Sains Malaysiana 52(12)(2023): 3463-3474

http://doi.org/10.17576/jsm-2023-5212-09

Synthesis, Antimalarial Activities of Secondary Amine-Substituted Eugenol Compounds against Plasmodium falciparum and in silico Molecular Docking Analysis

(Sintesis, Aktiviti Antimalaria Sebatian Eugenol Gantian-Amina Sekunder terhadap Plasmodium falciparum dan Analisis Dok Molekul in silico)

JUFRIZAL SYAHRI^1,*, RAHMIWATI HILMA¹, NURLAILI¹, MEIDITA KEMALA SARI¹, NENI FRIMAYANTI², AMATUL HAMIZAH ALI³ & JALIFAH LATIP³

¹Department of Chemistry, Universitas Muhammadiyah Riau, Jalan Tuanku Tambusai Ujung, Pekanbaru, Indonesia

²Sekolah Tinggi Ilmu Farmasi Riau, Pekanbaru, Indonesia

³Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia

Received: 16 February 2023/Accepted: 9 November 2023

Abstract

Multi-resistance cases with antimalarial drugs had been developed in over the years. One of the ways of developing antimalarial drugs is to focus on searching for the potential antifolate inhibitors against Plasmodium sp. from synthetic or natural products. The aims of this research was to synthesis secondary amine-substituted eugenol compounds through the Mannich reaction for antimalarial evaluation using Plasmodium falciparum 3D7. The compounds were also evaluated on Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) as a protein target and the compounds’ drug-likeness properties were determined. Five secondary amine-substituted eugenol compounds (1a-e) were synthesized via substitution of the secondary amine i.e., pyrrolidine, piperidine, methyl piperidine, and morpholine in the eugenol structures. The plasmodium lactate dehydrogenase assay (pLDH) showed that 1a and 1c had good antimalarial effects against P. falciparum 3D7 with the IC₅₀s values of 0.89 mM and 0.62 mM, respectively. The molecular docking analysis showed that 1a and 1c had perfect interaction with PfDHFR-TS (PDB ID: 1J3I) with strong hydrogen bond interactions occurring with PfDHFR-TS protein. The eugenol derivatives 1a and 1c exerted CDOCKER binding energies of -6.1407 and -6.6536 kcal/mol, respectively. Based on this research, it was found that PfDHFR-TS is a plausible protein target for the synthesized secondary amine-substituted eugenol in P. falciparum infection. The substitution of a secondary amine group for eugenol significantly enhanced the antimalarial properties of the compounds. Thus, eugenol derivatives are potential compounds to be pursued to combat folate resistance in malarial infection.

Keywords: Antimalarial activities; eugenol; Mannich reaction; PfDHFR-TS; Plasmodium falciparum 3D7

Abstrak

Kes pelbagai rintangan dengan dadah antimalarial telah dibangunkan selama bertahun-tahun. Salah satu cara pembangunan dadah antimalaria adalah dengan memberi tumpuan kepada pencarian dadah antifolat melawan Plasmodium sp. yang berpotensi daripada bahan semula jadi dan sintetik. Matlamat penyelidikan ini adalah untuk mensintesis sebatian eugenol gantian-amina sekunder melalui tindak balas Mannich untuk penilaian antimalaria menggunakan Plasmodium falciparum 3D7. Sebatian tersebut juga dinilai pada Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) sebagai sasaran protein dan sifat keserupaan dadah untuk sebatian sintesis telah ditentukan. Lima sebatian eugenol gantian- amina sekunder (1a-e) telah disintesis melalui penggantian amina sekunder iaitu pirolidin, piperidin, metil piperidin dan morfolin dalam struktur eugenol. Ujian plasmodium laktat dehidrogenase (pLDH) menunjukkan bahawa 1a dan 1c mempunyai kesan antimalaria yang baik terhadap P. falciparum 3D7 dengan nilai IC₅₀ masing-masing adalah 0.89 µM dan 0.62 µM. Analisis dok molekul mendedahkan bahawa 1a dan 1c mempunyai interaksi sempurna dengan PfDHFR-TS (PDB ID: 1J3I) yang mana interaksi ikatan hidrogen yang kuat berlaku dengan protein PfDHFR-TS. Sebatian terbitan eugenol 1a dan 1c memberikan tenaga pengikatan CDOCKER masing-masing sebanyak-6.1407 dan -6.6536 kcal/mol. Berdasarkan penyelidikan ini, didapati bahawa PfDHFR-TS adalah sasaran protein yang munasabah untuk eugenol gantina-amina sekunder yang disintesis. Penggantian kumpulan amina sekunder ke atas eugenol telah meningkatkan sifat antimalaria dengan ketara. Oleh itu, derivatif eugenol adalah sebatian yang berpotensi dibangunkan untuk memerangi rintangan folat dalam jangkitan malaria.

