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

Joshua R. Brown, E. Jeffrey 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

Research output: Contribution to journalArticle

60 Citations (Scopus)

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 languageEnglish
Pages (from-to)5585-5595
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number18
DOIs
StatePublished - Sep 15 2011
Externally publishedYes

Fingerprint

Epoxide Hydrolases
Structure-Activity Relationship
Urea
Tuberculosis
Derivatives
Mycobacterium tuberculosis
Libraries
Enzymes
Cytotoxicity
Drug Resistance
Molecules
Testing
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Brown, J. R., North, E. J., Hurdle, J. G., Morisseau, C., Scarborough, J. S., Sun, D., ... Lee, R. E. (2011). The structure-activity relationship of urea derivatives as anti-tuberculosis agents. Bioorganic and Medicinal Chemistry, 19(18), 5585-5595. https://doi.org/10.1016/j.bmc.2011.07.034

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 journalArticle

Brown, JR, North, EJ, Hurdle, JG, Morisseau, C, Scarborough, JS, Sun, D, Korduláková, J, Scherman, MS, Jones, V, Grzegorzewicz, A, Crew, RM, Jackson, M, McNeil, MR & Lee, RE 2011, 'The structure-activity relationship of urea derivatives as anti-tuberculosis agents', Bioorganic and Medicinal Chemistry, vol. 19, no. 18, pp. 5585-5595. https://doi.org/10.1016/j.bmc.2011.07.034
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. / The structure-activity relationship of urea derivatives as anti-tuberculosis agents. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 18. pp. 5585-5595.
@article{645da432de9d4be2841dc520c36eed57,
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.",
author = "Brown, {Joshua R.} and North, {E. Jeffrey} and Hurdle, {Julian G.} and Christophe Morisseau and Scarborough, {Jerrod S.} and Dianqing Sun and Jana Kordul{\'a}kov{\'a} and Scherman, {Michael S.} and Victoria Jones and Anna Grzegorzewicz and Crew, {Rebecca M.} and Mary Jackson and McNeil, {Michael R.} and Lee, {Richard E.}",
year = "2011",
month = "9",
day = "15",
doi = "10.1016/j.bmc.2011.07.034",
language = "English",
volume = "19",
pages = "5585--5595",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "18",

}

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

C2 - 21840723

AN - SCOPUS:80052588394

VL - 19

SP - 5585

EP - 5595

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 18

ER -