title: Antitubercular nitrofuran isoxazolines with improved pharmacokinetic properties.
abstract: A series of tetracyclic nitrofuran isoxazoline anti-tuberculosis agents was designed and synthesized to improve the pharmacokinetic properties of an initial lead compound, which had potent anti-tuberculosis activity but suffered from poor solubility, high protein binding and rapid metabolism. In this study, structural modifications were carried on the outer phenyl and piperidine rings to introduce solubilizing and metabolically blocking functional groups. The compounds generated were evaluated for their in vitro antitubercular activity, bacterial spectrum of activity, solubility, permeability, microsomal stability and protein binding. Pharmacokinetic profiles for the most promising candidates were then determined. Compounds with phenyl morpholine and pyridyl morpholine outer rings were found to be the most potent anti-tuberculosis agents in the series. These compounds retained a narrow antibacterial spectrum of activity, with weak anti-Gram positive and no Gram negative activity, as well as good activity against non-replicating Mycobacterium tuberculosis in a low oxygen model. Overall, the addition of solubilizing and metabolically blocked outer rings did improve solubility and decrease protein binding as designed. However, the metabolic stability for compounds in this series was generally lower than desired. The best three compounds selected for in vivo pharmacokinetic testing all showed high oral bioavailability, with one notable compound showing a significantly longer half-life and good tolerability supporting its further advancement.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.lastname: Rakesh
authors.forename: David
authors.initials: D
authors.lastname: Bruhn
authors.forename: Dora B
authors.initials: DB
authors.lastname: Madhura
authors.forename: Marcus
authors.initials: M
authors.lastname: Maddox
authors.forename: Robin B
authors.initials: RB
authors.lastname: Lee
authors.forename: Ashit
authors.initials: A
authors.lastname: Trivedi
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Scherman
authors.forename: Janet C
authors.initials: JC
authors.lastname: Gilliland
authors.forename: Veronica
authors.initials: V
authors.lastname: Gruppo
authors.forename: Michael R
authors.initials: MR
authors.lastname: McNeil
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
authors.forename: Bernd
authors.initials: B
authors.lastname: Meibohm
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry; D051379:Mice; D008826:Microbial Sensitivity Tests; D008861:Microsomes / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009581:Nitrofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D007555:Isoxazoles; D009581:Nitrofurans