| Summary: | <p>Novel 1,2,3-triazole-linked β-lactam–fluconazole conjugates <strong>12(a–l)</strong> were designed and synthesized. The compounds showed potent antifungal activity against two pathogenic <em>Candida</em> strains; <em>Candida albicans</em> ATCC 24433 and <em>Candida albicans</em> ATCC 10231 with MIC values in the range of 0.0625–2 μg mL<small><sup>−1</sup></small>. Compounds <strong>12h</strong>, <strong>12j</strong> and <strong>12k</strong> showed promising antifungal activity against all the tested fungal pathogens except <em>C. neoformans</em> ATCC 34554 compared to fluconazole. Compound <strong>12j</strong> in which the β-lactam ring was formed using <em>para</em>-anisidine and benzaldehyde was found to be more potent than fluconazole against all the fungal strains with an IC<small><sub>50</sub></small> value of <0.015 μg mL<small><sup>−1</sup></small> for <em>Candida albicans</em> (ATCC 24433). Mechanistic studies for active compounds revealed that the antifungal action was due to ergosterol inhibition. Compounds <strong>12h</strong> and <strong>12j</strong> at a concentration of 0.125 μg mL<small><sup>−1</sup></small> caused 91.5 and 96.8% ergosterol depletion, respectively, compared to fluconazole which at the same concentration caused 49% ergosterol depletion. The molecular docking study revealed that all the fluconazole β-lactam conjugates <strong>12(a–l)</strong> could snugly fit into the active site of lanosterol 14α-demethylase (CYP51) with varying degrees of affinities. As anticipated, the binding energy for compound <strong>12j</strong> (−58.961 kcal mol<small><sup>−1</sup></small>) was much smaller than that for fluconazole (−52.92 kcal mol<small><sup>−1</sup></small>). The synthesized compounds have therapeutic potential for the control of candidemia.</p>
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