Synthesis, Structural Characterization, In Vitro and In Silico Evaluations of Piperidine Carbodithioates as New Azole Antifungal Agents

Abstract

Several piperidine-carbodithioates were designed as new azole antifungal agents derived from fluconazole (FCZ) and efinaconazole. The target compounds were synthesized via sequential multicomponent reaction, and the structures of the compounds were fully characterized by spectroscopic data, including FT-IR, NMR, MS, and microanalysis. The obtained 13C NMR data showed that the methylene pairs in the piperidine ring have a complicated behavior with magnetically non-equivalent character due to the resonance effect of dithiocarbamate and conformational dissimilarities of the piperidine ring. All compounds displayed good in vitro antifungal activity against Candida strains (Candida albicans and Candida glabrata). The 4-methylpiperidine analog 6b showed higher activity (MICs = 0.063-0.5 mu g/mL), being more potent than the standard drug FCZ. In particular, the bioassay against the FCZ-resistant isolate of Candida glabrata revealed that compound 6b, with an MIC value of 1 mu g/mL, had potent activity against the resistant isolate. The docking study and molecular dynamics simulation of the promising compound 6b indicated the perfect targeting of the CYP51 enzyme of fungal pathogens C. albicans (CACYP51) and C. glabrata (CGCYP51). The 4-methylpiperidine-carbodithioate moiety is involved in several hydrophobic interactions in the active site of CYP51, indicating the key role of this hydrophobic side chain in the promising antifungal activity of compound 6b, compared to the parent drug FCZ.