Synthesis and Anticoagulant Activity of New Ethylidene and Spiro Derivatives of Pyrrolo[3,2,1- ij ]quinolin-2-ones
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hesis and Anticoagulant Activity of New Ethylidene and Spiro Derivatives of Pyrrolo[3,2,1-ij]quinolin-2-ones N. P. Novichikhinaa, A. A. Skoptsovaa, A. S. Shestakova, A. Yu. Potapova, E. A. Koshelevaa, O. A. Kozaderova, I. V. Ledenyovaa, N. A. Podoplelovab, M. A. Panteleevc, and Kh. S. Shikhalieva,* a
Voronezh State University, Voronezh, 394018 Russia
b
Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, 117997 Russia
c
Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, 109029 Russia *e-mail: [email protected] Received April 24, 2020; revised May 6, 2020; accepted May 20, 2020
Abstract—The reaction of pyrrolo[3,2,1-ij]quinoline-1,2-diones with methyl (het)aryl ketones gave the corresponding 1-(het)arylmethylidenepyrroloquinolin-2-ones, and 1,3-dipolar cycloaddition of the latter to azomethine ylide generated from sarcosine and paraformaldehyde afforded 4-acyl-1,4′,4′,6′-tetramethylspiro[pyrrolidine-3,1′-pyrrolo[3,2,1-ij]quinolin]-2′(4′H)-ones. The synthesized compounds were evaluated for inhibitory activity against blood coagulation factors Xa and XIa. Keywords: 4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione, ethylidene-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one, sarcosine, 1,3-dipolar cycloaddition, anticoagulants, factor Xa, factor XIa
DOI: 10.1134/S1070428020090080 Analysis of published data showed that search for inhibitors of factor Xa which is common for extrinsic and intrinsic blood coagulation pathways is one of the main lines in the design of efficient anticoagulants [1–6]. According to recent data, tetrahydroquinoline derivatives were found among these compounds [7]. Computer design of factor Xa inhibitors [8] revealed fairly active compounds in the series of 2,2,4-trimethyl1,2-dihydroquinoline [9] and 4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione derivatives [10–11]. The latter are inhibitors of protein kinases [12]. The strategy of search for new factor Xa inhibitors implies, among other methods, molecular hybridization [13], i.e., combination of two and more pharmacophores in a single molecule, which is achieved mainly by using selective coupling reactions. As applied to 4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones, such approach is possible, e.g., when a carbonyl group is present in the 1-position [14, 15]. Later on, this was also demonstrated for 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones [16, 17]. With the goal of searching for new inhibitors of factors Xa and XIa via molecular hybridization, it
seemed promising to combine 4H-pyrrolo[3,2,1-ij]quinoline scaffold with pharmacophoric aroylmethylidene [18] and spirooxindole systems [19, 20]. In particular, it is known that 2-oxindoles are privileged substructures in the design of new drugs since many 2-oxindole derivatives have passed clinical trials for cancer therapy [21–23]. The present work was aimed at synthesizing new ethylidene and spiro-pyrrolidine derivatives of pyrrolo[3,2,1-ij]quinolin-2-ones and studying their inhibitory activity against factors X
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