3-Amino-5-(indol-3-yl)methylene-4-oxo-2-thioxothiazolidine Derivatives as Antimicrobial Agents: Synthesis, Computational and Biological Evaluation

Herein we report the design, synthesis, computational, and experimental evaluation of the antimicrobial activity of fourteen new 3-amino-5-(indol-3-yl) methylene-4-oxo-2-thioxothiazolidine derivatives. The structures were designed, and their antimicrobial activity and toxicity were predicted in silico. All synthesized compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin and (for the majority of compounds) streptomycin. The most sensitive bacterium wasS. aureus(American Type Culture Collection ATCC 6538), whileL. monocytogenes(NCTC 7973) was the most resistant. The best antibacterial activity was observed for compound5d(Z)-N-(5-((1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-4-hydroxybenzamide (Minimal inhibitory concentration, MIC at 37.9-113.8 mu M, and Minimal bactericidal concentration MBC at 57.8-118.3 mu M). Three most active compounds5d, 5g,and5kbeing evaluated against three resistant strains, Methicillin resistantStaphilococcus aureus(MRSA),P. aeruginosa,andE. coli, were more potent against MRSA than ampicillin (MIC at 248-372 mu M, MBC at 372-1240 mu M). At the same time, streptomycin (MIC at 43-172 mu M, MBC at 86-344 mu M) did not show bactericidal activity at all. The compound5dwas also more active than ampicillin towards resistantP. aeruginosastrain. Antifungal activity of all compounds exceeded those of the reference antifungal agents bifonazole (MIC at 480-640 mu M, and MFC at 640-800 mu M) and ketoconazole (MIC 285-475 mu M and MFC 380-950 mu M). The best activity was exhibited by compound5g. The most sensitive fungal wasT. viride(IAM 5061), whileA. fumigatus(human isolate)was the most resistant. Low cytotoxicity against HEK-293 human embryonic kidney cell line and reasonable selectivity indices were shown for the most active compounds5d,5g,5k,7cusing thiazolyl blue tetrazolium bromide MTT assay. The docking studies indicated a probable involvement ofE. coliMur B inhibition in the antibacterial action, while CYP51 inhibition is likely responsible for the antifungal activity of the tested compounds.