Inhibition of Toxoplasma gondii by 1, 2, 4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine. (31st December 2022)

• Record Type: Journal Article
• Authors: Węglińska, Lidia; Bekier, Adrian; Trotsko, Nazar; Kaproń, Barbara; Plech, Tomasz; Dzitko, Katarzyna; Paneth, Agata
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 37:Number 1(2022)
• Page Start: 2621
• Page End: 2634
• Publication Date: 2022-12-31
• Subjects: s-triazole -- anti-Toxoplasma gondii activity -- selectivity index; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2022.2112576
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: A safer treatment for toxoplasmosis would be achieved by improving the selectivity profile of novel chemotherapeutics compared to the standard therapy pyrimethamine (PYR) and sulfadiazine (SDZ). We previously reported on the identification of the compounds with imidazole-thiosemicarbazide scaffold as potent and selective anti- Toxoplasma gondii ( T. gondii) agents. In our current research, we report on the optimisation of this chemical scaffold leading to the discovery cyclic analogue 20 b with s -triazole core structure. This compound displayed prominent CC30 to IC50 selectivity index (SI) of 70.72, making it 160-fold more selective than SDZ, 11-fold more selective than PYR, and 4-fold more selective than trimethoprim (TRI). Additionally, this compound possesses prerequisite drug-like anti- Toxoplasma properties to advance into preclinical development; it showed ability to cross the BBB, did not induce genotoxic and haemolytic changes in human cells, and as well as it was characterised by low cellular toxicity.