title: Effect of novel triazole-amino acid hybrids on growth and virulence of Candida species: in vitro and in vivo studies.
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-1in 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.
authors.affiliation: Medicinal Chemistry Lab, Department of Biosciences, Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi 110025, India. mabid@jmi.ac.in.
authors.forename: Babita
authors.initials: B
authors.lastname: Aneja
authors.forename: Mohammad
authors.initials: M
authors.lastname: Irfan
authors.forename: Charu
authors.initials: C
authors.lastname: Kapil
authors.forename: Mohamad Aman
authors.initials: MA
authors.lastname: Jairajpuri
authors.forename: Ronan
authors.initials: R
authors.lastname: Maguire
authors.forename: Kevin
authors.initials: K
authors.lastname: Kavanagh
authors.forename: M Moshahid A
authors.initials: MM
authors.lastname: Rizvi
authors.forename: Nikhat
authors.initials: N
authors.lastname: Manzoor
authors.forename: Amir
authors.initials: A
authors.lastname: Azam
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abid
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity; D002177:Candidiasis / Q000188:drug therapy; D015725:Fluconazole / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D058886:Sterol 14-Demethylase / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*; D014774:Virulence / Q000187:drug effects
chemical_list: D000596:Amino Acids; D000935:Antifungal Agents; D014230:Triazoles; D015725:Fluconazole; D058886:Sterol 14-Demethylase