The reaction of pyrrolo[3,2,1-ij]quinoline-1,2-diones with methyl (het)aryl ketones gave the corresponding 1-(het)arylmethylidenepyrroloquinolin-2-ones, and 1,3-dipolar cycloaddition of the latter to azomethine ylide generated from sarcosine and paraformaldehyde afforded 4-acyl-1,4′,4′,6′-tetramethylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinolin]-2′(4′H)-ones. The synthesized compounds were evaluated for inhibitory activity against blood coagulation factors Xa and XIa.

Cardiovascular diseases caused by blood coagulation system disorders are one of the leading causes of morbidity and mortality in the world. Research shows that blood clotting factors are involved in these thrombotic processes. Among them, factor Xa occupies a key position in the blood coagulation cascade. Another coagulation factor, XIa, is also a promising target because its inhibition can suppress thrombosis with a limited contribution to normal hemostasis. In this regard, the development of dual inhibitors as new generation anticoagulants is an urgent problem. Here we report the synthesis and evaluation of novel potential dual inhibitors of coagulation factors Xa and XIa. Based on the principles of molecular design, we selected a series of compounds that combine in their structure fragments of pyrrolo[3,2,1-ij]quinolin-2-one and thiazole, connected through a hydrazine linker. The production of new hybrid molecules was carried out using a two-stage method. The reaction of 5,6-dihydropyrrolo[3,2,1-ij]quinoline-1,2-diones with thiosemicarbazide gave the corresponding hydrazinocarbothioamides. The reaction of the latter with DMAD led to the target methyl 2-(4-oxo-2-(2-(2-oxo-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1(2H)-ylidene)hydrazineyl)thiazol-5(4H)-ylidene)acetates in high yields. In vitro testing of the synthesized molecules revealed that ten of them showed high inhibition values for both the coagulation factors Xa and XIa, and the IC₅₀ value for some compounds was also assessed. The resulting structures were also tested for their ability to inhibit thrombin.

Aldol addition of acyclic and cyclic ketones to 4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones afforded the corresponding 1-substituted 1-hydroxy-4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-ones. The short-time reduction of 4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones with sodium tetra­hydridoborate gave 1-hydroxy-4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-ones.

To develop efficient and structurally novel anticoagulants, a library of new hybrid molecules—(Z)-1-(2-(4-arylthiazol-2-yl)hydrazineylidene)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2-ones—was designed and synthesized through a two-step approach. The reaction of pyrrolo[3,2,1-ij]quinoline-1,2-diones with thiosemicarbazide produced thiosemicarbazones, which were subsequently reacted with α-bromoacetophenones. The structure of the resulting compounds was determined by HPLC-HRMS-ESI analysis, ¹H NMR spectroscopy, and ¹³C NMR spectroscopy. X-ray diffraction analysis unambiguously confirmed the structure of the resulting substances. The synthesized compounds were tested for their anticoagulant activity in vitro. Among the tested derivatives, two substances have a dual effect and exhibit 98–100% inhibitory ability against blood coagulation factors Xa and XIa at 30 μM. IC₅₀ values were also evaluated for these compounds. The results obtained show the high potential of the synthesized derivatives in the development of new multitarget anticoagulant drugs. The docking studies confirmed the experimental results.

Ction of 6-aryl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones with 3-acetylcoumarins led to the formation of a new series of 1-[2-oxo-2-(2-oxo-2H-chromen-3-yl)ethylidene]-6-aryl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2(1H)-ones. Primary in vitro screening of anticoagulant activity against coagulation factors Xa and XIa was performed for all target compounds. The IC₅₀ value was also determined for the structures that showed the highest inhibition values among synthesized molecules.