Vìsnik Odesʹkogo Nacìonalʹnogo Unìversitetu: Hìmìâ (Apr 2016)
INDENO[1,2,3-DE]PHTHALAZIN-3(2H)-ONE AND ITS ANALOGS – SYNTHESIS AND ANTIINFLAMMATORY PROPERTIES
Abstract
The purpose of this work was design planar polycyclic compounds as inhibitors of kinases, involved in the pro-inflammatory cascade. These compounds can be used as potential hits for the further anti-inflammatory drug design. Dibenzo[cd,g]indazol-6(2H)-one (1) has been shown as a competitive JNK inhibitor and antiviral agent and was used in this work as a prototype. Due to a presence of =N–NH– fragment in its structure 1 forms hydrogen bonds with methionine and aspartic acid residues in the JNK ATP-binding pocket. Bioisosteric modification of this compound leads to indeno[1,2,3-de]phthalazin-3(2H)-one (3), which also contains =N–NH– fragment in its structure. Further modification by «removing» bonds and/or fragments resulted in 4-phenylphthalazin-1(2H)-one (4), phthalazin-1(2H)-one (5), 6-phenyl-4,5-dihydropyridazin-3(2H)-one (8) and 6-methyl-4,5-dihydropyridazin-3(2H)-one (9) as potential ligands of JNK, which was confirmed by molecular docking. Compounds 3, 4, 5, 8 and 9 were synthesized by condensation of 9-oxo-9H-fluorene-1-carboxylic acid, 2-benzoylbenzoic acid, 2-formylbenzoic acid, 4-oxo-4-phenylbutanoic acid and 4-oxopentanoic acid respectively with hydrazine-hydrate. Structures were confirmed by a set of spectral methods (1H ЯМР spectroscopy, IR spectroscopy and mass spectrometry). Compounds 3, 4, 8 and 9 were shown as inhibitors of the inflammatory cytokines (IL-6 та TNF) and NF-κB production stimulated by bacterial LPS. Compound 3 appeared as the most active among other tested both in these tests and in the carrageenan rats paw edema prophylactics one. On the other hand JNK affinity of 3 appeared as very low with IC50 > 100 mM. So, it was shown, that indeno[1,2,3-de]phthalazin-3(2H)-one really demonstrates its' properties as a hit for further design of anti-inflammatory agents. It was also shown, that planar polycyclic ring system is essential structure peculiarity for such substances high activity. Not JNK but some other kinase with the similar structure of the ATP-binding pocket is the most likely target of 3.
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