title: Design, synthesis and anti-tuberculosis activity of 1-adamantyl-3-heteroaryl ureas with improved in vitro pharmacokinetic properties.
abstract: Out of the prominent global ailments, tuberculosis (TB) is still one of the leading causes of death worldwide due to infectious disease. Development of new drugs that shorten the current tuberculosis treatment time and have activity against drug resistant strains is of utmost importance. Towards these goals we have focused our efforts on developing novel anti-TB compounds with the general structure of 1-adamantyl-3-phenyl urea. This series is active against Mycobacteria and previous lead compounds were found to inhibit the membrane transporter MmpL3, the protein responsible for mycolic acid transport across the plasma membrane. However, these compounds suffered from poor in vitro pharmacokinetic (PK) profiles and they have a similar structure/SAR to inhibitors of human soluble epoxide hydrolase (sEH) enzymes. Therefore, in this study the further optimization of this compound class was driven by three factors: (1) to increase selectivity for anti-TB activity over human sEH activity, (2) to optimize PK profiles including solubility and (3) to maintain target inhibition. A new series of 1-adamantyl-3-heteroaryl ureas was designed and synthesized replacing the phenyl substituent of the original series with pyridines, pyrimidines, triazines, oxazoles, isoxazoles, oxadiazoles and pyrazoles. This study produced lead isoxazole, oxadiazole and pyrazole substituted adamantyl ureas with improved in vitro PK profiles, increased selectivity and good anti-TB potencies with sub μg/mL minimum inhibitory concentrations.
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: E Jeffrey
authors.initials: EJ
authors.lastname: North
authors.forename: Michael S
authors.initials: MS
authors.lastname: Scherman
authors.forename: David F
authors.initials: DF
authors.lastname: Bruhn
authors.forename: Jerrod S
authors.initials: JS
authors.lastname: Scarborough
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Maddox
authors.forename: Victoria
authors.initials: V
authors.lastname: Jones
authors.forename: Anna
authors.initials: A
authors.lastname: Grzegorzewicz
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Tamara
authors.initials: T
authors.lastname: Hess
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
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*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009159:Mycobacteriaceae / Q000187:drug effects*; D012995:Solubility; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D014508:Urea; D004851:Epoxide Hydrolases