Synthesis, antitumor testing and molecular modeling study of some new 6-substituted amido, azo or thioureido-quinazolin-4(3H)-ones.

Autor: Sabry MA; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt. Electronic address: mohamedas1992@yahoo.com., Ewida HA; Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt., Hassan GS; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt., Ghaly MA; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt., El-Subbagh HI; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt. Electronic address: subbagh@yahoo.com.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2019 Jul; Vol. 88, pp. 102923. Date of Electronic Publication: 2019 Apr 10.
DOI: 10.1016/j.bioorg.2019.102923
Abstrakt: A new series of 6-substituted amido, azo or thioureido-quinazolin-4(3H)-one was synthesized and tested for their in-vitro antitumor activity. Compounds 21, 53 and 60 showed broad spectrum antitumor activity with average IC 50 values of 6.7, 7.6 and 9.1 μM, respectively compared with methotrexate (1, IC 50 19.26 μM). As an attempt to reveal the mechanism of the antitumor potency, cell cycle analysis and DHFR inhibition were performed. Compounds 59 and 61 induced their cytotoxicity in Hela (IC 50 10.6 μM) and HCT-116 (IC 50 15.5 μM) cell lines, respectively through Pre-G1 apoptosis, inhibiting cell growth at G2-M phase. Compounds 29, 33, 59 and 61 showed DHFR inhibitory potency at IC 50 0.2, 0.2, 0.3 and 0.3 μM, respectively. The active DHFR inhibitors showed high affinity binding toward the amino acid residues Thr56, Ser59 and Ser118. The active compounds obeyed Lipinski's rule of five and could be used as template model for further optimization.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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