Design, synthesis and in silico studies of new quinazolinone derivatives as antitumor PARP-1 inhibitors.

Autor: Ramadan SK; Department of Chemistry, Faculty of Science, Ain Shams University Abbassia 11566 Cairo Egypt elsayedam@sci.asu.edu.eg., Elrazaz EZ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University Abbassia 11566 Cairo Egypt khaled.abouzid@pharma.asu.edu.eg., Abouzid KAM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University Abbassia 11566 Cairo Egypt khaled.abouzid@pharma.asu.edu.eg.; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City Sadat City Egypt., El-Naggar AM; Department of Chemistry, Faculty of Science, Ain Shams University Abbassia 11566 Cairo Egypt elsayedam@sci.asu.edu.eg.
Jazyk: angličtina
Zdroj: RSC advances [RSC Adv] 2020 Aug 10; Vol. 10 (49), pp. 29475-29492. Date of Electronic Publication: 2020 Aug 10 (Print Publication: 2020).
DOI: 10.1039/d0ra05943a
Abstrakt: Herein, we report an eco-friendly synthesis of a new series of quinazolinone-based derivatives as potential PARP-1 inhibitors. The 4-quinazolinone scaffold was utilized as a bioisostere to the phthalazinone core of the reference compound Olaparib. Most of the synthesized compounds displayed appreciable inhibitory activity against PARP-1. Compound 12c showed inhibitory activity at IC 50 = 30.38 nM comparable to Olaparib, which has IC 50 = 27.89 nM. Cell cycle analysis was performed for compounds 12a and 12c, and both exhibited cell growth arrest at G2/M phase in the MCF-7 cell line. In addition, both compounds increased the programmed apoptosis compared to the control. Furthermore, molecular docking of the final compounds into the PARP-1 active site was executed to explore their probable binding modes. Also, a computational QSAR and in silico ADMET study was performed. The results of this study revealed that some of the newly synthesized compounds could serve as a new framework to discover new PARP-1 inhibitors with anti-cancer activity.
Competing Interests: The authors declare no conflict of interest, financial or otherwise.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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