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Sains Malaysiana 54(1)(2025): 199-210
http://doi.org/10.17576/jsm-2025-5401-16
Benzalhydantoin Derivative-Based Inhibitors
of Eight Receptor Tyrosine Kinases: Synthesis, in-vitro and in-silico Study
(Perencatan Berasaskan Terbitan Benzalhidantoin bagi Lapan Reseptor Tirosina Kinase: Kajian Sintesis, in-vitro dan in-silico)
MUHAMMAD
NAUFAL1, IKA WIANI HIDAYAT1, ELVIRA HERMAWATI2,
YANA MAOLANA SYAH2 & JAMALUDIN AL-ANSHORI1,*
1Department of Chemistry, Faculty of
Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang km.21, Jatinangor, 45363, Indonesia
Received: 11 July
2024/Accepted: 31 October 2024
Abstract
Some
hydantoin derivatives have been explored for their potential as anticancer
agents by inhibiting receptor tyrosine kinases (RTKs). Benzalhydantoin derivatives were obtained from a two-step reaction: condensation and alkylation
reaction. The benzalhydantoin activities were
obtained from the enzymatic assay, while the molecular interaction was
simulated with molecular docking. Five known compounds (5-9) and
two new benzalhydantoin derivatives 10-11 have
been synthesized from the appropriate precursors with 4-71% yields. The
structures of the compounds were determined mainly by NMR and mass spectral
data. From the chemical shift of the H-7’, the configuration of the products 5, 7, 9-11 were determined as Z-isomer, while 6 and 8 were defined as E-isomer. A
bioassay of the seven derivatives at 10 µM against eight receptor tyrosine
kinases (EGFR, HER2, HER4, IGF1R, InsR, VEGFR-2, and
PDGFR-α and -β) showed that 8 ((Z)-5-8:(Z)-5-(4'-hydroxy-3'methoxybenzylidene)imidazolidine-2,4-dione and 10:
(Z)-5-(4'-methoxybenzylidene) imidazolidine-2,4-dione were moderately active
against VEGFR-2, with inhibition of 46 and 56%, respectively. In addition, 8 was also active against PDGFR-α and -β, with a 57% inhibition.
Further evaluation of 8 and 10 using AutoDock4 showed their
binding energy interactions with VEGFR2 (PDB ID: 4AG8) around -6.96 and -7.32
kcal/mol, respectively. Thus, both compounds are potential candidates to be
optimized further as inhibitors of angiogenesis blood vessel development.
Keywords:
Anticancer; hydantoin; N-heterocyclic; PDGFRα and -β; tyrosine
kinase; VEGFR-2
Abstrak
Beberapa terbitan hidantoin telah diterokai potensinya sebagai agen antikanser dengan menghalang reseptor tirosina kinase (RTK). Terbitan benzalhidantoin diperoleh daripada tindak balas dua langkah: tindak balas pemeluwapan dan alkilasi. Aktiviti benzalhidantoin diperoleh daripada ujian enzim, manakala interaksi molekul disimulasikan dengan dok molekul. Lima sebatian yang diketahui (5-9)
dan dua terbitan benzalhidantoin baharu 10-11 telah disintesis daripada prekursor yang sesuai dengan hasil 4-71%. Struktur sebatian ditentukan terutamanya oleh NMR
dan data spektrum jisim. Daripada anjakan kimia H-7’, konfigurasi produk 5, 7, 9-11 ditentukan sebagai isomer Z, manakala 6 dan 8 ditakrifkan sebagai isomer E. Bioasai daripada tujuh terbitan pada 10 µM terhadap lapan reseptor tirosina kinase (EGFR,
HER2, HER4, IGF1R, InsR, VEGFR-2 dan PDGFR-α dan
-β) menunjukkan bahawa adalah sederhana aktif terhadap VEGFR-2, dengan perencatan masing-masing 46 dan 56%. Di samping itu, 8 juga aktif terhadap PDGFR-α dan -β dengan perencatan 57%. Penilaian lanjut 8 dan 10 menggunakan AutoDock4 menunjukkan interaksi tenaga pengikat mereka dengan VEGFR2 (PDB ID:
4AG8) masing-masing sekitar -6.96 dan -7.32 kcal/mol. Oleh itu, kedua-dua sebatian adalah calon yang berpotensi untuk dioptimumkan lagi sebagai perencat perkembangan saluran darah angiogenesis.
Kata kunci: Antikanser; hidantoin; N-heterosiklik;
PDGFRα dan -β; tirosine kinase; VEGFR-2
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