Synthesis and anticoagulant activity of methyl 2-{2-[2-(4,4,6-trimethyl-2-oxo-4H-pyrrolo[3,2,1-ij]quinolin-1(2H)-ylidene)hydrazineyl]-4-oxothiazol-5(4H)-ylidene}acetates against blood clotting factors Xa, XIa and thrombin

Abstract

The sequential reaction of differently substituted 4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]-quinoline-1,2-diones with thiosemicarbazide and dimethyl acetylenedicarboxylate yielded a series of new 2-{2-[2-(4,4,6-trimethyl-2-oxo-4H-pyrrolo[3,2,1-ij]quinolin-1(2H)-ylidene)hydrazineyl]-4-oxothiazol-5(4H)-ylidene}acetates, 2-{[(1-{2-[5-(2-methoxy-2-oxoethylidene)-4-oxo-4,5-dihydrothiazol-2-yl]hydrazineylidene}-4,4-dimethyl-2-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-6-yl)methyl]thio}benzoic acids, and 2-{[(1-{2-[5-(2-methoxy-2-oxoethylidene)-4-oxo-4,5-dihydrothiazol-2-yl]hydrazineyl-idene}-4,4-dimethyl-2-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-6-yl)methyl]thio}-nicotinic acids. The synthesized compounds were isolated as single isomers having presumably the Z,Z configuration. Primary in vitro screening of inhibitory activity of the synthesized compounds against blood clotting factors Xa, XIa and thrombin was carried out. Efficient dual inhibitors of factors Xa and XIa and factor Xa and thrombin were identified.