SAR of a new antischistosomal urea carboxylic acid

Jianbo Wu, Chunkai Wang, Cécile Häberli, Karen L. White, David M. Shackleford, Gong Chen, Yuxiang Dong, Susan A. Charman, Jennifer Keiser, Jonathan L. Vennerstrom

Research output: Contribution to journalArticle

Abstract

Urea carboxylic acids, products of aryl hydantoin hydrolysis, were recently identified as a new antischistosomal chemotype. We now describe a baseline structure–activity relationship (SAR) for this compound series. With one exception, analogs of lead urea carboxylic acid 2 were quite polar with Log D7.4 values ranging from −1.9 to 1.8, had high aqueous solubilities in the range of 25–100 µg/mL, and were metabolically stable. None of the compounds had measurable in vitro antischistosomal activity or cytotoxicity, but four of these had moderate worm burden reduction (WBR) values of 42–70% when they were administered as single 100 mg/kg oral doses to S. mansoni-infected mice. These data indicate that with the exception of the gem-dimethyl substructure and the distal nitrogen atom of the urea functional group, the rest of the structure of 2 is required for in vivo antischistosomal activity.

Original languageEnglish (US)
Pages (from-to)3648-3651
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number23-24
DOIs
StatePublished - Dec 15 2018

Fingerprint

Carboxylic Acids
Urea
Hydantoins
Gems
Cytotoxicity
Solubility
Functional groups
Hydrolysis
Nitrogen
Atoms

Keywords

  • Antischistosomal
  • SAR
  • Urea carboxylic acid

ASJC Scopus subject areas

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

Cite this

Wu, J., Wang, C., Häberli, C., White, K. L., Shackleford, D. M., Chen, G., ... Vennerstrom, J. L. (2018). SAR of a new antischistosomal urea carboxylic acid. Bioorganic and Medicinal Chemistry Letters, 28(23-24), 3648-3651. https://doi.org/10.1016/j.bmcl.2018.10.039

SAR of a new antischistosomal urea carboxylic acid. / Wu, Jianbo; Wang, Chunkai; Häberli, Cécile; White, Karen L.; Shackleford, David M.; Chen, Gong; Dong, Yuxiang; Charman, Susan A.; Keiser, Jennifer; Vennerstrom, Jonathan L.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 28, No. 23-24, 15.12.2018, p. 3648-3651.

Research output: Contribution to journalArticle

Wu, J, Wang, C, Häberli, C, White, KL, Shackleford, DM, Chen, G, Dong, Y, Charman, SA, Keiser, J & Vennerstrom, JL 2018, 'SAR of a new antischistosomal urea carboxylic acid', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 23-24, pp. 3648-3651. https://doi.org/10.1016/j.bmcl.2018.10.039
Wu J, Wang C, Häberli C, White KL, Shackleford DM, Chen G et al. SAR of a new antischistosomal urea carboxylic acid. Bioorganic and Medicinal Chemistry Letters. 2018 Dec 15;28(23-24):3648-3651. https://doi.org/10.1016/j.bmcl.2018.10.039
Wu, Jianbo ; Wang, Chunkai ; Häberli, Cécile ; White, Karen L. ; Shackleford, David M. ; Chen, Gong ; Dong, Yuxiang ; Charman, Susan A. ; Keiser, Jennifer ; Vennerstrom, Jonathan L. / SAR of a new antischistosomal urea carboxylic acid. In: Bioorganic and Medicinal Chemistry Letters. 2018 ; Vol. 28, No. 23-24. pp. 3648-3651.
@article{90932fd1a7fa439a9946c4f5f17d77ff,
title = "SAR of a new antischistosomal urea carboxylic acid",
abstract = "Urea carboxylic acids, products of aryl hydantoin hydrolysis, were recently identified as a new antischistosomal chemotype. We now describe a baseline structure–activity relationship (SAR) for this compound series. With one exception, analogs of lead urea carboxylic acid 2 were quite polar with Log D7.4 values ranging from −1.9 to 1.8, had high aqueous solubilities in the range of 25–100 µg/mL, and were metabolically stable. None of the compounds had measurable in vitro antischistosomal activity or cytotoxicity, but four of these had moderate worm burden reduction (WBR) values of 42–70{\%} when they were administered as single 100 mg/kg oral doses to S. mansoni-infected mice. These data indicate that with the exception of the gem-dimethyl substructure and the distal nitrogen atom of the urea functional group, the rest of the structure of 2 is required for in vivo antischistosomal activity.",
keywords = "Antischistosomal, SAR, Urea carboxylic acid",
author = "Jianbo Wu and Chunkai Wang and C{\'e}cile H{\"a}berli and White, {Karen L.} and Shackleford, {David M.} and Gong Chen and Yuxiang Dong and Charman, {Susan A.} and Jennifer Keiser and Vennerstrom, {Jonathan L.}",
year = "2018",
month = "12",
day = "15",
doi = "10.1016/j.bmcl.2018.10.039",
language = "English (US)",
volume = "28",
pages = "3648--3651",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "23-24",

}

TY - JOUR

T1 - SAR of a new antischistosomal urea carboxylic acid

AU - Wu, Jianbo

AU - Wang, Chunkai

AU - Häberli, Cécile

AU - White, Karen L.

AU - Shackleford, David M.

AU - Chen, Gong

AU - Dong, Yuxiang

AU - Charman, Susan A.

AU - Keiser, Jennifer

AU - Vennerstrom, Jonathan L.

PY - 2018/12/15

Y1 - 2018/12/15

N2 - Urea carboxylic acids, products of aryl hydantoin hydrolysis, were recently identified as a new antischistosomal chemotype. We now describe a baseline structure–activity relationship (SAR) for this compound series. With one exception, analogs of lead urea carboxylic acid 2 were quite polar with Log D7.4 values ranging from −1.9 to 1.8, had high aqueous solubilities in the range of 25–100 µg/mL, and were metabolically stable. None of the compounds had measurable in vitro antischistosomal activity or cytotoxicity, but four of these had moderate worm burden reduction (WBR) values of 42–70% when they were administered as single 100 mg/kg oral doses to S. mansoni-infected mice. These data indicate that with the exception of the gem-dimethyl substructure and the distal nitrogen atom of the urea functional group, the rest of the structure of 2 is required for in vivo antischistosomal activity.

AB - Urea carboxylic acids, products of aryl hydantoin hydrolysis, were recently identified as a new antischistosomal chemotype. We now describe a baseline structure–activity relationship (SAR) for this compound series. With one exception, analogs of lead urea carboxylic acid 2 were quite polar with Log D7.4 values ranging from −1.9 to 1.8, had high aqueous solubilities in the range of 25–100 µg/mL, and were metabolically stable. None of the compounds had measurable in vitro antischistosomal activity or cytotoxicity, but four of these had moderate worm burden reduction (WBR) values of 42–70% when they were administered as single 100 mg/kg oral doses to S. mansoni-infected mice. These data indicate that with the exception of the gem-dimethyl substructure and the distal nitrogen atom of the urea functional group, the rest of the structure of 2 is required for in vivo antischistosomal activity.

KW - Antischistosomal

KW - SAR

KW - Urea carboxylic acid

UR - http://www.scopus.com/inward/record.url?scp=85055627978&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055627978&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2018.10.039

DO - 10.1016/j.bmcl.2018.10.039

M3 - Article

C2 - 30389288

AN - SCOPUS:85055627978

VL - 28

SP - 3648

EP - 3651

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 23-24

ER -