Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability

Michael S. Scherman, E. Jeffrey North, Victoria Jones, Tamara N. Hess, Anna E. Grzegorzewicz, Takeo Kasagami, In Hae Kim, Oleg Merzlikin, Anne J. Lenaerts, Richard E. Lee, Mary Jackson, Christophe Morisseau, Michael R. McNeil

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 μg/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high c Log P's and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with c Log P and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium.

Original languageEnglish
Pages (from-to)3255-3262
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number10
DOIs
StatePublished - May 15 2012
Externally publishedYes

Fingerprint

Epoxide Hydrolases
Mycobacterium tuberculosis
Chemical properties
Biological Availability
Libraries
Urea
Screening
Bacteria
Trehalose
In Vitro Techniques
Mycobacterium Infections
Human Activities
Oral Administration
Proteins
Growth
Serum

All Science Journal Classification (ASJC) codes

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

Cite this

Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability. / Scherman, Michael S.; North, E. Jeffrey; Jones, Victoria; Hess, Tamara N.; Grzegorzewicz, Anna E.; Kasagami, Takeo; Kim, In Hae; Merzlikin, Oleg; Lenaerts, Anne J.; Lee, Richard E.; Jackson, Mary; Morisseau, Christophe; McNeil, Michael R.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 10, 15.05.2012, p. 3255-3262.

Research output: Contribution to journalArticle

Scherman, MS, North, EJ, Jones, V, Hess, TN, Grzegorzewicz, AE, Kasagami, T, Kim, IH, Merzlikin, O, Lenaerts, AJ, Lee, RE, Jackson, M, Morisseau, C & McNeil, MR 2012, 'Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability', Bioorganic and Medicinal Chemistry, vol. 20, no. 10, pp. 3255-3262. https://doi.org/10.1016/j.bmc.2012.03.058
Scherman, Michael S. ; North, E. Jeffrey ; Jones, Victoria ; Hess, Tamara N. ; Grzegorzewicz, Anna E. ; Kasagami, Takeo ; Kim, In Hae ; Merzlikin, Oleg ; Lenaerts, Anne J. ; Lee, Richard E. ; Jackson, Mary ; Morisseau, Christophe ; McNeil, Michael R. / Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 10. pp. 3255-3262.
@article{ac7e7df52d5d4cabba2864c8104ecdf3,
title = "Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability",
abstract = "Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 μg/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high c Log P's and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with c Log P and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium.",
author = "Scherman, {Michael S.} and North, {E. Jeffrey} and Victoria Jones and Hess, {Tamara N.} and Grzegorzewicz, {Anna E.} and Takeo Kasagami and Kim, {In Hae} and Oleg Merzlikin and Lenaerts, {Anne J.} and Lee, {Richard E.} and Mary Jackson and Christophe Morisseau and McNeil, {Michael R.}",
year = "2012",
month = "5",
day = "15",
doi = "10.1016/j.bmc.2012.03.058",
language = "English",
volume = "20",
pages = "3255--3262",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "10",

}

TY - JOUR

T1 - Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability

AU - Scherman, Michael S.

AU - North, E. Jeffrey

AU - Jones, Victoria

AU - Hess, Tamara N.

AU - Grzegorzewicz, Anna E.

AU - Kasagami, Takeo

AU - Kim, In Hae

AU - Merzlikin, Oleg

AU - Lenaerts, Anne J.

AU - Lee, Richard E.

AU - Jackson, Mary

AU - Morisseau, Christophe

AU - McNeil, Michael R.

PY - 2012/5/15

Y1 - 2012/5/15

N2 - Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 μg/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high c Log P's and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with c Log P and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium.

AB - Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 μg/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high c Log P's and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with c Log P and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium.

UR - http://www.scopus.com/inward/record.url?scp=84860481546&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860481546&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2012.03.058

DO - 10.1016/j.bmc.2012.03.058

M3 - Article

VL - 20

SP - 3255

EP - 3262

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 10

ER -