Mono- and Dihydrazones with a 6-Methyluracil Fragment: Synthesis, Cytotoxicity and Antioxidant Activity
摘要
Objective: This study aimed to design and synthesize a series of novel carboxylic acid mono- and dihydrazones incorporating a 6-methyluracil moiety and to evaluate their potential as new therapeutic agents through in silico and in vitro assessments. Methods: Dihydrazones derived from adipic, azelaic, and sebacic acid hydrazides were synthesized. Their drug likeness and biological activity profiles (including cytotoxicity, antioxidant activity, acute toxicity, and hematotoxicity) were first predicted in silico using the OCHEM expert system. The subsequent in vitro evaluations included cytotoxicity screening against HepG2, A549, MCF-7, and HCT-116 cancer cell lines, and antioxidant activity assays (FRAP, ABTS, and DPPH). Results and Discussion: In silico predictions indicated promising properties for the compounds. However, in vitro cytotoxicity screening showed that most synthesized hydrazones were inactive against the tested cancer cell lines. An exception was 6-methyl-5-[(2-phenylhydrazono)methyl]pyridine-2,4(1H,3H)-dione, which exhibited moderate selective activity against HCT-116 cells (IC50 = 71.75 ± 8.29 µM). In antioxidant assays, 3-{2-[(6-mеthyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methylene]hydrazinyl}benzoic acid demonstrated high activity, comparable to ascorbic acid, and was identified as a lead compound. Conclusions: The results confirm that hydrazones containing a 6-methyluracil fragment are promising candidates for drug development. The identified lead compound with potent antioxidant activity is a candidate for further in-depth investigation for potential therapeutic applications.