Sains Malaysiana 53(8)(2024): 1901-1912

http://doi.org/10.17576/jsm-2024-5308-14

Sintesis, Aktiviti Antimalaria dan Pendekatan Dinamik Molekul Kompleks Logam Salofen

 (Synthesis, Antimalarial Activity, and Molecular Dynamic Approaches of Salophen Metal Complexes)

  AMATUL HAMIZAH ALI¹, NUR HAFIZAH MUKHTAR¹, NG YEE LING², NUR AQILAH ZAHIRAH NORAZMI¹, HANI KARTINI AGUSTAR³, LAU YEE LING², NURUL HUDA ABD KARIM¹, SITI FAIRUS MOHD YUSOFF¹, MOSTAFA YOUSEFZADEH BORZEHANDANI^4,5 & NURUL IZZATY HASSAN^1,*

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

²Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia

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

⁴Integrated Chemical BioPhysics Research, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang,Selangor, Malaysia

⁵Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

Diserahkan: 14 Disember 2023/Diterima: 14 Jun 2024

Abstrak

Malaria masih merupakan salah satu penyakit berjangkit yang utama di kawasan beriklim tropika. Pelbagai ubat antimalaria telah diperkenalkan sebelum ini seperti klorokuina, primakuina dan artemisinin. Namun, keberkesanan ubat antimalaria menjadi rumit disebabkan oleh penyebaran parasit Plasmodium yang ada kerintangan terhadap ubat sedia ada. Oleh demikian, penerokaan kompleks logam salofen berasaskan ligan bes Schiff yang berpotensi sebagai agen antimalaria dijalankan. Empat ligan berasaskan salofen a-d dan lapan kompleks logam salofen 1a-4a dan 1b-4b telah disintesis melalui tindak balas kondensasi bes Schiff. Aktiviti antimalaria sebatian ini telah diuji dengan asai Plasmodium laktat dehidrogenase terhadap Plasmodium falciparum 3D7 yang menunjukkan bahawa 1a, 3a dan 4b masing-masing (IC₅₀ = 14.74, 19.38 dan 12.13 µM) mempunyai kesan perencatan aktif terhadap parasit secara in vitro. Analisis dok molekul mendedahkan bahawa sebatian 1a, 3a dan 4b menunjukkan nilai pengikatan yang baik pada protein PfDHFR-TS iaitu nilai masing-masing adalah -9.7, -8.9 dan -9.5 kcal. mol^-1. Tambahan pula, simulasi dinamik molekul mendedahkan bahawa sebatian 1a dan 3a ditempatkan di dalam poket reseptor protein dengan sebatian dikelilingi oleh beberapa permukaan berpolar. Bagaimanapun, sebatian 4b membentuk sistem kompleks reseptor-ligan dengan konformasi yang paling stabil apabila kompleks diletakkan di dalam poket reseptor hidrofobik. Oleh itu, PfDHFR-TS dianggap sebagai sasaran protein parasit yang khusus untuk kompleks logam salofen. Kesimpulannya, kompleks logam salofen didapati mempunyai potensi tinggi untuk dibangunkan sebagai agen antimalaria dan mampu menjadi struktur templat kepada pembentukan ubat antimalaria bagi melawan kes kerintangan.

Kata kunci: Aktiviti antimalaria; dok molekul; dinamik molekul; kompleks logam salofen; PfDHFR-TS

Abstract

Malaria is still one of the main infectious diseases in tropical climates. Various antimalarial drugs have been introduced before, such as chloroquine, primaquine, and artemisinin. However, the effectiveness of antimalarial drugs is complicated by the spread of Plasmodium parasites’s resistance. This study was carried out to explore metal complexes based on Schiff base ligands with good potential as antimalarial agents. Four salophen-based ligands a-d, and eight salophen metal complexes 1a-4a and 1b-4b were synthesized via Schiff base condensation reaction. Antimalarial properties of these compounds were investigated by plasmodium lactate dehydrogenase assay against Plasmodium falciparum 3D7, which showed that 1a, 3a, and 4bpossessed active parasite inhibitory effect in vitro study (IC₅₀: 14.74, 19.38, and 12.13 µM, respectively). Molecular docking analysis showed that compounds 1a, 3a, and 4b showed good binding affinity values, i.e. -9.7, -8.9, and -9.5 kcal/mol on PfDHFR-TS. Furthermore, the molecular simulations showed that 1a and 3a accommodated in the receptor’s pocket where some polar surfaces surrounded the compounds. However, 4b built the highest conformational stable receptor-ligand complex system when positioned in the receptor’s hydrophobic pocket. Thus, PfDHFR-TS is a specific parasite protein target for the salophen metal complex. In conclusion, this study found that the salophen metal complex has a high potential to be developed as an antimalarial agent and can be a template structure for forming antimalarial drugs to fight resistance cases.

Keywords: Antimalarial activities; molecular docking; molecular dynamics; PfDHFR-TS; salophen metal complexes

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*Pengarang untuk surat-menyurat; email: drizz@ukm.edu.my