Kata kunci: Aktiviti antimalaria; eugenol; Plasmodium falciparum 3D7; PfDHFR-TS; reaksi Mannich

REFERENCES

Abdou, A., Elmakssoudi, A., El Amrani, A., JamalEddine, J. & Dakir, M. 2021. Recent advances in chemical reactivity and biological activities of eugenol derivatives. Medicinal Chemistry Research 30(5): 1011-1030.

Arango, V., Domínguez, J.J., Cardona, W., Robledo, S.M., Muñoz, D.L., Figadere, B. & Sáez, J. 2012. Synthesis and leishmanicidal activity of quinoline-triclosan and quinoline-eugenol hybrids. Medicinal Chemistry Research 21(11): 3445-3454.

Ashley, E.A., Dhorda, M., Fairhurst, R.M., Amaratunga, C., Lim, P., Suon, S., Sreng, S., Anderson, J.M., Mao, S., Sam, B. & Sopha, C. 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine 371(5): 411-423.

Bachiega, T.F., De Sousa, J.P.B., Bastos, J.K. & Sforcin, J.M. 2012. Clove and eugenol in noncytotoxic concentrations exert immunomodulatory/anti-inflammatory action on cytokine production by murine macrophages. The Journal of Pharmacy and Pharmacology 64(4): 610-616.

Barboza, J.N., da Silva Maia Bezerra Filho, C., Silva, R.O., Medeiros, J.V.R. & de Sousa, D.P. 2018. An overview on the anti-inflammatory potential and antioxidant profile of eugenol. Oxidative Medicine and Cellular Longevity 2018: 3957262. 

Batista, R., de Jesus Silva Jr., A. & 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.

Biersack, B., Ahmed, K., Padhye, S. & Schobert, R. 2018, Recent developments concerning the application of the Mannich reaction for drug design. Expert Opinion on Drug Discovery 13(1): 39-49.

Clemente, C.M., Pineda, T., Yepes, L.M., Upegui, Y., Allemandi, D.A., Robledo, S.M. & Ravetti, S. 2022. Eugenol carbonate activity against Plasmodium falciparum, Leishmania braziliensis, and Trypanosoma cruzi. Archiv der Pharmazie 355(3): 1-11.

Ginsburg, H. & Deharo, E. 2011. A call for using natural compounds in the development of new antimalarial treatments – An introduction. Malaria Journal 10(1): 2011.

Hyde, J.E. 2002. Mechanisms of resistance of Plasmodium falciparum to antimalarial drugs. Microbes and Infection 4(2): 165-174.

Jia, C.Y., Li, J.Y., Hao, G.F. & Yang, G.F. 2020. A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discovery Today 768(25): 248-258.

Julianto, T.S., Jumina, J., Sastrohamidjojo, H. & Mustofa, M. 2018. Synthesis and heme polymerization inhibitory assay of a new arylamino alcohol derivative compound from methyl eugenol and aniline. AIP Conference Proceedings 2026: 1-7.

Kamatou, G.P., Vermaak, I. & Viljoen, A.M. 2012. Eugenol - From the remote Maluku Islands to the international market place: A review of a remarkable and versatile molecule. Molecules 17(6): 6953-6981.

Lane, T., Anantpadma, M., Freundlich, J.S., Davey, R.A., Madrid, P.B. & Ekins, S. 2019. The natural product eugenol is an inhibitor of the Ebola virus in vitro. Pharmaceutical Research 36(7): 1-11.

Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 46: 3-26.

Maximino, S.C., Dutra, J.A., Rodrigues, R.P., Gonçalves, R.C., Morais, P.A., Ventura, J.A., Schuenck, R.P., Júnior, V.L., Kitagawa, R.R. & Borges, W.S. 2020. Synthesis of eugenol derivatives and evaluation of their antifungal activity against Fusarium solani f. sp. piperis. Current Pharmaceutical Design 26(14): 1532-1542.

