Design and synthesis of functionalized 4-aryl-Catechol derivatives as new antiinflammtory agents with in vivo efficacy

• DOI: 10.1016/j.ejmech.2022.114788
• Publication Date: 2022-09-27T15:46:14Z
• Authors: Ferdinando Bruno; Verena Krauth; Seyed Mohamed Nabavi; Veronika Temml; Florinda Fratianni; Giuseppe Spaziano; Filomena Nazzaro; Fiorita Roviezzo; Jianbo Xiao; Haroon Khan; Maria Preziosa Ro...; Bruno D'Agostino; Oliver Werz; Rosanna Filosa
• Keywords: 5-Lipoxygenase; Inflammation; 0301 basic medicine; Catechols; Benzene; Carrageenan; Antioxidants; 3. Good health; Mice; 03 medical and health sciences; Catechol; Leukocytes; Animals; Edema; Lipoxygenase Inhibitors; Leukotriene

Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases and the discovery of antioxidants is an attractive approach that can simultaneously tackle two or more therapeutic targets of the arachidonic acid cascade. We report that the simple structural variations on the 4-aryl-benzene-1,2-diol side-arm of the scaffold significantly influence the selectivity against 5-LOX vs 12- and 15-LOX. Derivatives 4 a-l were evaluated for their antioxidant activity, using the DPPH, and ferric ion reducing antioxidant power (FRAP) methods. Docking simulations proposed concrete binding of the catechol series to 5-LO. Selected active compound 4-(3,4-dihydroxyphenyl)dibenzofuran (4l) was also tested in different in vivo mouse models of inflammation. 4l (0.1 mg/kg; i.p.) impaired (I) bronchoconstriction in ovalbumin-sensitized mice challenged with acetylcholine, (II) exudate formation in carrageenan-induced paw edema, and (III) zymosan-induced leukocyte infiltration in air pouches. These results pave the way for investigating the therapeutic potential of 4-aryl-benzene-1,2-diol, as novel multitarget therapeutic drugs, able to regulate the complex inflammatory cascade mechanisms.