A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies

Abstract

In the context of an increased incidence of invasive fungal diseases, there is an imperative need of new antifungal drugs with improved activity and safety profiles. A novel series of acylhydrazones bearing a 1,4-phenylene-bisthiazole scaffold was designed based on an analysis of structures known to possess anti-Candida activity obtained from a literature review. Nine final compounds were synthesized and evaluated in vitro for their inhibitory activity against various strains of Candida spp. The anti-Candida activity assay revealed that some of the new compounds are as active as fluconazole against most of the tested strains. A molecular docking study was conducted in order to evaluate the binding poses towards lanosterol 14α-demethylase. An in silico ADMET analysis showed that the compounds possess drug-like properties and represent a biologically active framework that should be further optimized as potential hits.

Novel 2,4-Disubstituted-1,3-Thiazole Derivatives: Synthesis, Anti-Candida Activity Evaluation and Interaction with Bovine Serum Albumine

“…It can be observed that the binding affinity regularly increased with the lipophilicity of the C4-thiazole substituent. This might be explained by the hydrophobic interactions with the CYP51 lipophilic area that is located in the depth of the binding pocket (Figure 1), as previously reported by our research group [28]. Table 3.…”

“…It can be observed that the binding affinity regularly increased with the lipophilicity of the C4-thiazole substituent. This might be explained by the hydrophobic interactions with the CYP51 lipophilic area that is located in the depth of the binding pocket (Figure 1), as previously reported by our research group [28]. An additional interaction with the polar Tyr132 amino acid sidechain, which is located at the hydrophilic domain of the access channel to the binding site, is due to the presence of the etheric oxygen, which acts as a hydrogen bond acceptor.…”

Design and Synthesis of Novel 1,3-Thiazole and 2-Hydrazinyl-1,3-Thiazole Derivatives as Anti-Candida Agents: In Vitro Antifungal Screening, Molecular Docking Study, and Spectroscopic Investigation of their Binding Interaction with Bovine Serum Albumin

“…It could be noticed that the presence of a lipophilic, electron-donating substituent (–CH 3 ) in compounds 4e and 7e is associated with improved binding energy, as compared with the hydrophilic, electron withdrawing functional groups (–CN, –NO 2 ), given the hydrophobic environment (Phe233, Val510 amino acid residues) of the phenyl-thiazole fragment. The two distinct areas with different polarity identified in the binding regions from the access channel to the catalytic site of the lanosterol C14α-demethylase were thoroughly described in a previous study reported by our research group [18].…”

“…The in vitro anti- Candida screening was done according to the guidelines of the Clinical Laboratory Standards Institute (CLSI) [45]. The broth microdilution method was employed for the determination of MIC and MFC, as previously reported [18]. All the tested fungal strains were obtained from the Food Biotechnology Laboratory, Life Sciences Institute, University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, Romania.…”

“…The docking protocol in terms of search space size, grid spacing, center Cartesian coordinates, and 2Å cluster analysis was applied as previously reported [47,48], with the exception of the number of generated conformations for each ligand. This parameter was increased to 100 in order to assess a higher reproducibility of the results obtained from the molecular docking study [18].…”