Synthesis of 1,3-dialkylthioselenoglycolurils - novel antifungal agents

Abstract

A two-step synthesis of pharmacologically relevant 1,3-dialkyl-5-selenoxohexahydroimidazo[4,5-d]imidazole-2(1H)-thiones (thioselenoglycolurils) starting from readily available thioglycolurils was realized for the first time. The developed protocol involves S-methylation of initial thioglycolurils followed by selenation of thus formed isothiouronium salts with NaHSe generated in situ from grey Se and NaBH₄. In vitro study of antifungal activity against Sclerotinia sclerotiorum, Fusarium oxysporum, Fusarium maniliforme, Bipolaris sorokiniana, Venturia inaequalis, Rhizoctonia solani phytopathogens and yeasts Candida albicans and Cryptococcus neoformans, Candida auris, MDR Candida auris, Candida glabrata was performed. It was found that 8 thioselenoglycolurils completely inhibited the growth of V. inaequalis and R. solani fungi and partially suppress the growth of B. sorokiniana fungus (MGI 59–67 %) analogous to triadimefon (MGI 68 %). Effective antifungal action towards C. albicans and C. neoformans (MIC $\le$ 0.25 μg/mL) with no discernible toxicity against mamallian cells was revealed for 4 representatives of thioselenoglycolurils. Effective growth inhibition of gram-positive bacterium S. aureus, yeast C. neoformans, C. auris, MDR C. auris, C. glabrata was additionally noted for 1,3-diethylthioselenoglycoluril. Moreover, the latter compound has low toxicity (LD₅₀ = 129 mg/kg) and can be referred to as a lead candidate for the development of new antifungal pharmaceuticals.