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

Abstract

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 IC₅₀ = 30.38 nM comparable to Olaparib, which has IC₅₀ = 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.

Fig. 1. Chemical structures of the approved PARP-1 inhibitors (Rucaparib, Niraparib, and Talazoparib and Olaparib) and the target derivatives [(5a–c), (6a–c), (7a,b), (8a–c), (9a–c), (12a–c), and (13a–c)].

Scheme 1. Synthesis of compounds 3–7.

Scheme 2. Synthesis of compounds 8–9.

Scheme 3. Synthesis of compounds 11–13.

Fig. 2. Cell cycle analysis and apoptosis effect in the MCF-7 cell line when treated with compounds 12a and 12c.

Fig. 3. MCF-7 cell distribution upon treatment with compounds 12a and 12c.

Fig. 4. Percentage of cell death induced by compounds 12a and 12c in MCF-7 cells.

Fig. 5. Apoptosis induced in MCF-7 cells by compound 12a and 12c.

Fig. 6. 2D interaction diagram showing Olaparib (lead compound) docking pose interactions with the key amino acids in the PARP-1 active site.

Fig. 7. 2D interaction diagram of 7b in the active site of PARP-1 and 2D interaction diagram of 8a in the active site of PARP-1.

Fig. 8. 2D interaction diagram of 12a in the active site of PARP-1 and 3D interaction diagram of 12a in the active site of PARP-1.

Fig. 9. Predicted activity versus experimental activity (−log IC₅₀) values of the training set according to eqn (1) (r² = 0.754).

Fig. 10. ADMET plot for the newly synthesized compounds.