Synthesis, docking and in-vitro screening of mannich bases of thiosemicarbazide for anti-fungal activity

Mannich bases and thiosemicarbazide individually show antimicrobial, antifungal, anticonvulsant, antimalarial, analgesic and anti-inflammatory type of varied pharmacological activities. The novelty of the present work is the synthesis of mannich bases of thiosemicarbazide as mutual prodrugs. In step-1, mannich bases are synthesized using aldehyde, ketones and amines with aliphatic, aromatic, cyclic and heterocyclic nature. In step-2, the synthesized bases were condensed with thiosemicarbazide to form mannich bases of thiosemicarbazide. Structural characterization of synthesized compounds was done using IR, mass and H-NMR spectroscopy. The compounds were screened for anti-fungal activity using BHI (brain heart infusion) broth dilution method against Candida albicans and Apergillus niger. Docking of synthesized compounds was done on CYP51A1, P45014DM (Lanosterol 14 α-demethylase enzyme) using Vlife MDS 3.5 to conform the mechanism of antifungal activity. Docking study showed a strong hydrophobic interaction between amino acid residues Arganine (ARG141), Glutamine (GLU146), Leucine (LEU54), Lycine (LYC227), and Threonine (THR147) with the carbon of ketone, nitrogen of amine and sulfur of thiosemicarbazide. Strong Vander wall’s interactions are also observed with the carbon of ketone, nitrogen of amine and sulfur of thiosemicarbazide. Analogs with aromatic and substituted aromatic aldehydes showed least activity, while analogs with aliphatic aldehyde, ketones and amines showed greater activity in C. albicans compared to A. niger. Analogs having morpholine as amine showed comparable activity in both. Compounds K17, K18, K19, and K20 have shown comparable highest activities.