| Autor: |
Skoptsova AA; Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya Sq., 394018 Voronezh, Russia., Geronikaki A; School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece., Novichikhina NP; Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya Sq., 394018 Voronezh, Russia., Sulimov AV; Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia., Ilin IS; Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia., Sulimov VB; Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia., Bykov GA; Department of Biophysics at the Faculty of Physics, Lomonosov Moscow State University, 119992 Moscow, Russia., Podoplelova NA; Center for Theoretical Problems of Physicochemical Pharmakology, 119991 Moscow, Russia., Pyankov OV; State Research Center of Virology and Biotechnology 'Vector', 630559 Koltsovo, Russia., Shikhaliev KS; Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya Sq., 394018 Voronezh, Russia. |
| Abstrakt: |
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 IC 50 value for some compounds was also assessed. The resulting structures were also tested for their ability to inhibit thrombin. |
