Chemopreventive and antioxidant activity of 6-substituted imidazo[2,1-b]thiazoles

Abstract

The synthesis of new imidazo[2,1-b]thiazoles bearing phenolic groups is reported. These compounds and some previously described analogs were evaluated as antioxidant agents with three chemical model systems, and cancer chemopreventive potential was examined by inhibition of NO production, TNF-α activated NFκB activity, and aromatase activity, as well as induction of QR1 and RXRE binding. Two of the test compounds, 9 and 12, displayed promising activity by inhibiting iNOS, NFκB and aromatase in dose-dependent manner, with IC50 values in low micromolar range. The same compounds activated QR1 in a bifunctional manner. When incubated with human liver microsomes, the active compounds were further hydroxylated on the parent ring system, suggesting the next logical step in the development of these promising leads will entail synthetic production of metabolites followed by additional assessment of biological activity.

Keywords: 2,2-diphenyl-1-picrylhydrazyl; 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide; AhR; Antioxidants; BDE; BR; Bond Dissociation Enthalpies; Briggs–Rauscher; Chemopreventive agents; DPPH; IR; Imidazo[2,1-b]thiazoles; L-N(G)-monomethyl arginine citrate; L-NMMA; MTT; NFκB; Polyphenols; QR1, NAD(P)H; RAC; RNS; ROS; RXR; RXRE; Relative Antioxidant Capacity; SRB; SRM; TEAC; TNF; TPCK; Trolox Equivalent Antioxidant Activity; aryl hydrocarbon receptor; iNOS; inducible nitric oxide synthase; induction ratio; nuclear factor kappa beta; quinone reductase 1; reactive nitrogen species; reactive oxygen species; retinoid X receptor; retinoid X receptor response element; selected reaction monitoring; sulforhodamine B; tosyl phenylalanyl chloromethyl ketone; tumor necrosis factor.