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

Pouria Shirvani; Neda Fayyazi; Siska Van Belle; Zeger Debyser; Frauke Christ; Lotfollah Saghaie; Afshin Fassihi

doi:10.1016/j.bmcl.2022.128784

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. Epub 2022 May 13.

Authors

Pouria Shirvani¹, Neda Fayyazi², Siska Van Belle³, Zeger Debyser³, Frauke Christ³, Lotfollah Saghaie¹, Afshin Fassihi⁴

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Cell Proliferation
Humans
Indoles* / chemistry
Indoles* / pharmacology
MCF-7 Cells
Molecular Docking Simulation
Oxindoles / pharmacology
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Pyridones / chemistry
Pyridones / pharmacology
Structure-Activity Relationship
fms-Like Tyrosine Kinase 3 / antagonists & inhibitors
fms-Like Tyrosine Kinase 3 / metabolism

Substances

Antineoplastic Agents
Indoles
Oxindoles
Protein Kinase Inhibitors
Pyridones
indolin-2-one
fms-Like Tyrosine Kinase 3