Design, synthesis, biological activity and structure-activity relationship studies of chalcone derivatives as potential anti-Candida agents

• Published in: Journal of antibiotics Vol. 71; no. 8; pp. 702 - 712
• Main Authors: Andrade, Jéssica T., Santos, Felipe R. S., Lima, William G., Sousa, Carla D. F., Oliveira, Lohanna S. F. M., Ribeiro, Rosy I. M. A., Gomes, Ana J. P. S., Araújo, Marcelo G. F., Villar, José A. F. P., Ferreira, Jaqueline M. S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Springer Nature; Nature Publishing Group
• Subjects: 13; 631/326/22/1292; 64; 692/699/255/1672; Animals; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Biotechnology & Applied Microbiology; Candida albicans - drug effects; Candida albicans - isolation & purification; Candidiasis, Vulvovaginal - drug therapy; Cell Line; Cercopithecus aethiops; Chalcones - chemical synthesis; Chalcones - pharmacology; Cricetinae; Cytotoxicity; Drug Design; Female; Humans; Immunology; Life Sciences; Life Sciences & Biomedicine; Medicinal Chemistry; Microbial Sensitivity Tests; Microbiology; Organic Chemistry; Pharmacology & Pharmacy; Rats; Rats, Wistar; Science & Technology; Structure-Activity Relationship; Vero Cells; Yeasts; ANTIBACTERIAL; SERIES; ANTIFUNGAL EVALUATION; MECHANISM; ANALOGS; DISCOVERY
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-018-0048-9

Vulvovaginal candidiasis (VVC) affects millions of women around the world every year. Candida albicans is the most frequently isolated pathogen in women and its rapid ability to develop resistance to first and second line therapies has boosted the search for new and effective antifungal agents. In this study, we show the in vitro anti-Candida activity of fifteen synthetic chalcone analogs and their antifungal potential in an in vivo model of VVC. Chalcone 12 showed potent antifungal effects, being able to inhibit the growth of Candida spp. at a concentration of 15.6 µg mL −1 . In addition, mechanism of action studies have indicated the ergosterol fungal membrane as the target of this compound. Despite a considerable antifungal activity, the chalcone 12 showed high cytotoxicity in kidney cells lineages. Moreover, this compound was able to reduce Candida-associated virulence, impairing yeast–hyphal transition in C. albicans . An in vivo model of VVC showed that chalcone 12 significantly reduces the fungal load. Taken together, these findings showed that the chalcone 12 is a potent anti-Candida agent in vitro beyond of contribute to improve the fungal infection in a model of CVV. However, it showed low selectivity and high toxicity, suggesting molecular modifications to minimize these proprieties.