Synthesis and properties of novel hybrid molecules bearing 4H-pyrrolo[3,2,1-ij]quinolin-2-one and thiazole moieties

Novichikhina, N. P.; Ashrafova, Z. E.; Stolpovskaya, Nadezhda V.; Ledenyova, Irina V.; Kholyavka, M. G.; Подоплелова, Н. А.; Panteleev, Mikhail A.; Шихалиев, Х. С.

doi:10.1007/s11172-022-3615-y

Cited by 5 publications

(7 citation statements)

References 34 publications

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“…In a number of our previous publications aimed at the synthesis and study of the anticoagulant activity of functional derivatives of pyrrolo[3,2,1- ij ]quinolin-2-ones, promising results were obtained and the promise of these structures in the synthesis of new inhibitors of factors Xa and XIa shown [ 55 , 56 , 57 , 58 , 59 , 60 ]. It has been shown that 5,6-dihydro-4 H -pyrrolo[3,2,1- ij ]quinolin-2-ones, and in particular 6-aryl-substituted ones, tend to exhibit higher activity compared to their unsaturated analogues [ 55 , 56 , 66 ].…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, we also demonstrated that molecules combining in their structure fragments of 5,6-dihydro-4 H -pyrrolo[3,2,1- ij ]quinolin-2-one and thiazole act as both selective and dual inhibitors of Xa factors and XIa [ 56 , 57 ]. High inhibition values for both factors were also found for a compound in which pyrrolo[3,2,1- ij ]quinolin-2-one is linked to a thiazole derivative via a hydrazine linker [ 58 ].…”

Section: Resultsmentioning

confidence: 99%

“…At the first stage, the corresponding hydrazinocarbothioamides 2a-q were obtained by condensation of pyrrolo[3,2,1- ij ]quinoline-1,2-diones 1a-q with thiosemicarbazide. The reaction was carried out by analogy with [ 58 , 81 ], in which the reagents were boiled in isopropyl alcohol. However, in our case the best results were achieved by boiling the starting compounds in methanol with the addition of catalytic amounts of HCl.…”

Section: Resultsmentioning

confidence: 99%

“…The preparation of the target molecules 3a-q was carried out in two stages by analogy with [ 58 , 81 ]. Initially, to the corresponding 5,6-dihydro-4 H -pyrrolo[3,2,1- ij ]quinoline-1,2-dione 1a-q (1 mmol) and thiosemicarbazide (1.1 mmol), methanol (10 mL) and 1–2 drops of HCl was added.…”

Section: Methodsmentioning

confidence: 99%

“…Prompted by all the above-mentioned, and our previous studies [ 55 , 56 , 57 , 58 , 59 , 60 ], we designed and synthesized, based on the hybridization approach, new methyl 2-(4-oxo-2-(2-(2-oxo-5,6-dihydro-4 H -pyrrolo[3,2,1- ij ]quinolin-1(2 H )-ylidene)hydrazineyl)thiazol-5(4H)-ylidene)acetates and studied their inhibitory properties against blood clotting factors Xa and XIa in vitro.…”

Section: Introductionmentioning

confidence: 96%

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Design, Synthesis, and Evaluation of New Hybrid Derivatives of 5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one as Potential Dual Inhibitors of Blood Coagulation Factors Xa and XIa

Skoptsova,

Geronikaki,

Novichikhina

et al. 2024

Molecules

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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.

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