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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