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Synthesis and vasorelaxing evaluation of α-methylidene-γ-butyrolactone bearing quinolin-2(1H)-one and 3,4-dihydroquinolin-2(1H)-one derivatives

2001; Elsevier BV; Volume: 36; Issue: 11-12 Linguagem: Inglês

10.1016/s0223-5234(01)01270-3

1768-3254

Tai‐Chi Wang, Yueling Zhao, Daih‐Huang Kuo,

Free Radicals and Antioxidants

The main objective of this investigation was to explore the vasorelaxing structure-activity relationships of alpha-methylidene-gamma-butyrolactone bearing quinolin-2(1H)-ones and their 3,4-dihydro derivatives. These target compounds were synthesised in two steps starting from aryl-OH which was treated with a bromomethyl ketone followed by a Reformatsky-type condensation. Quinolin-2(1H)-one alpha-methylidene-gamma-butyrolactones exhibited less vasorelaxing activity than their 3,4-dihydro counterparts. Compounds with a methyl or a phenyl group at the C(gamma) of the lactone were more vasorelaxant than the C(gamma)-fluorophenyl derivatives in the 3,4-dihydroquinolin-2(1H)-one series. When comparing the positional isomers, alpha-methylidene-gamma-butyrolactone substituted at the 7-position of the 3,4-dihydroquinolin-2(1H)-ones were more active than their 6-substituted counterparts, which in turn were more active than the 8-substituted derivatives. The vasorelaxing effect of these 3,4-dihydroquinolin-2(1H)-ones was proved to be dose dependent. Among them, 7-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenyfuran-2-yl)methoxy]-quinolin-2(1H)-one (10b) was the most potent with an IC(50) of 9.2 microM on the KCl-induced vasoconstriction of pig coronary arteries.