Sains Malaysiana 49(11)(2020): 2667-2677

http://dx.doi.org/10.17576/jsm-2020-4911-06

Design, Synthesis and Biological Evaluation of Aminoalkylated Chalcones as Antimalarial Agent

(Reka Bentuk, Sintesis dan Penilaian Biologi ke atas Aminoteralkil Kalkon sebagai Agen Antimalaria)

JUFRIZAL SYAHRI¹*, HASMALINA NASUTION¹, BETA ACHROMI NUROHMAH², BAMBANG PURWONO², EMMY YUANITA³, NUR HANIS ZAKARIA⁴ & NURUL IZZATY HASSAN⁴

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

²Department of Chemistry, Universitas Gadjah Mada, Jalan Kaliurang Sekip Utara Bulaksumur 21, 55281, Yogyakarta, Indonesia

³Department of Chemistry, Universitas Mataram, Jalan Majapahit 62A, Mataram, Indonesia

⁴Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor Darul Ehsan, Malaysia

Received: 10 April 2020/Accepted: 28 May 2020

Abstract

Aminoalkylated chalcone compounds (4a-4c) have been designed using Quantitative Structure-Activity Relationship (QSAR) analysis, synthesized and evaluated for theirin vitro antimalarial activity. The best QSAR model obtained was log IC₅₀ = 705.132 (qC7) - 65.573 (qC3) - 24.845 (qC4) - 4.634 (qC13) - 220.479 and statistical analysis showed R² of 0.937, suggesting that the QSAR model was able to predict the actual antimalarial activity by 93.7% accuracy. The addition of secondary amines to the chalcone compounds was successfully carried out using the Mannich reaction, which was confirmed by spectroscopic analysis. The in vitro antimalarial activity of the synthesized compounds were screened against the 3D7 strain of Plasmodium falciparum (CQ sensitive). All of the compounds exhibited strong activity with IC₅₀ values ranging from 0.54 ± 0.649 to 1.12 ± 0.369 µM. The molecular docking studies investigated interactions of the prepared compounds to the binding site of wild-type Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (Pf-DHFR-TS) (PDB ID: IJ3I) and quadruple mutant Pf-DHFR-TS (PDB ID: IJ3K). Some hydrogen bond and π – π interactions were observed with the side chain of Ala16, Asp54, Cys15, Leu164, Tyr170, and Met55 in both the wild and mutant Pf-DHFR types. It has also been found that all the tested compounds were obeyed the Lipinski’s rule. This study proposed that compound 4b can be developed as the new lead of the antimalarial agent.

Keywords: Antimalarial; chalcone; Mannich reaction; molecular docking; QSAR

Abstrak

Sebatian aminoteralkil kalkon (4a-4c) telah direka bentuk menggunakan analisis Hubungan Struktur-Aktiviti Kuantitatif (QSAR) telah disintesis dan dinilai untuk aktiviti antimalaria secara in vitro. Model QSAR terbaik yang diperoleh adalah log IC₅₀ = 705.132 (qC7)-65.573 (qC3)-24.845 (qC4)-4.634 (qC13)-220.479 dan analisis statistik menunjukkan R² sebanyak 0.937, seterusnya mencadangkan bahawa model QSAR ini berupaya untuk meramalkan aktiviti antimalaria sebenar dengan ketepatan 93.7%. Penambahan amina sekunder telah dijalankan menggunakan tindak balas Mannich dan disahkan melalui analisis spektroskopi. Kesemua sebatian disaring menentang strain Klorokuina-sensitif (3D7) Plasmodium falciparum. Semua sebatian menunjukkan aktiviti baik dengan nilai IC₅₀ antara 0.54 ± 0.649 sehingga 1.12 ± 0.369 μM. Interaksi sebatian ini juga dikaji melalui kajian dok pada tapak pengikatan protein jenis liar Pf-DHFR-TS (PDB ID: IJ3I) dan mutan Pf-DHFR-TS (PDB ID: IJ3K). Ikatan hidrogen dan interaksi π-π sebatian dengan rantai sisi asid amino Ala16, Asp54, Cys15, Leu164, Tyr170 dan Met55 jelas diperhatikan pada kedua-dua protein tersebut. Sebatian yang dikaji ini juga didapati mematuhi peraturan Lipinski. Potensi aktiviti antimalaria yang ditunjukkan oleh sebatian 4b mampu dibangunkan sebagai sebatian utama.

Kata kunci: Antimalaria; kajian dok; kalkon; QSAR; tindak balas Mannich

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