Cellular apoptosis and cell cycle arrest as potential therapeutic targets for eugenol derivatives in Candida auris

Abstract

Candida auris, the youngest Candida species, is known to cause candidiasis and candidemia in humans and has been related to several hospital outbreaks. Moreover, Candida auris infections are largely resistant to the antifungal drugs currently in clinical use, necessitating the development of novel medications and approaches to treat such infections. Following up on our previous studies that demonstrated eugenol tosylate congeners (ETCs) to have antifungal activity, several ETCs (C1-C6) were synthesized to find a lead molecule with the requisite antifungal activity against C. auris. Preliminary tests, including broth microdilution and the MUSE cell viability assay, identified C5 as the most active derivative, with a MIC value of 0.98 g/mL against all strains tested. Cell count and viability assays further validated the fungicidal activity of C5. Apoptotic indicators, such as phosphatidylserine externalization, DNA fragmentation, mitochondrial depolarization, decreased cytochrome c and oxidase activity and cell death confirmed that C5 caused apoptosis in C. auris isolates. The low cytotoxicity of C5 further confirmed the safety of using this derivative in future studies. To support the conclusions drawn in this investigation, additional in vivo experiments demonstrating the antifungal activity of this lead compound in animal models will be needed.

Antifungal Activities of Natural Products and Their Hybrid Molecules

“…Eugenol-based hybrid molecules 32 in Figure 5 showed notable antifungal activity against C. auris , resulting from its capability to induce apoptosis and cell cycle arrest. This compound’s low toxicity towards red blood cells compared to eugenol reveals its safe usage in vivo [ 106 ]. P’eret et al demonstrated the antifungal activity of novel imidazoles and 1,2,4-triazoles hybrid molecules synthesized from dihydroeugenol and eugenol.…”

Enantioselective high‐performance liquid chromatography combined with spectroscopic methods and theoretical calculations: A valid strategy to determine the absolute configuration of eugenol derivatives

“…13 Since molecular modification of the structures of bioactive natural molecules is a widely used approach to obtain drug candidates with improved efficacy and reduced toxicity, eugenol has been used as a target molecule for the preparation of novel semi-synthetic bioactive compounds. [14][15][16][17][18] Recently, some of us have reported the synthesis and biological activity of a series of racemic mixtures of eugenol derivatives obtained by structural modifications of eugenol at the allyl group. 19 In particular, compound 1, whose structure is shown in Figure 1, showed in vitro antimicrobial activity.…”

“…Since molecular modification of the structures of bioactive natural molecules is a widely used approach to obtain drug candidates with improved efficacy and reduced toxicity, eugenol has been used as a target molecule for the preparation of novel semi‐synthetic bioactive compounds 14–18 …”

Inhibition of apoptosis and biofilm formation in Candida auris by click-synthesized triazole-bridged quinoline derivatives

“…18,19 Furthermore, click chemistry techniques, such as the CuAAC reaction, facilitate the synthesis of these hybrid molecules with improved efficiency and precision. 20 By harnessing the synergistic properties of triazoles and quinolines, and in continuation of our search for better antifungal leads, [21][22][23][24] in this study, we synthesized new triazole bridged quinoline derivatives and evaluated them for their antifungal activity prole. Furthermore, we investigated their mechanisms of action and predicted their physicochemical properties to pinpoint lead antifungal molecules with drug-like properties.…”