Ultrasound- and Molecular Sieves-Assisted Synthesis, Molecular Docking and Antifungal Evaluation of 5-(4-(Benzyloxy)-substituted phenyl)-3-((phenylamino)methyl)-1,3,4-oxadiazole-2(3H)-thiones

Abstract

A novel series of 5-(4-(benzyloxy)substituted phenyl)-3-((phenyl amino)methyl)-1,3,4-oxadiazole-2(3H)-thione Mannich bases 6a-o were synthesized in good yield from the key compound 5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazole-2(3H)-thione by aminomethylation with paraformaldehyde and substituted amines using molecular sieves and sonication as green chemistry tools. The antifungal activity of the new products was evaluated against seven human pathogenic fungal strains, namely, Candida albicans ATCC 24433, Candida albicans ATCC 10231, Candida glabrata NCYC 388, Cryptococcus neoformans ATCC 34664, Cryptococcus neoformans PRL 518, Aspergillus fumigatus NCIM 902 and Aspergillus niger ATCC 10578. The synthesized compounds 6d, 6f, 6g, 6h and 6j exhibited promising antifungal activity against the tested fungal pathogens. In molecular docking studies, derivatives 6c, 6f and 6i showed good binding at the active site of C. albicans cytochrome P450 enzyme lanosterol 14 α-demethylase. The in vitro antifungal activity results and docking studies indicated that the synthesized compounds have potential antifungal activity and can be further optimized as privileged scaffolds to design and develop potent antifungal drugs.

Keywords: 1,3,4-oxadiazoles; Mannich reaction; antifungal activity; molecular docking; molecular sieves; ultrasound.

Scheme 1

Synthesis of Mannich bases 6a–o.

Figure 1

Docking of compounds 6c, 6f, 6i and standard fluconazole. Ligands are shown in red color. Hydrogen bonds are shown in green color. Hydrophobic bonds are shown in sky blue color.

Figure 2

Ramachandran Plot for structural validation.