Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents

Abstract

The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time-kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells. Many of these molecules exhibited broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against non-albicans Candida and Aspergillus strains. The most promising compounds were found to be less hemolytic than the FDA-approved antifungal agent voriconazole (VOR). Finally, we demonstrate that the synthetic alkylated piperazine-azole hybrids do not function by fungal membrane disruption, but instead by disruption of the ergosterol biosynthetic pathway via inhibition of the 14α-demethylase enzyme present in fungal cells.

(1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine derivatives suppress Candida albicans virulence by interfering with morphological transition

“…Many synthetic piperazine derivatives have been reported to exhibit promising antifungal activity by causing the death of fungal cells (Moraca et al ., 2014; Thamban et al ., 2017). However, our study verified for the first time that (1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine scaffolds could be developed as antifungal agents against C. albicans using an anti‐virulence strategy.…”

Artificial Intelligence Guided De Novo Molecular Design Targeting COVID-19

“…The tailored incorporation of a fluoro-alkyl or fluoro-aromatic group (Enamine also having cyclic amines) into bioactive compounds influences the binding a nity, stability, lipophilicity, membrane permeability and bioactivity [13]. Examples including some of our top compounds such as ligand 2 and ligand 6 consists of fluoromethyl group (CF3) which are known to improve adsorption digestion metabolism and extraction (ADME) and pharmaco-kinetic properties [13,32], see Figure 6a. It is worth noting that heterocycles and fused rings constitute of about 70 % of the drug market with one of the reasons being the limited entropic e↵ects showcased by their molecular rigidity.…”

Metabolite profiling of IMID‐2, a novel anticancer molecule of piperazine derivative: In silico prediction, in vitro and in vivo metabolite characterization using UPLC–QTOF–MS/MS

“…The first piperazine derivative diethylcarbamazine was used as an anthelmintic. Additionally, it has been used as a pharmacophore for various classes of compounds in a wide range of therapeutic areas such as anticancer (Manouchehrizadeh et al, 2020; Yarim et al, 2012), antipsychotic (Brito et al, 2019), anthelminthic, antifungal (Franåois et al, 2009; Thamban Chandrika et al, 2018), antibacterial (Amani, 2014; Ondoh et al, 2005), antidepressant (Kędzierska et al, 2019) and HIV protease inhibitor (Bungard et al, 2017; Tagat et al, 2001) agents. Piperazine derivatives’ anticancer moiety acts by binding various biological targets.…”