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

Abstract

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 Candida spp. Compounds 10a and 10c 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 Candida parapsilosis 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.

1,4-Bis(2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl)piperazine

“…For the selective synthesis of 1,4-bis-((−)-nopol)piperazine 2, we performed the reaction of (−)-nopol with methanesulfonyl chloride (MsCl) according to [3] to obtain a corresponding mesylate with 95% yield. (−)-Nopol mesylate then reacted with 0.5 equivalents of piperazine in the presence of potassium carbonate under reflux in acetonitrile, giving the target product 2 with a good yield of 75% (Scheme 2).…”

“…In recent endeavors directed towards the synthesis of azole-monoterpene hybrids with antifungal activity, we successfully obtained piperazine derivatives containing various monoterpene fragments, for example 1-(2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl)piperazine 1 was derived from (−)-nopol mesylate (Scheme 1) [3]. However, during the synthesis, in addition to monosubstituted piperazine 1, the formation of product 2 with an m/z value of 382 Da in GC/MS spectrum, which corresponds to the attachment of two monoterpene moieties to piperazine was also observed, but this minor compound was not isolated due to its insignificant amount in the reaction mixture.…”

Therapeutic Potential of Myrtenal and Its Derivatives—A Review

“…Compound 10, which is a myrtenol-containing analogue of azole antifungals, demonstrated promising antifungal activity against both fluconazole-susceptible and fluconazoleresistant strains, including fluconazole-resistant clinical isolates of Candida parapsilosis and Candida glabrata, with excellent minimum inhibitory concentration in submicrogram and nanogram range. The compound was up to 100 times more active than fluconazole [160].…”

Therapeutic Potential of Myrtenal and Its Derivatives–A Review

“…Compound 10 which is a myrtenol-containing analogue of azole antifungals demonstrated promising antifungal activity against both fluconazole-susceptible and fluconazole-resistant strains, including fluconazole-resistant clinical isolates of Candida parapsilosis and Candida glabrata with excellent minimum inhibitory concentration in submicrogram and nanogram range. The compound was up to 100 times more active than fluconazole [152].…”