Formamidine-based thiuram disulfides: Synthesis, structural characterization, biological studies, and preliminary cheminformatics evaluation

Abstract

In this study, we present the synthesis and biological evaluation of a series of formamidine-based thiuram disulfides using computational tools. Six compounds were synthesized via, the oxidation of formamidine-based dithiocarbamates. These were, N,N′-bis(2,6-dimethylphenyl)formamidine dithiocarbamate (L1), N,N′-bis(2,6-disopropylphenyl) formamidine dithiocarbamate (L2), N,N′-dimesitylformamidine dithiocarbamate (L3), N’-(2,6-dichlorophenyl-N-(2,6-dimethylphenyl)formamidine dithiocarbamate (L4), N’-(2,6-dichlorophenyl)-N-(2,6-diisopropylphenyl)formamidine dithiocarbamate (L5) and N’-(2,6-dichlorophenyl)-N-mesitylformamidine dithiocarbamate (L6). The oxidation of the dithiocarbamates with iodine produced sulfur-sulfur coupling compounds L1’ (1), L2’ (2), L3’ (3), L4’ (4), L5’ (5) and L6’ (6). All the compounds were characterized using UV–vis, FT-IR, 1H and 13C NMR, mass spectrometry and by elemental analysis. In addition, the single crystal structures of compounds 1, 2, 4 and 5 are reported and confirm the coupling of formamidine dithiocarbamates moieties in 1–6. In vitro antimicrobial study revealed that all the compounds displayed moderate to good activities against Gram-negative bacteria, Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, and Pseudomonas aeruginosa, but none of the six were active against Gram-positive bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus. Compounds 4 and 5 were found to be more active than ciprofloxacin against S. typhimurium and all compounds exhibited poor antioxidant activity when compared to ascorbic acid. Pharmacological estimations of 1–6 revealed that all the compounds had minimal violations of Lipinski’s rule but exhibited inclinations to be orally bioavailable and less toxic.