2. Academic Validation
  3. Design, synthesis, in silico studies, and antiproliferative evaluations of novel indolin-2-one derivatives containing 3-hydroxy-4-pyridinone fragment

Design, synthesis, in silico studies, and antiproliferative evaluations of novel indolin-2-one derivatives containing 3-hydroxy-4-pyridinone fragment

  • Bioorg Med Chem Lett. 2022 Aug 15:70:128784. doi: 10.1016/j.bmcl.2022.128784.
Pouria Shirvani 1,  Neda Fayyazi 2,  Siska Van Belle 3,  Zeger Debyser 3,  Frauke Christ 3,  Lotfollah Saghaie 1,  Afshin Fassihi 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Science, Hezar Jerib, 817416-73461, Isfahan, Iran.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Science, Hezar Jerib, 817416-73461, Isfahan, Iran; Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
  • 3 Department of Pharmacological and Pharmaceutical Sciences, Laboratory of Molecular Virology and Gene Therapy, KU Leuven, Belgium.
  • 4 Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Science, Hezar Jerib, 817416-73461, Isfahan, Iran. Electronic address: Fassihi@pharm.mui.ac.ir.
PMID: 35569690 DOI: 10.1016/j.bmcl.2022.128784
Abstract

Keeping in view the pharmacological properties of indolinones as promising scaffold as kinase inhibitors, herein, a novel series of 3-hydrazonoindolin-2-one derivatives bearing 3-hydroxy-4-pyridinone moiety were synthesized, studied by molecular docking, and fully characterized by spectroscopic techniques. All the prepared compounds were evaluated for their cytotoxicity attributes against a panel of tumor cell lines, including non-small cell lung Cancer (A549), breast carcinoma (MCF-7), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). They displayed moderate to promising antiproliferative effects toward A549 and MCF-7 cells but remarkable results against AML and CML. Especially, compound 10k was found to be more potent against AML (EC50 = 0.69 μM) compare to the Other halogen-substituted derivatives. FMS-like tyrosine kinase 3 (FLT3) is known to be expressed in AML Cancer cells. The molecular docking studies demonstrated that our prepared compounds were potentially bound to AML active site through essential H-bond and Other vital interactions with critical binding residues.

Keywords

Anticancer; FLT3; Hydroxypyridinone; Indolin-2-one; Molecular docking; c-Met.

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