Synthesis of 2-substituted benzimidazole derivatives as potential p38 MAP kinase inhibitors

Cilj ovog rada bila je sinteza 2-supstituiranih benzimidazolnih derivata kao potencijalnih inhibitora p38 MAP kinaze. Dizajn spojeva proveden je prema podacima molekulskog uklapanja spojeva u aktivno mjesto enzima p38 MAP kinaze. Kondenzacijom priređenih derivata benzaldehida s o-fenilendiaminom, uz NaHSO3 ili p-benzokinon, priređeni su nesupstituirani (18) i 5(6)-imidazolin supstituirani (20–25 i 41−55) benzimidazoli. Benzaldehidni prekursori s N-1 supstiuiranim 1,2,3-triazolom (7, 9–11 i 14–16) pripravljeni su Huisgenovom 1,3-dipolarnom cikloadicijom kataliziranom bakrom. Kako bi se odredio utjecaj supstituenta na inhibitornu aktivnost sintetizirani su 5(6)-imidazolin supstituirani derivati benzimidazola s benzoilnim (41–43), morfolinoilnim (44–46), piridinskim (47–49), etilmorfolinskim (50–52) i dietilaminoetilnim (53–55) supstituentima povezani preko fenoksimetilenske premosnice. Provedene su in silico analize strukturnih svojstava i molekulsko uklapanje novopripravljenih spojeva u aktivno mjesto ne-aktivne (DFG-out) konformacije enzima p38 MAP kinaze. Strukture svih priređenih spojeva potvrđene su 1H i 13C NMR spektroskopijom. Inhibitorno djelovanje na p38 MAPK i antiproliferativna ispitivanja priređenih spojeva na zloćudne tumorske stanice su u tijeku.The aim of this work was the synthesis of 2-substituted benzimidazole derivatives as potential p38 MAP kinase inhibitors. The targeted compounds were designed according to the molecular docking results to p38 MAP kinase. Unsubstituted (18) and 5 (6)-imidazoline substituted (20–25 and 41–55) benzimidazoles were synthesized by condensation of prepared benzaldehyde derivatives with o-phenylenediamine, in the presence of NaHSO3 or p-benzoquinone. The benzaldehyde precursors with different N-1 substituted 1,2,3-triazoles (7, 9–11 and 14–16) were synthesized by copper-catalyzed Huisgen 1,3-dipolar cycloaddition. In order to determine the influence of various substituents on inhibitory activity, 5(6)-imidazoline substituted benzimidazole derivatives with benzoyl (41–43), morpholinoyl (44–46), pyridine (47–49), ethylmorpholine (50–52) and diethylaminoethyl (53–55) substituents linked to the phenoxymethylene linker were prepared. In silico analysis of structural properties and molecular docking of novel compounds at DFG-out conformation of p38 MAP kinase were performed. The structures of all prepared compounds were confirmed by 1H and 13C NMR spectroscopy. Inhibitory activities on p38 MAPK and antiproliferative assay of prepared compounds on malignant tumor cells are underway