Click synthesis of pyrrolidine-based 1,2,3-triazole derivatives as antifungal agents causing cell cycle arrest and apoptosis in Candida auris.

The emergence of multidrug-resistant fungal pathogens such as Candida auris is one of the major reasons WHO has declared fungal infections as a public health threat. Multidrug resistance, high mortality rates, frequent misidentification, and involvement in hospital outbreaks of this fungus demand the development of novel therapeutic drugs. In this direction, we report the synthesis of novel pyrrolidine-based 1,2,3-triazole derivatives using Click Chemistry (CC) and evaluation of their antifungal susceptibility against C. auris following Clinical and Laboratory Standards Institute (CLSI) guidelines. The fungicidal activity of the most potent derivative (P6) was further quantitatively confirmed by the MUSE cell viability assay. For insight mechanisms, the effect of the most active derivative on cell cycle arrest was studied using MuseTM Cell Analyzer and apoptotic mode of cell death was determined by studying phosphatidylserine externalization and mitochondrial depolarization. In vitro susceptibility testing and viability assays showed that all the newly synthesized compounds have antifungal activity with P6 being the most potent derivative. Cell cycle analysis revealed that P6 arrested the cells in S-phase in a concentration dependent manner and the apoptotic mode of cell death was confirmed by the movement of cytochrome c from mitochondria to cytosol with membrane depolarization. The hemolytic assay confirmed the safe use of P6 for further in vivo studies.

Novel terpene based 1,4,2-dioxazoles: synthesis, characterization, molecular properties and screening against Entamoeba histolytica.

In present investigation a series of 20 dioxazole analogues (1-20) were synthesized, characterized and subjected to molecular properties prediction, anti-amoebic screening and cytotoxicity evaluation. Out of the twenty compounds viz. 3,5-substituted-1,4,2-dioxazoles, six compounds have shown IC(50) values in the range (1.00-1.10 µM) lower than the standard drug metronidazole (IC(50) = 1.45 µM). The toxicological studies of the active compounds on H9c2 rat cardiac myoblasts showed that all compounds were nontoxic. The pKa, and log P values have also been predicted. Compound 8 showed the most promising results based on anti-amoebic evaluation, cytotoxicity studies and physico-chemical properties prediction.