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    Effect of novel triazole–amino acid hybrids on growth and virulence of Candida species: in vitro and in vivo studies


    Aneja, Babita and Irfan, Mohammad and Kapil, Charu and Jairajpuri, Mohamad Aman and Maguire, Ronan Cathal and Kavanagh, Kevin and Rizvi, Moshahid A. and Manzoor, Nikhat and Azam, Amir and Abid, Mohammad (2016) Effect of novel triazole–amino acid hybrids on growth and virulence of Candida species: in vitro and in vivo studies. Organic and Biomolecular Chemistry, 14. pp. 10599-10619. ISSN 1477-0520

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    Abstract

    The increasing incidence of human candidiasis and the tendency of Candida species to become resistant to existing chemotherapies are well-recognized health problems. The present study demonstrates the successful synthesis of novel triazole–amino acid hybrids with potent in vitro and in vivo inhibitory activity against Candida species. Particularly, compounds 68 and 70 showed potent in vitro activity against fluconazole (FLC) resistant as well as sensitive clinical isolates of Candida albicans. Time kill curve analysis of lead inhibitors 68 and 70 showed their fungistatic nature. Secretion of hydrolytic enzymes, mainly proteinases and phospholipases, decreased considerably in the presence of 68 and 70 indicating their interference in fungal virulence. TEM analysis of Candida cells exposed to compounds 68 and 70 clearly showed morphological changes and intracellular damage as their possible mode of action. A preliminary mechanistic study carried out on the two most effective inhibitors (68 and 70) revealed the inhibition of ergosterol biosynthesis thereby causing the cells to lose their integrity and viability. The selected compounds did not show significant cytotoxicity up to a concentration of 200 μg mL−1 in the HEK293 cell line. An in silico analysis of 68 and 70 binding to a modeled C. albicans CYP51 showed critical H-bonding as well as hydrophobic interactions with the important active site residues indicating the basis of their anti-Candida role. Studies on the larvae of Galleria mellonella showed that the selected inhibitors (68 and 70) were non-toxic, did not provoke an immune response and significantly reduced Candida proliferation in vivo.

    Item Type: Article
    Additional Information: Cite as: Org. Biomol. Chem., 2016,14, 10599-10619
    Keywords: novel triazole–amino acid hybrids; growth; virulenc; Candida species;
    Academic Unit: Faculty of Science and Engineering > Biology
    Faculty of Science and Engineering > Chemistry
    Item ID: 11088
    Identification Number: https://doi.org/10.1039/C6OB01718E
    Depositing User: Dr. Kevin Kavanagh
    Date Deposited: 24 Sep 2019 14:26
    Journal or Publication Title: Organic and Biomolecular Chemistry
    Publisher: Royal Society of Chemistry
    Refereed: Yes
    URI:

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