Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity

• Main Authors: Nikolai S. Li-Zhulanov (Author), Nadezhda P. Zaikova (Author), Suat Sari (Author), Dolunay Gülmez (Author), Suna Sabuncuoğlu (Author), Keriman Ozadali-Sari (Author), Sevtap Arikan-Akdagli (Author), Andrey A. Nefedov (Author), Tatyana V. Rybalova (Author), Konstantin P. Volcho (Author), Nariman F. Salakhutdinov (Author)
• Format: Book
• Published: MDPI AG, 2023-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics12050818; 2079-6382
• Keywords: triazole antifungals; monoterpenoids; hybrids; clinical isolates; CYP51; <i>Candida</i> spp.; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 12, Iss 5, p 818 (2023)

Azole antifungals, including fluconazole, have long been the first-line antifungal agents in the fight against fungal infections. The emergence of drug-resistant strains and the associated increase in mortality from systemic mycoses has prompted the development of new agents based on azoles. We reported a synthesis of novel monoterpene-containing azoles with high antifungal activity and low cytotoxicity. These hybrids demonstrated broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against both fluconazole-susceptible and fluconazole-resistant strains of <i>Candida</i> spp. Compounds <b>10a</b> and <b>10c</b> with cuminyl and pinenyl fragments demonstrated up to 100 times lower MICs than fluconazole against clinical isolates. The results indicated that the monoterpene-containing azoles had much lower MICs against fluconazole-resistant clinical isolates of <i>Candida parapsilosis</i> than their phenyl-containing counterpart. In addition, the compounds did not exhibit cytotoxicity at active concentrations in the MTT assay, indicating potential for further development as antifungal agents.