Title:Synthesis of New Bis-pyrazolines Endowed with Potent Antifungal Activity against <i>Candida albicans</i> and <i>Aspergillus niger</i>
VOLUME: 18 ISSUE: 1
Author(s):Belgin Sever, Mehlika Dilek Altintop* and Ahmet Özdemir
Affiliation:Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir
Keywords:Bis-pyrazoline, dithiocarbamate, oxadiazole, antifungal activity, aspergillosis and candidiasis.
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.
