Exploration of the VEGFR-2 Inhibition Activity of Phthalazine Derivatives: Design, Synthesis, Cytotoxicity, ADMET, Molecular Docking and Dynamic Simulation

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Jul 9

PMID 38979468

Authors

Hatem Hussein Bayoumi

Mohamed-Kamal Ibrahim

Mohammed A Dahab

Fathalla Khedr

Khaled El-Adl

Affiliations

Soon will be listed here.

Abstract

Novel phthalazine derivatives were designed, synthesized and evaluated against Hep G2 and MCF-7 as VEGFR-2 inhibitors. In particular, compounds 2g and 4a were found to be the most potent derivatives among all the tested compounds against MCF-7 and Hep G2 cancer cell lines with IC values of 0.15 and 0.12 and 0.18 and 0.09 μM respectively. Moreover, compounds 3a, 3c, 5a and 5b displayed excellent anticancer activities against MCF-7 and Hep G2 cancer cell lines. The highly active derivatives 2g, 3a, 3c, 4a, 5a and 5b were evaluated for their inhibitory activities against VEGFR-2. The tested compounds displayed high to low inhibitory activities with IC values ranging from 0.148 to 0.892 μM. Among them, compounds 2g and 4a were found to be the most potent derivatives that inhibited VEGFR-2 with IC values of 0.148 and 0.196 μM respectively. Compounds 3a, 3c, 5a and 5b exhibited good activity with IC values of 0.375, 0.892, 0.548 and 0.331 μM respectively. Sorafenib was used as a reference drug in this study. Molecular modeling studies were carried out for all compounds against the VEGFR-2 active site. The data obtained from biological testing highly correlated with those obtained from molecular modeling studies. Moreover, MD simulation results indicated the stability of ligand-target interaction. Furthermore, our derivatives 2g and 4a showed a good calculated ADMET profile.

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