Synthesis,biological evaluation and molecular modeling study of [1,2,4]-Triazolo[4,3-c]quinazolines: New class of EGFR-TK inhibitors |
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| Institution: | 1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and Technology, Egypt;1. Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt;1. Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo 113701, Egypt;2. Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, P.O. Box 11795, Ain Helwan, Cairo, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt;3. Regional Center of Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, P.O. Box 33516, Kafrelsheikh, Egypt;5. Department of Applied Organic Chemistry, National Research Centre, P.O. Box 12622, Dokki, Giza, Egypt |
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| Abstract: | New series of triazolo4,3-c]quinazolines were designed, synthesized and their structures were elucidated using different spectroscopic techniques. They were evaluated for their in vitro antitumor activity against HepG2, MCF-7, PC-3, HCT-116 and HeLa cancer cell lines using MTT assay. It was found that all compounds showed variable in vitro cytotoxicity. Distinct derivatives exhibited higher inhibitory activity against the tested cell lines with IC50 values ranging from 8.27 to 10.68 µM using DOX standard (IC50 = 4.17–8.87 µM). In vitro epidermal growth factor receptor (EGFR) inhibition assay was performed. Results revealed that compounds 8, 19 and 21 exhibited worthy EGFR inhibitory activity with IC50 values ranging from 0.69 to1.8 µM in comparison to the reference drug Gefitinib (IC50 = 1.74 µM). Further investigation showed that active candidates 8, 19 and 21 caused cell cycle arrest at the G2/M phase, and interestingly, induced cell death by apoptosis of MCF-7 cells cumulatively with 7.14, 17.52 and 24.88%, respectively, compared with DOX as a positive reference (29.09%). Molecular modeling studies, including docking, flexible alignment and surface mapping, were also done to study the interaction mode into the active site of EGFR kinase domain. There was a good agreement between modeling results and biological results. ADMET analysis and parameters of Lipinski’s rule of five were calculated. Pharmacokinetic parameters showed that compound 8 had more expected penetration through blood brain barrier than Gefitinib. The present work displayed new triazoloquinazoline based derivatives with potent cytotoxicity and promising EGFR inhibition activity. |
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| Keywords: | Triazoloquinazoline Synthesis Antitumor activity EGFR assay Apoptosis Molecular docking studies |
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