Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine-Quinolone Carboxamides

Ziwei Hu; Janardhan Banothu; Mallesh Beesu; Collin J. Gustafson; Michael J.H. Brush; Kathryn L. Trautman; Alex C.D. Salyer; Balaji Pathakumari; Sunil A. David

doi:10.1021/acsmedchemlett.8b00540

Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine-Quinolone Carboxamides

Ziwei Hu, Janardhan Banothu, Mallesh Beesu, Collin J. Gustafson, Michael J.H. Brush, Kathryn L. Trautman, Alex C.D. Salyer, Balaji Pathakumari, Sunil A. David

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification of analogues that induce chemokines and cytokines in a TLR2-dependent manner. These results represent new leads for the development of vaccine adjuvants.

Original language	English (US)
Pages (from-to)	132-136
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	10
Issue number	1
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00540
State	Published - Oct 1 2019

Bibliographical note

Funding Information:
*Phone: (612) 625-3848. E-mail: [email protected]. ORCID Sunil A. David: 0000-0003-1655-4641 Author Contributions ‡These authors contributed equally. Funding This work was supported by NIH/NIAID contract HHSN272201400056C. Notes The authors declare no competing financial interest.

Keywords

Toll-like receptor 2
Vaccine adjuvants
chemokines
cytokines
dihydropyridine-quinolones

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10.1021/acsmedchemlett.8b00540

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331173

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title = "Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine-Quinolone Carboxamides",

abstract = "Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification of analogues that induce chemokines and cytokines in a TLR2-dependent manner. These results represent new leads for the development of vaccine adjuvants.",

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author = "Ziwei Hu and Janardhan Banothu and Mallesh Beesu and Gustafson, {Collin J.} and Brush, {Michael J.H.} and Trautman, {Kathryn L.} and Salyer, {Alex C.D.} and Balaji Pathakumari and David, {Sunil A.}",

note = "Funding Information: *Phone: (612) 625-3848. E-mail: [email protected]. ORCID Sunil A. David: 0000-0003-1655-4641 Author Contributions ‡These authors contributed equally. Funding This work was supported by NIH/NIAID contract HHSN272201400056C. Notes The authors declare no competing financial interest.",

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doi = "10.1021/acsmedchemlett.8b00540",

language = "English (US)",

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AU - Hu, Ziwei

AU - Banothu, Janardhan

AU - Beesu, Mallesh

AU - Gustafson, Collin J.

AU - Brush, Michael J.H.

AU - Trautman, Kathryn L.

AU - Salyer, Alex C.D.

AU - Pathakumari, Balaji

AU - David, Sunil A.

N1 - Funding Information: *Phone: (612) 625-3848. E-mail: [email protected]. ORCID Sunil A. David: 0000-0003-1655-4641 Author Contributions ‡These authors contributed equally. Funding This work was supported by NIH/NIAID contract HHSN272201400056C. Notes The authors declare no competing financial interest.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification of analogues that induce chemokines and cytokines in a TLR2-dependent manner. These results represent new leads for the development of vaccine adjuvants.

AB - Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification of analogues that induce chemokines and cytokines in a TLR2-dependent manner. These results represent new leads for the development of vaccine adjuvants.

KW - Toll-like receptor 2

KW - Vaccine adjuvants

KW - chemokines

KW - cytokines

KW - dihydropyridine-quinolones

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Identification of Human Toll-like Receptor 2-Agonistic Activity in Dihydropyridine-Quinolone Carboxamides

Abstract

Bibliographical note

Keywords

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