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.
| Original language | English |
|---|---|
| Pages (from-to) | 5585-5595 |
| Number of pages | 11 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 19 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 15 2011 |
| Externally published | Yes |
Fingerprint
All Science Journal Classification (ASJC) codes
- Pharmaceutical Science
- Drug Discovery
- Organic Chemistry
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry
- Biochemistry
Cite this
The structure-activity relationship of urea derivatives as anti-tuberculosis agents. / Brown, Joshua R.; North, E. Jeffrey; Hurdle, Julian G.; Morisseau, Christophe; Scarborough, Jerrod S.; Sun, Dianqing; Korduláková, Jana; Scherman, Michael S.; Jones, Victoria; Grzegorzewicz, Anna; Crew, Rebecca M.; Jackson, Mary; McNeil, Michael R.; Lee, Richard E.
In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 18, 15.09.2011, p. 5585-5595.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The structure-activity relationship of urea derivatives as anti-tuberculosis agents
AU - Brown, Joshua R.
AU - North, E. Jeffrey
AU - Hurdle, Julian G.
AU - Morisseau, Christophe
AU - Scarborough, Jerrod S.
AU - Sun, Dianqing
AU - Korduláková, Jana
AU - Scherman, Michael S.
AU - Jones, Victoria
AU - Grzegorzewicz, Anna
AU - Crew, Rebecca M.
AU - Jackson, Mary
AU - McNeil, Michael R.
AU - Lee, Richard E.
PY - 2011/9/15
Y1 - 2011/9/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052588394&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052588394&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2011.07.034
DO - 10.1016/j.bmc.2011.07.034
M3 - Article
VL - 19
SP - 5585
EP - 5595
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 18
ER -