Synthesis of New Bis-pyrazolines Endowed with Potent Antifungal Activity against Candida albicans and Aspergillus niger

Author(s): Belgin Sever, Mehlika Dilek Altintop*, Ahmet Özdemir

Journal Name: Letters in Drug Design & Discovery

Volume 18 , Issue 1 , 2021

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Graphical Abstract:


Background: Due to the increasing number of cases of invasive fungal infections (IFIs), there is an urgent need to identify potent antifungal agents capable of combating IFIs. Pyrazolines are one such class of therapeutically active agents that could be considered to fulfill this need.

Objective: In this context, this paper aims to identify two new series of bis-pyrazolines endowed with potent antifungal activity against Candida albicans and Aspergillus niger.

Methods: Two new series of bis-pyrazolines (4a-i, 5a-e) were synthesized through an efficient and versatile synthetic procedure. The compounds were screened for their antifungal effects on C. albicans and A. niger using a broth microdilution method. Their cytotoxic effects on NIH/3T3 mouse embryonic fibroblast cells were determined using MTT assay. Molecular docking studies were performed in the active site of lanosterol 14 α-demethylase (CYP51) to shed light on their antifungal effects using Schrödinger’s Maestro molecular modeling package.

Results: 5,5'-(1,4-Phenylene)bis[1-(2-(5-phenyl-1,3,4-oxadiazol-2-yl)thio)acetyl)-3-(2-thienyl)-4,5- dihydro-1H-pyrazole] (4a) and 5,5'-(1,4-phenylene)bis[1-(2-(4-(2-hydroxyethyl)-1-piperazinylthiocarbamoyl) thio)acetyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazole] (5a) were found as the most promising antifungal agents in this series. Compounds 4a and 5a showed pronounced antifungal activity against C. albicans (MIC= 0.016 mg/mL) and A. niger (MIC= 0.008 mg/mL). Based on MTT assay, their antifungal effects were selective (IC50 > 0.500 mg/mL for NIH/3T3 cell line). Molecular docking studies suggested that compounds 5a-e might show their anticandidal effects via CYP51 inhibition in regard to their stronger interactions in the active site of CYP51.

Conclusion: Compounds 4a and 5a stand out as potential antifungal agents for the management of IFIs caused by C. albicans and A. niger.

Keywords: Bis-pyrazoline, dithiocarbamate, oxadiazole, antifungal activity, aspergillosis and candidiasis.

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Article Details

Year: 2021
Published on: 26 February, 2021
Page: [3 - 15]
Pages: 13
DOI: 10.2174/1570180817999201008155247
Price: $65

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