Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-<i>ij</i>]Quinolin-2(1<i>H</i>)-one as New Inhibitors of Factor Xa and Factor XIa
Nadezhda Novichikhina,
Ivan Ilin,
Anna Tashchilova,
Alexey Sulimov,
Danil Kutov,
Irina Ledenyova,
Mikhail Krysin,
Khidmet Shikhaliev,
Anna Gantseva,
Ekaterina Gantseva,
Nadezhda Podoplelova,
Vladimir Sulimov
Affiliations
Nadezhda Novichikhina
Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya sq., 394018 Voronezh, Russia
Ivan Ilin
Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia
Anna Tashchilova
Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia
Alexey Sulimov
Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia
Danil Kutov
Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia
Irina Ledenyova
Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya sq., 394018 Voronezh, Russia
Mikhail Krysin
Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya sq., 394018 Voronezh, Russia
Khidmet Shikhaliev
Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya sq., 394018 Voronezh, Russia
Anna Gantseva
Faculty of Physics, Lomonosov Moscow State University, 119992 Moscow, Russia
Ekaterina Gantseva
Faculty of Physics, Lomonosov Moscow State University, 119992 Moscow, Russia
Nadezhda Podoplelova
Russian Children’s Clinical Hospital of the Pirogov Russian National Research Medical University of the Ministry of Healthcare of the Russian Federation, 119571 Moscow, Russia
Vladimir Sulimov
Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia
Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1-ij]quinolin-2(1H)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-ij]quinolin-2(1H)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C6,8,9 positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC50 value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor.
