Journal Article

Synthesis of α-Santonin Derivatives Linked to N -, S -, and O -Heterocycles via 1,2,3-Triazole-Linker: Investigation of Antimicrobial Effects

Tari, Kitti, Szekeres, András, Kovács, Adriána, Zupkó, István, Szakonyi, Zsolt, Le, Tam Minh, Boncz, Mária Fanni

2026

Overview

: Resistant pathogenic bacteria and fungi are a growing problem worldwide; therefore, the discovery of new active ingredients is an important challenge for which the functionalization of natural terpenes with biologically active heterocycles can provide a basis. To reach this goal, a series of 1,4-disubstituted-1,2,3-triazole conjugates was designed and synthesized starting from commercially available α-santonin. : The key azido derivative intermediate was prepared according to literature procedures via Michael addition between dehydrosantonin and the TMSN /AcOH/Et N system at its highly reactive -methylene- -lactone motif. Subsequently, the obtained azide was applied to regioselective Huisgen 1,3-dipolar cycloaddition reaction with a wide range of terminal alkynes bearing -, - and -heterocycles. These include pyridine, pyrimidine, purine, quinoline, indol, or coumarin to afford the sesquiterpene-heterocycle chimaeras. All triazole conjugates were screened for in vitro antiproliferative activity by MTT assay against HeLa, MDA-MB231, SiHa, MCF-7 and A2780 human cancer cell lines compared with fibroblast cells (NIH/3T3) to check their cytotoxicity and antimicrobial effects on two Gram-positive ( , ) pathogenic bacteria, two Gram-negative ( and ) pathogenic bacteria, and two yeasts ( and ). : The results indicated that most of the examined compounds expressed weak activity against human cell lines, while some of them showed moderate activity against (up to 99% inhibition at 100 µg/mL conc.), (up to 51% inhibition at 10 µg/mL conc.) and (up to 52% inhibition at 10 µg/mL conc.). : Further structural modification of the best, selective antibacterial and antifungal compounds may open the possibility to the development of effective natural sesquiterpene-based selective antimicrobial agents.

• Publisher: MDPI AG,Multidisciplinary Digital Publishing Institute (MDPI)
• Subject: Alkynes / antibacterial / antifungal / Antifungal agents / Antiinfectives and antibacterials / Antimicrobial activity / Antimicrobial agents / Azide / Bacteria / Biological activity / Cancer / Candida krusei / Cells / click reaction / Conjugates / Coumarin / Cycloaddition / Cytotoxicity / E coli / Escherichia coli / Fibroblasts / Fungicides / Gram-negative bacteria / Heterocyclic aromatic compounds / Michael addition / Pyrimidines / Quinoline / sesquiterpene / Terpenes / Triazoles / Tumor cell lines / α-santonin