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Sains Malaysiana 53(12)(2024): 3307-3318
http://doi.org/10.17576/jsm-2024-5312-14
Aktiviti Antimalaria dan Skizontisida Sebatian Analog 4-aminokuinolina-pirano[2,3-c]pirazol terhadap Plasmodium knowlesi A1H1 dan Analisis Dok Molekul
(Antimalarial and Schizonticidal Activities of 4-aminoquinoline-pyrano[2,3-c]pyrazole Analogs against Plasmodium knowlesi A1H1 and Molecular Docking
Analysis)
SITI NURFATEHAH KAMAL1,#, AMATUL HAMIZAH ALI2,#, NG YEE
LING3, MOHD ASYRAF SHAMSUDIN2, SITI NUR HIDAYAH JAMIL2,
HANI KARTINI AGUSTAR1, NURUL IZZATY HASSAN2, MOHD RIDZUAN
MOHD ABD RAZAK4, LAU YEE LING3 & JALIFAH LATIP2,*
1Jabatan Sains Bumi dan Alam Sekitar, Fakulti Sains dan Teknologi, Universiti Kebangsaan Malaysia,
43600 UKM Bangi, Selangor, Malaysia
Received: 4 December 2023/Accepted:
7 October 2024
#These authors contributed
equally
Abstrak
Kemunculan jangkitan zoonosis Plasmodium knowlesi dan perkembangan kerintangan parasit terhadap ubat antimalaria sedia ada memacu penyelidikan dinamik bagi meneroka dan mencari agen antimalaria yang baharu. Penghibridan farmakoforik ialah suatu strategi gabungan dua sebatian yang berlainan farmakofor untuk mencegah kerintangan parasit terhadap ubat antimalaria sedia ada dan mengurangkan kesan sampingan ubat antimalaria. Lima terbitan kuinolina telah menunjukkan aktiviti antimalaria terhadap parasit malaria iaitu kesan analog 4-aminokuinolina-pirano[2,3-c]pirazol terhadap strain Plasmodium falciparum 3D7 dan
K1. Oleh itu, objektif kajian ini adalah untuk menilai aktiviti antimalaria dan skizontisida analog 4-aminokuinolina-pirano[2,3-c]pirazol terhadap strain parasit zoonotik iaitu Plasmodium knowlesi A1H1 yang telah diadaptasi dalam darah manusia. Kesemua analog kuinolina telah diuji secara in vitro terhadap P. knowlesi A1H1 menggunakan plasmodium laktat dehidrogenase (pLDH) dan ujian pematangan skizon (SMA). Analisis dok molekul analog kuinolina turut dilakukan pada satu protein sasaran, Plasmodium sp. pengangkut rintang-klorokuina (PfCRT)
yang bertujuan untuk memahami kemungkinan potensi protein ini sebagai sasaran antimalaria analog kuinolina tersebut. Hasil yang diperoleh menunjukkan bahawa analog 2 dan 5 (EC50 = 0.15-0.16
µM) mempunyai kesan antiplasmodium yang poten terhadap P. knowlesi. Tambahan lagi, analog 2 dan 5 mempunyai kesan skizontisida yang poten terhadap P. knowlesi berbanding sebatian analog yang lain. Suatu kajian menggunakan analisis dok in silico menunjukkan bahawa analog 2 dan 5 mempunyai konformasi pengikatan sempurna dalam tapak domain transmembran-1 PfCRT dengan masing-masing mempunyai nilai afiniti pengikatan -9.1 kcal/mol.
Hasil kajian ini mencadangkan bahawa analog 2 dan 5 menghalang pertumbuhan parasit zoonotik P. knowlesi dan menyasarkan protein parasit PfCRT sebagai sasaran molekul berpotensi.
Kata kunci: Aktiviti antiplasmodium; dok molekul; malaria; Plasmodium knowlesi; skizontisid;
4-aminokuinolina-pirano[2,3-c]pirazol
Abstract
The emergence of the zoonotic
infection Plasmodium knowlesi, as well as the
development of parasite resistance to current antimalarial drugs, is driving
the dynamic research into a new antimalarial agent. Pharmacophoric
hybridization is a combination strategy to prevent drug resistance and
drug-drug interactions. Five quinoline derivatives namely
4-aminoquinoline-pyrano[2,3-c]pyrazole analogues showed potent antimalarial activities against Plasmodium
falciparum strains 3D7 and K1. The objective of this study is to evaluate
the antimalarial and schizonticidal activities of
4-aminoquinoline-pyrano[2,3-c]pyrazole analogs against the human-adapted zoonotic parasite
strain, Plasmodium knowlesi A1H1. All
quinoline analogs were tested in vitro against P. knowlesi A1H1 using the plasmodium lactate
dehydrogenase (pLDH) and schizont maturation assays
(SMA). Molecular docking analysis of these quinoline analogs on a protein target, Plasmodium sp. chloroquine resistant transporter (PfCRT), was performed to understand the possible
antimalarial target of these quinoline analogs. The
results showed that analogs 2 and 5 have potent antiplasmodial effects against P. knowlesi (EC50 = 0.15-0.16 µM). Furthermore,
compared to all test compounds, analogs 2 and 5 had good schizonticidal effects. A study using in
silico docking showed that analogs 2 and 5 had perfect binding conformations in the PfCRT’s transmembrane domain 1 site, with binding affinities of -9.1 kcal/mol,
respectively. The results of this study suggested that quinoline analogs 2 and 5 inhibited the growth of the zoonotic
parasite P. knowlesi and targeted the parasite
protein PfCRT as a potential molecular target.
Keywords: Antiplasmodial activities; malaria; molecular docking; Plasmodium knowlesi; schizonticide; 4-aminoquinoline-pyrano[2,3-c]pyrazole
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