Sains Malaysiana 51(10)(2022): 3215-3236

http://doi.org/10.17576/jsm-2022-5110-09

Substituted 3-styryl-2-pyrazoline Derivatives as an Antimalaria: Synthesis, in vitro Assay, Molecular Docking, Druglikeness Analysis, and ADMET Prediction

(Penggantian Terbitan 3-styryl-2-pyrazoline sebagai Antimalaria: Sintesis, Asai in vitro, Dok Molekul, Analisis Keserupaan Dadah dan Ramalan ADMET)

LINDA EKAWATI¹, BETA ACHROMI NUROHMAH¹, JUFRIZAL SYAHRI² & BAMBANG PURWONO^1,*

¹Department of Chemistry, Faculty of Mathematics and Natural Science, Universitas Gadjah Mada, Jalan Kaliurang Sekip Utara Bulaksumur 21, Yogyakarta, 55281 Indonesia

²Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Muhammadiyah Riau, Jalan Tuanku Tambusai Ujung Nomor 1, Pekanbaru Indonesia

Diserahkan: 23 Oktober 2021/Diterima: 12 Mei 2022

Abstract

The synthesis, in vitro antimalarial assay, molecular docking, drug-likeness analysis, and ADMET prediction of substituted 3-styryl-2-pyrazoline derivatives as antimalaria have been conducted. The synthesis of N-phenyl (1a‒3a) and N-acetyl-substituted (1b‒3b) 3-styryl-2-pyrazolines was carried out using dibenzalacetone derivatives and hydrazine hydrate or phenylhydrazine. An in vitro antimalarial assay was conducted against the chloroquine-sensitive Plasmodium falciparum 3D7 strain, while molecular docking was performed toward the crystal protein of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) (PDB ID: 1J3I). Furthermore, the prediction of drug-like properties was determined by assessing Lipinski’s rules, and the pharmacokinetic parameters were also studied in-silico, including absorption, distribution, metabolism, excretion, and toxicity (ADMET). The in vitro assay showed that 3a (IC₅₀ 0.101 µM) has excellent antimalarial activity, followed by 2a (0.177 µM), and 1b (0.258 µM). Molecular docking has supported the in vitro assay by showing the lowest CDOCKER energy for 3a (‒56.316 kcal/mol), then 2a (‒51.2603 kcal/mol), and 1b (‒48.8774 kcal/mol). The drug-like properties showed that all of the prepared compounds were acceptable based on Lipinski’s rules and predicted to be potentially orally bioavailable. The ADMET analysis provided information that 3a and 2a could be proposed as the best lead antimalarial drugs with further modification to reduce the lipophilicity and toxicity properties.

Keywords: ADMET; antimalarial; dibenzalacetone; molecular docking; pyrazoline

Abstrak

Sintesis, asai antimalaria in vitro, dok molekul, analisis keserupaan dadah dan ramalan ADMET bagi terbitan 3-styryl-2-pyrazoline yang digantikan sebagai antimalaria telah dijalankan. Sintesis N-fenil (1a‒3a) dan N-acetyl-substituted (1b‒3b) 3-styryl-2-pyrazolines telah dijalankan menggunakan terbitan dibenzalaseton dan hidrazina hidrat atau fenilhidrazina. Ujian antimalaria in vitro telah dijalankan terhadap strain Plasmodium falciparum 3D7 yang sensitif terhadap klorokuin, manakala dok molekul dilakukan ke arah protein kristal Plasmodium falciparum dihidrofolat reduktase-timidilat sintase (PfDHFR-TS) (PDB ID: 1J3I). Tambahan pula, ramalan sifat seperti ubat ditentukan dengan menilai peraturan Lipinski dan parameter farmakokinetik juga dikaji secara in siliko, termasuk penyerapan, pengedaran, metabolisme, perkumuhan dan ketoksikan (ADMET). Ujian in vitro menunjukkan bahawa 3a (IC₅₀ 0.101 µM) mempunyai aktiviti antimalaria yang sangat baik, diikuti oleh 2a (0.177 µM), dan 1b (0.258 µM). Dok molekul telah menyokong ujian in vitro dengan menunjukkan tenaga CDOCKER terendah untuk 3a (‒56.316 kcal/mol), kemudian 2a (‒51.2603 kcal/mol) dan 1b (‒48.8774 kcal/mol). Sifat keserupaan dadah menunjukkan bahawa semua sebatian yang disediakan boleh diterima berdasarkan peraturan Lipinski dan diramalkan berpotensi bio tersedia secara oral. Analisis ADMET memberikan maklumat bahawa 3a dan 2a boleh dicadangkan sebagai ubat antimalaria terbaik dengan pengubahsuaian selanjutnya untuk mengurangkan sifat lipofilis dan ketoksikan.

Kata kunci: ADMET; antimalaria; dibenzalaseton; dok molekul; pirazolin

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^*Pengarang untuk surat-menyurat; email: purwono.bambang@ugm.ac.id