In vitro evaluation of arylsubstituted imidazoles derivatives as antiprotozoal agents and docking studies on sterol 14α-demethylase (CYP51) from Trypanosoma cruzi, Leishmania infantum, and Trypanosoma brucei.

Autor: Rojas Vargas JA; Chemistry Department, Exact and Natural Science Faculty, Oriente University, Santiago de Cuba, Cuba. jarojas@uo.edu.cu., López AG; Chemistry Department, Exact and Natural Science Faculty, Oriente University, Santiago de Cuba, Cuba., Pérez Y; Chemistry Department, Exact and Natural Science Faculty, Oriente University, Santiago de Cuba, Cuba., Cos P; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium., Froeyen M; Medicinal Chemistry, Department of Pharmacy, Rega Institute, KU Leuven, Leuven, Belgium.
Jazyk: angličtina
Zdroj: Parasitology research [Parasitol Res] 2019 May; Vol. 118 (5), pp. 1533-1548. Date of Electronic Publication: 2019 Mar 23.
DOI: 10.1007/s00436-019-06206-z
Abstrakt: There is an urgent need to discover and develop new drugs to combat parasitic diseases as Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei), and leishmaniasis (Leishmania ssp.). These diseases are considered among the 13 most unattended diseases worldwide according to the WHO. In the present work, the synthesis of 14 arylsubstituted imidazoles and its molecular docking onto sterol 14α-demethylase (CYP51) was executed. In addition, the compounds, antiprotozoal activity against T. brucei, T. cruzi, Trypanosoma brucei rhodesiense, and Leishmania infantum was evaluated. In vitro antiparasitic results of the arylsubstituted imidazoles against T. brucei, T. cruzi, T.b. rhodesiense, and L. infantum indicated that all samples from arylsubstituted imidazole compounds presented interesting antiparasitic activity to various extent. The ligands 5a, 5c, 5e, 5f, 5g, 5i, and 5j exhibited strong activity against T. brucei, T. cruzi, T.b. rhodesiense, and L. infantum with IC 50 values ranging from 0.86 to 10.23 μM. Most samples were cytotoxic against MRC-5 cell lines (1.12 < CC 50  < 51.09 μM) and only ligand 5c showed a good selectivity against all tested parasites. According to the results of the molecular docking, the aromatic substituents in positions 1, 4, and 5 have mainly stabilizing hydrophobic interactions with the enzyme matrix, while the oxygen from NO 2 , SO 3 H, and OH groups interacts with the Fe 2+ ion of the Heme group.
Databáze: MEDLINE
Externí odkaz: