Novel derivatives of Mycosidine (3,5-substituted thiazolidine-2,4-diones) are synthesized by Knoevenagel condensation and reactions of thiazolidines with chloroformates or halo-acetic acid esters. Furthermore, 5-Arylidene-2,4-thiazolidinediones and their 2-thioxo analogs containing halogen and hydroxy groups or di(benzyloxy) substituents in 5-benzylidene moiety are tested for antifungal activity in vitro. Some of the synthesized compounds exhibit high antifungal activity, both fungistatic and fungicidal, and lead to morphological changes in the Candida yeast cell wall. Based on the use of limited proteomic screening and toxicity analysis in mutants, we show that Mycosidine activity is associated with glucose transport. This suggests that this first-in-class antifungal drug has a novel mechanism of action that deserves further study.

Aminomethylation of 9b,10-dihydro-1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino-[1,7-a]indole-1,3(2H)-diones or 1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino[1,7-a]indole-1,3(2H)-diones resulted in dialkylaminomethyl derivatives. Alkylation of the nitrogen atom of maleimide moiety of polyannelated diazepines with 1,3-dibromopropane and subsequent reaction with thiourea or its N-alkyl derivatives gave isothiourea-carrying compounds. The compounds containing isothiourea moiety were active against individual human serine/threonine and tyrosine kinases at low micromolar concentrations. Dialkylaminomethyl derivatives of diazepines sensitized Streptomyces lividans with overexpressed aminoglycoside phosphotransferase type VIII (aphVIII) to kanamycin by inhibiting serine/threonine kinase(s) mediated aphVIII phosphorylation.

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The wide spread of pathogens resistance requires the development of new antimicrobial agents capable of overcoming drug resistance. The main objective of the study is to elucidate the effect of substitutions in tris(1H-indol-3-yl)methylium derivatives on their antibacterial activity and toxicity to human cells. A series of new compounds were synthesized and tested. Their antibacterial activity in vitro was performed on 12 bacterial strains, including drug resistant strains, that were clinical isolates or collection strains. The cytotoxic effect of the compounds was determined using an test with HPF-hTERT (human postnatal fibroblasts, immortalized with hTERT) cells. The activity of the obtained compounds depended on the carbon chain length. Derivatives with C5–C6 chains were more active. The minimum inhibitory concentration (MIC) of the most active compound on Gram-positive bacteria, including MRSA, was 0.5 μg/mL. Compounds with C5–C6 chains also revealed high activity against Staphylococcus epidermidis (1.0 and 0.5 μg/mL, respectively) and moderate activity against Gram-negative bacteria Escherichia coli (8 μg/mL) and Klebsiella pneumonia (2 and 8 μg/mL, respectively). However, they have no activity against Salmonella cholerasuis and Pseudomonas aeruginosa. The most active compounds revealed higher antibacterial activity on MRSA than the reference drug levofloxacin, and their ratio between antibacterial and cytotoxic activity exceeded 10 times. The data obtained provide a basis for further study of this promising group of substances.