Synthesis and Antimicrobial Activity of Thiohydantoins Obtained from L-Amino Acids

Background: Thiohydantoins are an important class of heterocyclic compounds in drug discovery since they are related to a wide range of biological properties including antimicrobial activity. Objective: The objective of this study was to synthesize a series of thiohydantoins derived from L-aminoacids and to evaluated their inhibitory effect on the growth of Gram-negative and Gram-positive bacteria. Methods: All title compounds were synthetized by reaction of L-amino acids with thiourea or ammonium thiocyanate. Their antimicrobial activities were evaluated against bacterial strains by broth microdilution assays. The time-kill kinetics, the antibiofilm activity and the cytotoxicity to mammalian cells were determined for the compound that exhibited the best antimicrobial profile (1b). Results: Eleven thiohydantoins were readily obtained in good yields (52-95%). In general, thiohydantoins were more effective against Gram-positive bacteria. Compound 1b (derived from L-alanine) showed the best antibacterial activity against Staphylococcus epidermis ATCC 12228 and S. aureus BEC 9393 with MIC values of 940 and 1921 mu M, respectively. The time-kill kinetics demonstrated time-dependent bactericidal effect in both strains for this derivative. Besides, 1b also exhibited antibacterial activity against biofilms of S. epidermidis ATCC 12228, leading to a 40% reduction in their metabolic activity compared to the untreated control. No cytotoxicity of 1b to mammalian cells was observed at MIC values. Conclusion: The data reported herein indicate relevant antimicrobial activity of thiohydantoins derived from L-aminoacid, mainly 1b, as potential pharmacophore to guide further chemical modification aiming at the search for new and improved antimicrobial agents.