Synthesis and vasorelaxing evaluation of alpha-methylidene-gamma-butyrolactone bearing quinolin-2(1H)-one and 3,4-dihydroquinolin-2(1H)-one derivatives.
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.
Wang
T C
TC
Department of Pharmacy, Tajen Institute of Technology, Pingtung, Taiwan, ROC. tcwang@ccsun.tajen.edu.tw
Zhao
Y L
YL
Kuo
D H
DH
D015107:4-Butyrolactone / Q000737:chemistry; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C450184:7-((2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenyfuran-2-yl)methoxy)-quinolin-2(1H)-one; D005663:Furans; D011804:Quinolines; D014665:Vasodilator Agents; C037219:quinoline; D015107:4-Butyrolactone