Synthesis of new bis‐pyrazole linked hydrazides and their in vitro evaluation as antimicrobial and anti‐biofilm agents: A mechanistic role on ergosterol biosynthesis inhibition in Candida albicans

New bis‐pyrazole linked hydrazides analogues were designed, synthesized and evaluated as potential antifungal agents. Compounds 13d, 13j, 13l, 13p and 13r showed most potent antifungal activity against various Candida strains with MIC values ranging from 3.9 to 15.6 µg/ml. The mechanism of action towards antifungal potency was demonstrated by inhibiting fungal lanosterol 14α‐demethylase (CYP51) enzyme and further validated by docking studies.

Abstract

Literature reports suggest that pyrazoles and hydrazides are potential antimicrobial pharmocophores. Considering this fact, a series of nineteen conjugates containing hybrids of bis‐pyrazole scaffolds joined through a hydrazide linker were synthesized and further evaluated for their antimicrobial activity against a panel of Gram‐positive and Gram negative bacteria along with Candida albicans MTCC 3017 strain. Although the derivatives exhibited good antibacterial activity, some of the derivatives (13d, 13j, 13l, 13p and 13r) showed excellent anti‐Candida activity with MICs values of 3.9 μg/mL, which was equipotent to that of the standard Miconazole (3.9 μg/mL), which has inspired us to further explore their anti‐Candida activity. The same compounds were also tested for anti‐biofilm studies against various Candida strains and among them, compounds 13l and 13r efficiently inhibited the formation of fungal biofilms. Field emission scanning electron micrographs revealed that one of the promising compound 13r showed cell damage and in turn cell death of the Candida strain. These potential conjugates (13l and 13r) also demonstrated promising ergosterol biosynthesis inhibition against some of the strains Candida albicans, which were further validated through molecular docking studies. In silico computational studies were carried out to predict the binding modes and pharmacokinetic parameters of these conjugates.

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