Thiazoles with cyclopropyl fragment as antifungal, anticonvulsant, and anti-Toxoplasma gondii agents: synthesis, toxicity evaluation, and molecular docking study

Krzysztof Z Łączkowski,Anna Biernasiuk,Agata Paneth,Angelika Baranowska-Łączkowska,Adrian Bekier,Anna Furgała,Kinga Sałat,Natalia Konklewska,Anna Malm,Katarzyna Dzitko

doi:10.1007/s00044-018-2221-x

Abstract

Synthesis and investigation of antifungal, anticonvulsant and anti-Toxoplasma gondii activities of ten novel (2-(cyclopropylmethylidene)hydrazinyl)thiazole 3a–3j are presented. Among the derivatives, compounds 3a–3d and 3f–3j possess very high activity against Candida spp. ATCC with MIC = 0.015–7.81 µg/ml. Compounds 3a–3d and 3f–3j possess also very high activity towards most of strains of Candida spp. isolated from clinical materials with MIC = 0.015–7.81 µg/ml. The activity of these compounds is similar and even higher than the activity of nystatin used as positive control. Additionally, compounds 3c and 3e showed interesting anticonvulsant activities in the MES test, whereas compounds 3f and 3i demonstrated the anticonvulsant activity in PTZ-induced seizures. Noteworthy, none of these compounds impaired animals’ motor skills in the rotarod test. Moreover, thiazoles 3a, 3h, and 3j showed significant anti-Toxoplasma gondii activity, with IC50 values 31–52 times lower than those observed for sulfadiazine. The results of the cytotoxicity evaluation, anti-Candida spp. and anti-Toxoplasma gondii activity studies showed that Candida spp. and Toxoplasma gondii growth was inhibited at non-cytotoxic concentrations for the mouse L929 fibroblast and the African green monkey kidney (VERO) cells. Molecular docking studies indicated secreted aspartic proteinase (SAP) as possible antifungal target.

Highlights

Candida spp. is the most common group of nosocomial pathogens that cause invasive fungal infection leading to hospitalizations and death (Richards et al 2000)
The majority of candidiasis cases are caused by Candida albicans, non-C. albicans, such as Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei has recently been found an important group of pathogens that cause bloodstream infections (IC) (Macphail et al 2002)
All obtained products were purified on silica gel column chromatography, and fully characterized spectroscopically using 1H and 13C nuclear magnetic resonance (NMR), GC-EIMS, and elemental analyses

Summary

Introduction

Candida spp. is the most common group of nosocomial pathogens that cause invasive fungal infection leading to hospitalizations and death (Richards et al 2000). The majority of candidiasis cases are caused by Candida albicans, non-C. albicans, such as Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei has recently been found an important group of pathogens that cause bloodstream infections (IC) (Macphail et al 2002). C. glabrata is the second most commonly isolated pathogen, occurring especially in the elderly people suffering from cancer and under azole prophylaxis, while C. parapsilosis occurs mainly in catheterized neonates in southern Europe, Asia and South America. In 2016, the Infectious Disease Society of America (IDSA) published new guidelines for the use of echinocandins, azoles and lipid formulations of amphotericin B in the treatment of candidemia, and other forms of invasive candidiasis (Pappas et al 2016)

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