium bromide with copper acetate in methanol and aqueous solutions. Indonesian Journal of Chemical Research 2(2): 171-175.

Yong, A.S.J., Navaratnam, P., Kadirvelu, A. & Pillai, N. 2018. Re-emergence of malaria in Malaysia: A review article. Open Access Library Journal 5(2): 1-16.

Yusoff, L.M., Yusoff, S.F.M., Ismail, W. & Yamin, B.M. 2014. Synthesis and characterization of Ni (II) complex with 5, 5, 7, 12, 12, 14-hexamethyl-1, 4, 8, 11-tetraazacyclotetradeca-7, 14-dienium bromide. In AIP Conference Proceedings 1614(1): 358-361.

Yusoff, S.F.M., Huddin, A.A.S., Yusoff, L.M., Yamin, B.M. & Ong, W.L. 2015. Synthesis, characterization, and antibacterial activity of Cu (II), Ni (II), and Zn (II) complexes of 14-membered macrocyclictetraaza ligand. Oriental Journal of Chemistry 31(3): 1751.

Zakaria, N.H., Hassan, N.I. & Wai, L.K. 2020. Molecular docking study of the interactions between Plasmodium falciparum lactate dehydrogenase and 4-aminoquinoline hybrids. Sains Malaysiana 49(8): 1905-1913.

^*Corresponding author; email: drizz@ukm.edu.my