- Development of Benzenesulfonamide Derivatives as Potent Glutathione Transferase Omega-1 Inhibitors
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Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1β and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the kinact/KI values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine kinact/KI values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of 25, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.
- Xie, Yiyue,Tummala, Padmaja,Oakley, Aaron J.,Deora, Girdhar Singh,Nakano, Yuji,Rooke, Melissa,Cuellar, Matthew E.,Strasser, Jessica M.,Dahlin, Jayme L.,Walters, Michael A.,Casarotto, Marco G.,Board, Philip G.,Baell, Jonathan B.
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p. 2894 - 2914
(2020/04/08)
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- Benzenesulfonamide derivatives and methods for their production
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A compound having the structural formula STR1 wherein: R is hydrogen, C1 -C4 alkyl, C1 -C4 haloalkyl, formyl, C2 -C6 alkanoyl, C3 -C4 alkenyl or C3 -C4 alkynyl, or alkali metal; X is C1 -C4 alkyl, C1 -C8 alkoxy, cyano, or halogen; Y is hydrogen, halogen, or C1 -C4 dialkylamino; R1 is hydrogen, C1 -C8 straight chain or branched alkyl, C3 -C8 cycloalkyl, C3 -C8 alkenyl, C3 -C8 alkoxy or C3 -C8 hydroxyalkyl; R2 is hydrogen, C1 -C8 straight chain or branched alkyl, C3 -C8 alkenyl, C3 -C8 cycloalkyl, halo substituted C3 -C8 alkenyl, C3 -C8 alkynyl, C1 -C4 alkoxy, hydroxy C1 -C4 alkyl, cyano C1 -C4 alkyl, 2,3-epoxypropyl, 2,2-dialkoxyethyl, alkoxyalkyl, phenyl, aralkyl, C1 -C4 acyl, C1 -C4 carbalkoxyalkyl, C1 -C4 carbalkoxyalkyl substituted by C1 -C4 alkyl, phenylmethyl or methylthioethyl, (1,3-dioxolan-2-yl)alkyl, dialkylaminoethyl, or tetrahydrofuranylmethyl; R3 is hydrogen, halogen or C1 -C4 alkyl; R4 is C1 -C4 alkyl or C1 -C4 haloalkyl; R1 and R2 taken together form a C3 -C8 membered heterocyclic ring containing one or more heteroatoms. In addition, processes and novel intermediate compounds that are useful for making the compound are set forth. A method for controlling weeds which comprises applying a herbicidally effective amount of the compound recited above is described. Also disclosed is a composition useful as an herbicide which includes a compound of this invention and a suitable carrier therefor.
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