Evaluation of analogues of furan-amidines as inhibitors of NQO2.
Bioorg Med Chem Lett
; 28(8): 1292-1297, 2018 05 01.
Article
em En
| MEDLINE
| ID: mdl-29567345
ABSTRACT
Inhibitors of the enzyme NQO2 (NRH quinone oxidoreductase 2) are of potential use in cancer chemotherapy and malaria. We have previously reported that non-symmetrical furan amidines are potent inhibitors of NQO2 and here novel analogues are evaluated. The furan ring has been changed to other heterocycles (imidazole, N-methylimidazole, oxazole, thiophene) and the amidine group has been replaced with imidate, reversed amidine, N-arylamide and amidoxime to probe NQO2 activity, improve solubility and decrease basicity of the lead furan amidine. All compounds were fully characterised spectroscopically and the structure of the unexpected product N-hydroxy-4-(5-methyl-4-phenylfuran-2-yl)benzamidine was established by X-ray crystallography. The analogues were evaluated for inhibition of NQO2, which showed lower activity than the lead furan amidine. The observed structure-activity relationship for the furan-amidine series with NQO2 was rationalized by preliminary molecular docking and binding mode analysis. In addition, the oxazole-amidine analogue inhibited the growth of Plasmodium falciparum with an IC50 value of 0.3⯵M.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinona Redutases
/
Inibidores Enzimáticos
/
Furanos
/
Amidinas
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Reino Unido