New Hybrid Tetrahydropyrrolo[3,2,1-ij]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation

Author:

Novichikhina Nadezhda P.1ORCID,Shestakov Alexander S.1,Medvedeva Svetlana M.1ORCID,Lagutina Anna M.1,Krysin Mikhail Yu.1ORCID,Podoplelova Nadezhda A.23,Panteleev Mikhail A.23,Ilin Ivan S.45,Sulimov Alexey V.45,Tashchilova Anna S.45,Sulimov Vladimir B.45,Geronikaki Athina6ORCID,Shikhaliev Khidmet S.1

Affiliation:

1. Department of Organic Chemistry, Faculty of Chemistry, Voronezh State University, Universitetskaya pl. 1, 394018 Voronezh, Russia

2. Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 117997 Moscow, Russia

3. Center for Theoretical Problems of Physicochemical Pharmakology, 119991 Moscow, Russia

4. Dimonta, Ltd., 117186 Moscow, Russia

5. Research Computing Center, Lomonosov Moscow State University, 119992 Moscow, Russia

6. School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece

Abstract

Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we report the synthesis and evaluation of novel pyrroloquinolinedione-based rhodanine derivatives, which were chosen from 24 developed derivatives by docking as potential molecules to inhibit the clotting factors Xa and XIa. For the synthesis of new hybrid derivatives of pyrrolo[3,2,1-ij]quinoline-2-one, we used a convenient structural modification of the tetrahydroquinoline fragment by varying the substituents in positions 2, 4, and 6. In addition, the design of target molecules was achieved by alkylating the amino group of the rhodanine fragment with propargyl bromide or by replacing the rhodanine fragment with 2-thioxoimidazolidin-4-one. The in vitro testing showed that eight derivatives are capable of inhibiting both coagulation factors, two compounds are selective inhibitors of factor Xa, and two compounds are selective inhibitors of factor XIa. Overall, these data indicate the potential anticoagulant activity of these molecules through the inhibition of the coagulation factors Xa and XIa.

Funder

Russian Science Foundation

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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