Design, Synthesis, and Biological Evaluation of N-Acyl-Hydrazone-Linked Quinazolinone Derivatives with Antioxidant, Antimicrobial, and Anticancer Potential

TL;DR

This paper describes the synthesis and testing of new compounds with potential antioxidant, antimicrobial, and anticancer properties.

Contribution

A green synthesis method for N-acyl-hydrazones with multiple biological activities is introduced and evaluated.

Findings

Compound 1c showed the highest antioxidant activity among the synthesized derivatives.

Compounds 1a and 1b were most effective against C. albicans and S. aureus.

Selected compounds showed selective anticancer effects with minimal toxicity to normal cells.

Abstract

Objectives: Combining two pharmacophores into one molecule with multiple applications presents interest in the field of medicinal chemistry. Quinazolinones are among privileged scaffolds due to their wide biological activities, whereas hydrazones are versatile linkers with pharmacological potential. Thus, this article focused on a green method for the synthesis of new N-acyl-hydrazones of 2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetohydrazide and the exploration of their biological potential. Methods: The novel N-acyl-hydrazones (1a–1f) were synthesized under microwave irradiation, using various substituted salicylaldehydes and benzaldehydes. The products were characterized by FT-IR, 1H-NMR, 13C-NMR, and HRMS. Their pharmacological profile was assessed by in silico methods and docking simulations. Biological evaluation included antioxidant, antimicrobial, and cytotoxic activities, as well as preliminary toxicity on Artemia franciscana. Results: Spectroscopic data indicated syn-E and anti-E isomers. Compound 1c showed the highest antioxidant activity. Antimicrobial assays indicated narrow-spectrum activity, with compounds 1a and 1b being most effective against C. albicans and S. aureus. Biofilm inhibition assays revealed that 1a and 1c interfered with microbial adhesion, highlighting their potential in combating biofilm-associated infections. Cytotoxicity tests on HT-29 and A431 cancer cell lines showed selective anticancer effects for compounds 1a–1d, with minimal toxicity on normal Vero cells, especially for 1b and 1d. Toxicity against Artemia franciscana correlated with in vitro cytotoxicity data, revealing low lethality for all N-acyl-hydrazones. Docking studies indicate that the antibacterial activity may involve inhibition of S. aureus DNA gyrase B, whereas the cytotoxic effects could be mediated by interaction with the EGFR kinase. Conclusions: These findings may increase the chances of identifying a lead compound in this class, supporting the further development of selected N-acyl-hydrazones and their pharmacological exploration.

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