• Home
  • Search Results
  • The structure-activity relationship of urea derivatives as anti-tuberculosis agents.

The structure-activity relationship of urea derivatives as anti-tuberculosis agents.

Bioorganic & medicinal chemistry (2011-08-16)
Joshua R Brown, Elton J North, Julian G Hurdle, Christophe Morisseau, Jerrod S Scarborough, Dianqing Sun, Jana Korduláková, Michael S Scherman, Victoria Jones, Anna Grzegorzewicz, Rebecca M Crew, Mary Jackson, Michael R McNeil, Richard E Lee
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Isoniazid, analytical standard, ≥99% (TLC)
Sigma-Aldrich
1,3-Diphenylurea, 98%
Sigma-Aldrich
1-Bromo-4-methylpentane, 97%
Sigma-Aldrich
3-Chloro-4-methylphenyl isocyanate, 98%

Social Media

LinkedIn icon
Twitter icon
Facebook Icon
Instagram Icon

MilliporeSigma

Research. Development. Production.

We are a leading supplier to the global Life Science industry with solutions and services for research, biotechnology development and production, and pharmaceutical drug therapy development and production.

© 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

Reproduction of any materials from the site is strictly forbidden without permission.