Novel 2-aryl-4-aryloxyquinoline-based fungistatics for Mucor circinelloides. Biological evaluation of activity, QSAR and docking study

Zygomycetes are ubiquitous saprophytes in natural environments which transform organic matter. Some zygomycetes of gender Mucor have attracted interest in health sector. Due to its ability as opportunistic microorganisms infecting immuno-compromised people and to the few available pharmacological treatments, the mucormycosis is receiving worldwide attention. Concerning to the pharmacological treatments, some triazolebased compounds such as fluconazole are extensively used. Nevertheless, we focused in the quinolines since they are broadly used models for the design and development of new synthetic antifungal agents. In this study, the fungistatic activity on M. circinelloides of various 2-aryl-4-aryloxyquinoline-based compounds was discovered, and in some cases, it resulted better than reference compound fluconazole. These quinoline derivatives were synthesized via the C-sp(2)-O bond formation using diaryliodonium(III) salts chemistry. A QSAR study was carried out to quantitatively correlate the chemical structure of the tested compounds with their biological activity. Also, a docking study to identify a plausible action target of our more active quinolines was carried out. The results highlighted an increased activity with the fluorine- and nitro-containing derivatives. In light of the few mucormycosis pharmacological treatments, herein we present some non-described molecules with excellent in vitro activities and potential use in the mucormycosis treatment.

Automated summary

Zygomycetes are widely distributed saprophytic fungi in natural environments that play a role in organic matter transformation. Some zygomycetes of gender Mucor have attracted attention in the health sector due to their ability to infect immunocompromised individuals and the limited pharmacological treatments available for mucormycosis. In this study, a series of 2-aryl-4-aryloxyquinoline-based compounds were found to have fungistatic activity against M. circinelloides, and in some cases, their activity was superior to the reference compound fluconazole. These quinoline derivatives were synthesized using diaryliodonium(III) salts chemistry. A quantitative structure-activity relationship (QSAR) study was conducted to correlate the chemical structure of the compounds with their biological activity. Docking studies were also performed to identify potential targets for the more active quinolines. The results suggested that fluorine- and nitro-containing derivatives exhibited increased activity. This study presents non-described molecules with excellent in vitro activities and potential use in the treatment of mucormycosis.