 |
 |
 |
 |
 |
 |
Sains Malaysiana 51(10)(2022):
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 PURWONO1,*
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
Received: 23 October
2021/Accepted: 12 May 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
REFERENCES
Adebayo, J.O., Tijjani, H., Adegunloye,
A.P., Ishola, A.A., Balogun, E.A. & Malomo, S.O. 2020. Enhancing the antimalarial activity
of artesunate. Parasitology Research 119(9):
2749-2764.
Aher, R.B., Wanare, G., Kawathekar, N., Kumar, R.R., Kaushik, N.K., Sahal, D. & Chauhan, V.S. 2011. Dibenzylideneacetone analogues as novel Plasmodium falciparum inhibitors. Bioorganic and Medicinal
Chemistry Letters 21(10): 3034-2036.
Batista,
R., Silva, A.J. Jr. & de Oliveira, A.B. 2009. Plant-derived antimalarial
agents: New leads and efficient phytomedicines. Part II. Non-alkaloidal natural
products. Molecules 14(8): 3037-3072.
Belete, T.M. 2020.
Recent progress in the development of new antimalarial drugs with novel
targets. Drug Design, Development
and Therapy 14: 3875-3889.
Charris, J.E., Monasterios,
M.C., Acosta, M.E., Rodríguez, M.A., Gamboa, N.D.,
Martínez, G.P., Rojas, H.R., Mijares, M.R. & De Sanctis, J.B. 2019.
Antimalarial, antiproliferative, and apoptotic activity of quinoline-chalcone
and quinoline-pyrazoline hybrids. A dual action. Medicinal Chemistry Research 28: 2050-2066.
Chugh, A., Kumar, A., Verma, A., Kumar, S. & Kumar, P. 2020. A review of
antimalarial activity of two or three nitrogen atoms containing heterocyclic
compounds. Medicinal Chemistry Research 29: 1723-1750.
Daina, A., Michielin, O. & Zoete, V.
2017. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of
small molecules. Scientific Report 7: 42717.
de Souza, J.E., do Nascimento, M.F.A., Borsodi, M.P.G., de Almeida, A.P., Rossi-Bergmann, B., de
Oliveira, A.B. & Costa, S.S. 2018. Leaves from the tree Poincianella pluviosa as a renewable source of antiplasmodial compounds against chloroquine-resistant Plasmodium falciparum. Journal of the Brazilian Chemical Society 29(6):
1318-1327.
Dong, J., Wang, N.N., Yao,
Z.J., Zhang, L., Cheng, Y., Ouyang, D., Lu, A.P. & Cao, D.S. 2018. ADMETlab: A platform for systematic ADMET evaluation based
on a comprehensively collected ADMET database. Journal of Cheminformatics 10(1): 29.
Ekawati, L., Purwono, B.
& Mardjan, M.I.D. 2020. Synthesis N-phenyl
pyrazoline from dibenzalacetone and heme polymerization inhibitory activity
(HPIA) assay. Key Engineering Materials 840: 245-250.
Ertl, P., Rohde, B. & Selzer, P. 2000. Fast
calculation of molecular polar surface area as a sum of fragment-based
contributions and its application to the prediction of drug transport
properties. Journal of Medicinal
Chemistry 43(20): 3714-3717.
Hadni, H. & Elhallaoui, M. 2019. Molecular docking and QSAR studies for
modeling the antimalarial activity of hybrids 4-anilinoquinoline-triazines
derivatives with the wild-type and mutant receptor pf-DHFR. Heliyon 5(8): e02357.
Han, Y., Zhang, J., Hu, C.Q., Zhang, X., Ma, B.
& Zhang, P. 2019. In silico ADME
and toxicity prediction of ceftazidime and its impurities. Frontiers in
Pharmacology 10: 434.
Hakkola, J., Hukkanen, J., Turpeinen, M. & Pelkonen, O. 2020. Inhibition and induction of CYP
enzymes in humans: An update. Archives
of Toxicology 94: 3671-3722.
Ibrahim, Z.Y., Uzairu, A., Shallangwa, G. & Abechi, S.
2020. Molecular docking studies, drug-likeness and in-silico ADMET prediction of some novel β-Amino alcohol
grafted 1,4,5-trisubstituted 1,2,3-triazoles derivatives as elevators of p53
protein levels. Scientific African 10: e00570.
Kalaria, P.N., Karad, S.C.
& Raval, D.K. 2018. A review on diverse
heterocyclic compounds as the privileged scaffolds in antimalarial drug discovery. European Journal of Medicinal Chemistry 158: 917-936.
Kumar, P., Choonara, Y.E. & Pillay, V.
2014. In silico affinity
profiling of neuroactive polyphenols for post-traumatic calpain inactivation: A
molecular docking and atomistic simulation sensitivity analysis. Molecules 20(1): 135-168.
Leroy, D. 2017. How to tackle antimalarial resistance? EMBO Molecular Medicine 9(2): 133-134.
Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J. 2001. Experimental and
computational approaches to estimate solubility and permeability in drug
discovery and development settings. Advanced
Drug Delivery Review 46(1-3): 3-26.
