Potent Antimicrobial Azoles: Synthesis, In Vitro and In Silico Study

• Published in: Antibiotics (Basel) 2024-11, Vol.13 (11), p.1044
• Main Authors: Özdemir, Zeynep, Zenni, Yaren Nur, Karakurt, Arzu, Sari, Suat, Saraç, Selma, Akdağ, Mevlüt, Merde, İrem Bozbey, Kart, Didem, Venanzoni, Roberto, Flores, Giancarlo Angeles, Angelini, Paola, Kabier, Muzammil, Mathew, Bijo, Carradori, Simone
• Format: Article
• Language: English
• Subjects: (arylalkyl)azole; Antibacterial activity; Antibacterial agents; Antifungal activity; Antimicrobial activity; Antimicrobial agents; Azoles; Azoles (Class of compounds); Bacteria; Carbon; Chemotherapy; Ciprofloxacin; Coliforms; dermatophytes; E coli; Effectiveness; Fungi; Fungicides; Gram-negative bacteria; Gram-positive bacteria; Griseofulvin; Heterocyclic compounds; imidazole; Infections; Lanosterol; Minimum inhibitory concentration; Molecular docking; molecular modelling; Morbidity; Nitrogen; oxime ether; Production processes; Scaffolds; Sodium; Temperature-sensitive mutant; Testing
• ISSN: 2079-6382; 2079-6382
• DOI: 10.3390/antibiotics13111044

: The increase in fungal infections, both systemic and invasive, is a major source of morbidity and mortality, particularly among immunocompromised people such as cancer patients and organ transplant recipients. Because of their strong therapeutic activity and excellent safety profiles, azole antifungals are currently the most extensively used systemic antifungal drugs. Antibacterial properties of various topical antifungals, such as oxiconazole, which features oxime ether functionality, were discovered, indicating an exciting prospect in antimicrobial chemotherapy. : In this study, eleven new oxime ether derivatives with the azole scaffold ( - ) were synthesized and tested for their antimicrobial effects using the microdilution method to obtain broad-spectrum hits. : Although the title compounds showed limited efficacy against species, they proved highly effective against dermatophytes. Compounds and were the most potent derivatives against and , with minimum inhibitory concentration (MIC) values lower than those of the reference drug, griseofulvin. The MIC of and were 0.491 μg/mL and 0.619 μg/mL against (MIC of griseofulvin: 2.52 μg/mL). The compounds were also tested against Gram-positive and Gram-negative bacteria. Briefly, was the most active against and , with MIC values much better than that of ciprofloxacin (MIC of = 1.56 μg/mL and 1.23 μg/mL, MIC of ciprofloxacin = 31.49 and 125.99 μg/mL, respectively). Molecular docking suggested a good fit in the active site of fungal lanosterol 14α-demethylase (CYP51) and bacterial FtsZ (Filamenting temperature-sensitive mutant Z) protein. : As a result, the title compounds emerged as promising entities with broad antifungal and antibacterial effects, highlighting the utility of oxime ether function in the azole scaffold.