title: The structure-activity relationship of urea derivatives as anti-tuberculosis agents.
abstract: The treatment of tuberculosis is becoming more difficult due to the ever increasing prevalence of drug resistance. Thus, it is imperative that novel anti-tuberculosis agents, with unique mechanisms of action, be discovered and developed. The direct anti-tubercular testing of a small compound library led to discovery of adamantyl urea hit compound 1. In this study, the hit was followed up through the synthesis of an optimization library. This library was generated by systematically replacing each section of the molecule with a similar moiety until a clear structure-activity relationship was obtained with respect to anti-tubercular activity. The best compounds in this series contained a 1-adamantyl-3-phenyl urea core and had potent activity against Mycobacterium tuberculosis plus an acceptable therapeutic index. It was noted that the compounds identified and the pharmacophore developed is consistent with inhibitors of epoxide hydrolase family of enzymes. Consequently, the compounds were tested for inhibition of representative epoxide hydrolases: M. tuberculosis EphB and EphE; and human soluble epoxide hydrolase. Many of the optimized inhibitors showed both potent EphB and EphE inhibition suggesting the antitubercular activity is through inhibition of multiple epoxide hydrolase enzymes. The inhibitors also showed potent inhibition of humans soluble epoxide hydrolase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolase inhibition towards the M. tuberculosis enzymes.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 1000, Memphis, TN 38105, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Brown
authors.forename: Elton J
authors.initials: EJ
authors.lastname: North
authors.forename: Julian G
authors.initials: JG
authors.lastname: Hurdle
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Jerrod S
authors.initials: JS
authors.lastname: Scarborough
authors.forename: Dianqing
authors.initials: D
authors.lastname: Sun
authors.forename: Jana
authors.initials: J
authors.lastname: Korduláková
authors.forename: Michael S
authors.initials: MS
authors.lastname: Scherman
authors.forename: Victoria
authors.initials: V
authors.lastname: Jones
authors.forename: Anna
authors.initials: A
authors.lastname: Grzegorzewicz
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Crew
authors.forename: Mary
authors.initials: M
authors.lastname: Jackson
authors.forename: Michael R
authors.initials: MR
authors.lastname: McNeil
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D036081:Receptors, Eph Family / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D014508:Urea; D036081:Receptors, Eph Family; D004851:Epoxide Hydrolases