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    Synthesis and biological evaluation of new fluconazole β-lactam conjugates linked via 1,2,3-triazole

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    Novel 1,2,3-triazole-linked &beta;-lactam&ndash;fluconazole conjugates&nbsp;12(a&ndash;l)&nbsp;were designed and synthesized. The compounds showed potent antifungal activity against two pathogenic&nbsp;Candida&nbsp;strains;&nbsp;Candida albicans&nbsp;ATCC 24433 and&nbsp;Candida albicans&nbsp;ATCC 10231 with MIC values in the range of 0.0625&ndash;2 &mu;g mL&minus;1. Compounds&nbsp;12h,&nbsp;12j&nbsp;and&nbsp;12k&nbsp;showed promising antifungal activity against all the tested fungal pathogens except&nbsp;C. neoformans&nbsp;ATCC 34554 compared to fluconazole. Compound&nbsp;12j&nbsp;in which the &beta;-lactam ring was formed using&nbsp;para-anisidine and benzaldehyde was found to be more potent than fluconazole against all the fungal strains with an IC50&nbsp;value of &lt;0.015 &mu;g mL&minus;1&nbsp;for&nbsp;Candida albicans&nbsp;(ATCC 24433). Mechanistic studies for active compounds revealed that the antifungal action was due to ergosterol inhibition. Compounds&nbsp;12h&nbsp;and&nbsp;12j&nbsp;at a concentration of 0.125 &mu;g mL&minus;1&nbsp;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 &beta;-lactam conjugates&nbsp;12(a&ndash;l)&nbsp;could snugly fit into the active site of lanosterol 14&alpha;-demethylase (CYP51) with varying degrees of affinities. As anticipated, the binding energy for compound&nbsp;12j&nbsp;(&minus;58.961 kcal mol&minus;1) was much smaller than that for fluconazole (&minus;52.92 kcal mol&minus;1). The synthesized compounds have therapeutic potential for the control of candidemia.</p
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