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Open AccessFeature PaperArticle

Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

1
Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, 1 Universitetskaya sq., 394018 Voronezh, Russia
2
Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia
3
Dimonta, Ltd., 117186 Moscow, Russia
4
Faculty of Physics, Lomonosov Moscow State University, 119992 Moscow, Russia
5
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
6
Center for Theoretical Problems of Physicochemical Pharmakology, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
Academic Editor: Athina Geronikaki
Molecules 2020, 25(8), 1889; https://doi.org/10.3390/molecules25081889
Received: 29 March 2020 / Revised: 14 April 2020 / Accepted: 17 April 2020 / Published: 19 April 2020
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. View Full-Text
Keywords: pyrroloquinolinones; anticoagulants; molecular docking; factor Xa; factor XIa pyrroloquinolinones; anticoagulants; molecular docking; factor Xa; factor XIa
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MDPI and ACS Style

Novichikhina, N.; Ilin, I.; Tashchilova, A.; Sulimov, A.; Kutov, D.; Ledenyova, I.; Krysin, M.; Shikhaliev, K.; Gantseva, A.; Gantseva, E.; Podoplelova, N.; Sulimov, V. Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa. Molecules 2020, 25, 1889.

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