Novel 4-Anilinoquinazoline Derivatives as Potent Anticancer Agents: Design, Synthesis, Cytotoxic Activity, and Docking Study
Fatemeh Azmian Moghadam A , Sara Dabirian B , Mahtab Ghasemi Dogaheh A , Mohammad Mojabi A , Fatemeh Yousefbeyk C and Saeed Ghasemi
A D
A Department of Medicinal Chemistry, School of Pharmacy, Guilan University of Medical Sciences, Rasht 41491-73774, Iran.
B Department of Pharmaceutical Biotechnology, School of Pharmacy, Guilan University of Medical Sciences, Rasht 41491-73774, Iran.
C Department of Pharmacognosy, School of Pharmacy, Guilan University of Medical Sciences, Rasht 41491-73774, Iran.
D Corresponding author. Email: ghasemi_saeed@yahoo.com
Australian Journal of Chemistry 74(10) 730-739 https://doi.org/10.1071/CH21147
Submitted: 28 June 2021 Accepted: 23 September 2021 Published: 22 October 2021
Abstract
The simultaneous inhibition of EGFR and VEGFR-2 is a promising method in cancer treatment. In the present work, several 4-anilinoquinazoline derivatives encompassing different substitutions at the C-4 and C-7 positions of a quinazoline core were designed, synthesised, and evaluated for their cytotoxicity on A431, HUVEC, and HU02 cell lines. Docking studies were carried out to test the interactions of all synthesised compounds with EGFR and VEGFR-2. Furthermore, a wound healing assay was done for the investigation of cell migration. The most potent compound was 8l followed by the compounds 8i and 8j which showed better cytotoxic activities on A431 and HUVEC cell lines than the standard (Vandetanib). The compounds 8f and 8a represented the best docking energies of 8.99 and 9.35 kcal mol−1 for EGFR and VEGFR, respectively. Moreover, molecular docking studies exhibited that compound 8l showed efficient binding affinity against both EGFR and VEGFR-2. It can bind to these receptors through the formation of essential hydrogen bonds between the quinazoline N1 atom and the Met796 backbone of EGFR and two hydrogen bonds with Cys919 and Thr916 of VEGFR-2 with energies of –7.99 and –7.85 kcal mol−1, respectively. In addition, this compound displayed the highest activity on cell migration and wound healing. Compound 8l with the highest cytotoxic activity can be considered a candidate for further investigation and structural optimisation as an antiproliferative agent.
Keywords: synthesis, anticancer activity, 4-anilinoquinazoline, molecular docking, wound healing, EGFR, VEGFR.
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