Mina, P.R., Kumar, S., Agarwal, K., Kumar, R., Pal, A., Tandon, S., Yadav, S.K., Yadav, S. & Darokar, M.P. 2021. 4-chloro eugenol interacts synergistically with artesunate against drug resistant P. falciparum inducing oxidative stress. Biomedicine and Pharmacotherapy 137: 111311.

Ministry of Health, Indonesia (MOH). 2018. Report on the Latest Situational Developments in Indonesia’s Malaria Control Programme. https://www.malaria.id/laporan (Accessed 1 December 2022).

Pereira, R.B., Pinto, N.F.S., Fernandes, M.J.G., Vieira, T.F., Rodrigues, A.R.O., Pereira, D.M., Sousa, S.F., Castanheira, E.M.S., Gil Fortes, A. & Gonçalves, M.S.T. 2021. Amino alcohols from eugenol as potential semisynthetic insecticides: Chemical, biological, and computational insights. Molecules 26(21): 1-20.

Pontes, K.A.O., Silva, L.S., Santos, E.C., Pinheiro, A.S., Teixeira, D.E., Peruchetti, D.B., Silva-Aguiar, R.P., Wendt, C.H.C., Miranda, K.R., Coelho-de-Souza, A.N., Leal-Cardoso, J.H., Caruso-Neves, C. & Pinheiro, A.A.S. 2021. Eugenol disrupts Plasmodium falciparum intracellular development during the erythrocytic cycle and protects against cerebral malaria. Biochimica et Biophysica Acta 1865(3): 129813.

Rieckmann, K.H., Sax, L.J., Campbell, G.H., Mrema, J.E. 1978. Drug sensitivity of plasmodium falciparum. An in vitro microtechnique. The Lancet 311(8054): 22-23.

Shibeshi, M.A., Kifle, Z.D. & Atnafie, S.A. 2020. Antimalarial drug resistance and novel targets for antimalarial drug discovery. Infection and Drug Resistance 13: 4047-4060.

Silva, C.G., Yudice, E.D.C., Campini, P.A.L. & Rosa, D.S. 2021. The performance evaluation of Eugenol and Linalool microencapsulated by PLA on their activities against pathogenic bacteria. Materials Today Chemistry 21: 100493.

Suwito, H., Jumina, Mustofa, Pudjiastuti, P., Fanani, M.Z., Kimata-Ariga, Y., Katahira, R., Kawakami, T., Fujiwara, T., Hase, T., Sirat, H.M. & Puspaningsih, N.N.T. 2014. Design and synthesis of chalcone derivatives as inhibitors of the ferredoxin - Ferredoxin-NADP+ reductase interaction of Plasmodium falciparum: Pursuing new antimalarial agents. Molecules 19(12): 21473-21488.

Syahri, J., Nasution, H., Nurohmah, B.A., Purwono, B. & Yuanita, E. 2020. Novel aminoalkylated chalcone: Synthesis, biological evaluation, and docking simulation as potent antimalarial agents. Journal of Applied Pharmaceutical Science 10(6): 001-005.

Syahri, J., Yuanita, E., Nurohmah, B.A., Armunanto, R. & Purwono, B. 2017. Chalcone analogue as potent anti-malarial compounds against Plasmodium falciparum: Synthesis, biological evaluation, and docking simulation study. Asian Pacific Journal of Tropical Biomedicine 7(8): 675-679.

World Health Organization. 2021. World Malaria Report, 2021. Geneva, Switzerland: WHO Press.

Xiong, G., Wu, Z., Yi, J., Fu, L., Yang, Z., Hsieh, C., Yin, M., Zeng, X., Wu, C., Lu, A., Chen, X., Hou, T. & Cao, D. 2021. ADMETlab 2.0: 770 an integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Research 49(771): w5-w14.

Yuthavong, Y., Yuvaniyama, J., Chitnumsub, P., Vanichtanankul, J., Chusacultanachai, S., Tarnchompoo, B., Vilaivan, T. & Kamchonwongpaisan, S. 2005. Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: Structural basis for antifolate resistance and development of effective inhibitors. Parasitology 130(3): 249-259.

Zari, A.T., Zari, T.A. & Hakeem, K.R. 2021. Anticancer properties of eugenol: A review. Molecules 26(23): 7407.

*Corresponding author; email: jsyachri@umri.ac.id