Manohar, S., Khan, A.I., Kandi, A.K., Raj, K.,
Sun, G., Yang, X., Molina, A.D.C., Wang, B. & Rawat, D.S. 2013. Synthesis,
antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin. Bioorganic and
Medicinal Chemistry Letters 23(1): 112-116.
Nauduri, D. & Reddy, G.B.S. 1998 Antibacterial and
antimycotics Part 1: Synthesis and activity of 2-Pyrazolines derivatives. Chemical
and Pharmaceutical Bulletin 46(8): 1254-1260.
Nigam, M., Atanassova,
M., Mishra, A.P., Pezzani, R., Devkota,
H.P., Plygun, S., Salehi, B., Setzer, W.N. &
Sharifi-Rad, J. 2019. Bioactive compounds and health benefits of Artemisia
species. Natural Product Communications 14(7): 1-17.
Pajouhesh, H. &
Lenz, G.R. 2005. Medicinal chemical properties of successful central nervous
system drugs. NeuroRx 2(4):
541-553.
Pandey, A.K., Sharma, S., Pandey, M., Alam, M.M., Shaquiquzzaman, M.
& Akhter, M. 2016. 4,5-Dihydrooxazole-pyrazoline hybrids: Synthesis and
their evaluation as potential antimalarial agents. European
Journal of Medicinal Chemistry 123: 476-486.
Purwono, B., Nurohmah, B.A., Fathurrohman,
P.Z. & Syahri, J. 2021. Some 2-arylbenzimidazole
derivatives as an antimalarial agent: Synthesis, activity assay, molecular
docking and pharmacological evaluation. Rasayan Journal of
Chemistry 14(1): 94-100.
Septiana, I., Purwono, B.,
Anwar, C., Nurohmah, B.A. & Syahri,
J. 2022. Synthesis and docking study of 2–Aryl-4,5-diphenyl-1H-imidazole
derivatives as lead compounds for antimalarial agent. Indonesian Journal of
Chemistry 22(05). https://doi.org/10.22146/ijc.67777
Sharma, N., Mohanakrishnan,
D. & Shard, A. 2012. Stilbene-chalcone hybrids: Design, synthesis, and
evaluation as a new class of antimalarial scaffolds that trigger cell death
through stage specific Apoptosis. Journal
of Medicinal Chemistry 55(1): 297-311.
Syahri, J., Nasution, H., Nurohmah, B.A., Purwono, B. & Yuanita, E. 2020a. Novel aminoalkylated chalcone:
Synthesis, biological evaluation, and docking simulation as potent antimalarial
agents. Journal of Applied Pharmaceutical
Science 10(6): 1-005.
Syahri, J., Nasution, H., Nurohmah, B.A., Purwono, B., Yuanita, E. & Hassan, N.I. 2020b. Design, synthesis and
biological evaluation of aminoalkylated chalcones as Tse, E.G., Korsik, M. & Todd, M.H. 2019. The past, present and future
of anti-malarial medicines. Malaria
Journal 18(1): 93.
Tyagi, R., Rosa, B.A. & Mitreva, M. 2019. Chapter 12 - Omics-driven knowledge-based
discovery of anthelmintic targets and drugs. In In Silico Drug Design: Repurposing Techniques and Methodologies, edited by
Kunal Roy. Academic Press. pp. 329-358.
Wang, Y.,
Huang, W., Chen, S., Chen, S.Q. & Wang, S.F. 2011.
Synthesis, structure and tyrosinase inhibition of natural phenols derivatives. Journal of Chinese Pharmaceutical Science 20: 235-244.
Wanare, G., Aher, R., Kawathekar, N., Ranian, R.,
Kaushik, N.K. & Sahal, D. 2010. Synthesis of
novel
World Health Organization (WHO). 2020. World
Malaria Report 2020: 20 Years of Global Progress and Challenges. Geneva.
License: CC BY-NC-SA 3.0 IGO.
Xiong, G., Wu, Z., Yi, J., Fu, L., Yang, Z., Hsieh,
C., Yin, M., Zeng, X., Wu, C., Lu, A., Chen, X., Hou, T. & Cao, D. 2021. ADMETlab 2.0: An integrated online
platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Research 49(W1): W5-W14.
Yuvaniyama, J., Chitnumsub, P., Kamchonwongpaisan,
S., Vanichtanankul, J., Sirawaraporn, W., Taylor, P., Taylor, P.,
Walkinshaw, M.D. & Yuthavong, Y.
2003. Insights into antifolate resistance from malarial DHFR-TS
structures. Nature Structural &
Molecular Biology 10(5): 357-365.
Zerroug, A., Belaidi, S., BenBrahim, I.,
Sinha, L. & Chtita, S. 2019. Virtual screening in
drug-likeness and structure/activity relationship of pyridazine derivatives as
anti-Alzheimer drugs. Journal of King Saud University-Science 31(4): 595-601.
*Corresponding author;
email: purwono.bambang@ugm.ac.id
|
|||
|
