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 SYAHRI1,*, 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
Diserahkan:
16 Februari 2023/Diterima: 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
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*Pengarang untuk surat-menyurat; email: jsyachri@umri.ac.id
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