title: Anthranilic acid-based inhibitors of phosphodiesterase: design, synthesis, and bioactive evaluation.
abstract: Our previous studies identified two 2-benzoylaminobenzoate derivatives 1, which potently inhibited superoxide (O(2)˙(-)) generation induced by formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in human neutrophils. In an attempt to improve their activities, a series of anthranilic acid derivatives were synthesized and their anti-inflammatory effects and underlying mechanisms were investigated in human neutrophils. Of these, compounds 17, 18, 46, 49, and 50 showed the most potent inhibitory effect on FMLP-induced release of O(2)˙(-) in human neutrophils with IC(50) values of 0.20, 0.16, 0.15, 0.06, and 0.29 μM, respectively. SAR analysis showed that the activities of most compounds were dependent on the ester chain length in the A ring. Conversely, a change in the linker between the A and B ring from amide to sulfonamide or N-methyl amide, as well as exchanges in the benzene rings (A or B rings) by isosteric replacements were unfavorable. Further studies indicated that inhibition of O(2)˙(-) production in human neutrophils by these anthranilic acids was associated with an elevation in cellular cAMP levels through the selective inhibition of phosphodiesterase 4. Compound 49 could be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases.
authors.affiliation: Graduate Institute of Natural Products, Chang Gung University, Taoyuan, 33302, Taiwan.
authors.forename: Yih-Dih
authors.initials: YD
authors.lastname: Cheng
authors.forename: Tsong-Long
authors.initials: TL
authors.lastname: Hwang
authors.forename: Han-Hsiang
authors.initials: HH
authors.lastname: Wang
authors.forename: Tai-Long
authors.initials: TL
authors.lastname: Pan
authors.forename: Chin-Chung
authors.initials: CC
authors.lastname: Wu
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Chang
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Liu
authors.forename: Tzu-Chi
authors.initials: TC
authors.lastname: Chu
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsieh
mesh_terms: D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D010726:Phosphodiesterase Inhibitors; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases