Synthesis of 4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones containing a piperazine fragment and study of their inhibitory properties against protein kinases

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

“…Derivatives of PQs with a tetrahydroquinoline fragment 7a-с were obtained by the condensation of pyrroloquinolindiones 10 with rhodanine 11 (Scheme 1). Recently, we showed that the amination of 5-bromo-6-methylene-PQD 12 with monosubstituted piperazines 13 proceeds according to the tele-substitution scheme with the formation of 6-piperazinylmethyl-PQD 14 [27]. This unusual conjugated nucleophilic addition-elimination reaction was selected to obtain PQD 14a, c-f (Scheme 2).…”

“…Figure 4. Substituted 1,2,3,4-tetrahydroquinolines(5,6), N-acetylaminomethyl-1,2-dihydroquinoline(8), and hybrid moieties studied in this work as the basis for FXa and FXIa inhibitors (7 and 9-shown in boxes).Derivatives of PQs with a tetrahydroquinoline fragment 7a-c were obtained by the condensation of pyrroloquinolindiones 10 with rhodanine 11 (Scheme 1).Recently, we showed that the amination of 5-bromo-6-methylene-PQD 12 with monosubstituted piperazines 13 proceeds according to the tele-substitution scheme with the formation of 6-piperazinylmethyl-PQD 14[27]. This unusual conjugated nucleophilic addition-elimination reaction was selected to obtain PQD 14a, c-f (Scheme 2).Condensation of PQD 14a,c-f with rhodanine 11 in acetic acid led to the desired 6-piperazinylmethyl-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-ylidene-2-thioxothiazolidin-4-ones 9a-f.…”

“…Chemicals Starting 4,4,6-trimethyl-6-phenyl-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-1,2(4H)-dione (10a), 4,4,6,9-tetramethyl-6-phenyl-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-1,2(4H)-dione (10b), 6-(4-chlorophenyl) -4,4,6,8-tetramethyl-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-1,2(4H)-dione (10c) were provided by Alinda Chemical Ltd., Moscow, Russian Federation. 5-Bromo-8-methoxy-4,4-dimethyl-6-methylene-5,6 -dihydro-1H-pyrrolo[3,2,1-ij]quinoline-1,2(4H)-dione (12a), 5-bromo-8-fluoro-4,4-dimethyl-6-methylene -5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-1,2(4H)-dione (12b), 8-methoxy-4,4-dimethyl-6-((4-phenylpiperazine-1-yl)methyl)-1H-pyrrolo[3,2,1-ij]quinolin-1,2(4H)-dione (14b) were prepared according to the reported procedure[27]. Other reagents were purchased from commercial suppliers and used as received.8-R-4,4-dimethyl-6-((4-R 1 -piperazine-1-yl)methyl)-1H-pyrrolo[3,2,1-ij]quinolin-1,2(4H)-diones 14a,c-f were obtained by our previously published procedure[27].Ethyl 4-((8-Methoxy-4,4-dimethyl-1,2-dioxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-yl)methyl)piperazine-1 -carboxylate 14a.…”

In Search of Non-covalent Inhibitors of SARS-CoV-2 Main Protease: Computer Aided Drug Design Using Docking and Quantum Chemistry

“…The compounds are small drug-like molecules. Among them there are hydroquinoline derivatives with antibacterial, antifungal, anticoagulant activity [22,25,34,37,38], aminopyrimidines and pyrrolo[3,2,1-ij]quinolin-2-ones, which are factor Xa and protein kinases inhibitors [50,54], various plant growth stimulants of the getarylcarboxylic acid class [63,64].…”

Synthesis and study of new 2H-pyranoquinolin-2-one-based inhibitors of blood coagulation factors Xa and XIa

“…In the framework of a rational and effi cient design of biologically active compounds, researchers widely use the method of molecular hybridization, which is based on the combination of several pharmacophore fragments in one molecule. [24][25][26][27][28][29][30][31][32] The implementation of such an approach in order to search for new highly effi cient inhibitors of blood coagulation factors Xa and XIa based on the hybridization of hydroquinoline (A) and coumarin (B) rings seems to be very promising. 2H-Pyranо [3,2-g]quinolinones exemplify this type of hybrid molecules.…”