Structure-Activity Relationship for the Oxadiazole Class of Antibacterials

Marc A. Boudreau; Derong Ding; Jayda E. Meisel; Jeshina Janardhanan; Edward Spink; Zhihong Peng; Yuanyuan Qian; Takao Yamaguchi; Sebastian A. Testero; Peter I. O'Daniel; Erika Leemans; Elena Lastochkin; Wei Song; Valerie A. Schroeder; William R. Wolter; Mark A. Suckow; Shahriar Mobashery; Mayland Chang

doi:10.1021/acsmedchemlett.9b00379

Structure-Activity Relationship for the Oxadiazole Class of Antibacterials

Marc A. Boudreau, Derong Ding, Jayda E. Meisel, Jeshina Janardhanan, Edward Spink, Zhihong Peng, Yuanyuan Qian, Takao Yamaguchi, Sebastian A. Testero, Peter I. O'Daniel, Erika Leemans, Elena Lastochkin, Wei Song, Valerie A. Schroeder, William R. Wolter, Mark A. Suckow, Shahriar Mobashery, Mayland Chang

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

18 Scopus citations

Abstract

A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for in vitro toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection. Oxadiazole 72c shows potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.

Original language	English
Pages (from-to)	322-326
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	3
DOIs	https://doi.org/10.1021/acsmedchemlett.9b00379
State	Published - Mar 12 2020

Bibliographical note

Funding Information:
This work was supported by grants AI090818 (to MC and SM) and by AI104987 (to SM) from the National Institutes of Health. YQ is a Ruth L. Kirschstein National Research Service Award Fellow of the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, supported by training grant T32 GM075762 from the National Institutes of Health.

Publisher Copyright:
Copyright © 2019 American Chemical Society.

Keywords

Antibacterials
oxadiazoles
penicillin-binding proteins
structure-activity relationship

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/acsmedchemlett.9b00379

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Boudreau, M. A., Ding, D., Meisel, J. E., Janardhanan, J., Spink, E., Peng, Z., Qian, Y., Yamaguchi, T., Testero, S. A., O'Daniel, P. I., Leemans, E., Lastochkin, E., Song, W., Schroeder, V. A., Wolter, W. R., Suckow, M. A., Mobashery, S., & Chang, M. (2020). Structure-Activity Relationship for the Oxadiazole Class of Antibacterials. ACS Medicinal Chemistry Letters, 11(3), 322-326. https://doi.org/10.1021/acsmedchemlett.9b00379

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abstract = "A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for in vitro toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection. Oxadiazole 72c shows potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.",

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author = "Boudreau, {Marc A.} and Derong Ding and Meisel, {Jayda E.} and Jeshina Janardhanan and Edward Spink and Zhihong Peng and Yuanyuan Qian and Takao Yamaguchi and Testero, {Sebastian A.} and O'Daniel, {Peter I.} and Erika Leemans and Elena Lastochkin and Wei Song and Schroeder, {Valerie A.} and Wolter, {William R.} and Suckow, {Mark A.} and Shahriar Mobashery and Mayland Chang",

note = "Funding Information: This work was supported by grants AI090818 (to MC and SM) and by AI104987 (to SM) from the National Institutes of Health. YQ is a Ruth L. Kirschstein National Research Service Award Fellow of the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, supported by training grant T32 GM075762 from the National Institutes of Health. Publisher Copyright: Copyright {\textcopyright} 2019 American Chemical Society.",

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doi = "10.1021/acsmedchemlett.9b00379",

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Boudreau, MA, Ding, D, Meisel, JE, Janardhanan, J, Spink, E, Peng, Z, Qian, Y, Yamaguchi, T, Testero, SA, O'Daniel, PI, Leemans, E, Lastochkin, E, Song, W, Schroeder, VA, Wolter, WR, Suckow, MA, Mobashery, S & Chang, M 2020, 'Structure-Activity Relationship for the Oxadiazole Class of Antibacterials', ACS Medicinal Chemistry Letters, vol. 11, no. 3, pp. 322-326. https://doi.org/10.1021/acsmedchemlett.9b00379

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T1 - Structure-Activity Relationship for the Oxadiazole Class of Antibacterials

AU - Boudreau, Marc A.

AU - Ding, Derong

AU - Meisel, Jayda E.

AU - Janardhanan, Jeshina

AU - Spink, Edward

AU - Peng, Zhihong

AU - Qian, Yuanyuan

AU - Yamaguchi, Takao

AU - Testero, Sebastian A.

AU - O'Daniel, Peter I.

AU - Leemans, Erika

AU - Lastochkin, Elena

AU - Song, Wei

AU - Schroeder, Valerie A.

AU - Wolter, William R.

AU - Suckow, Mark A.

AU - Mobashery, Shahriar

AU - Chang, Mayland

N1 - Funding Information: This work was supported by grants AI090818 (to MC and SM) and by AI104987 (to SM) from the National Institutes of Health. YQ is a Ruth L. Kirschstein National Research Service Award Fellow of the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, supported by training grant T32 GM075762 from the National Institutes of Health. Publisher Copyright: Copyright © 2019 American Chemical Society.

PY - 2020/3/12

Y1 - 2020/3/12

N2 - A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for in vitro toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection. Oxadiazole 72c shows potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.

AB - A structure-activity relationship (SAR) for the oxadiazole class of antibacterials was evaluated by syntheses of 72 analogs and determination of the minimal-inhibitory concentrations (MICs) against the ESKAPE panel of bacteria. Selected compounds were further evaluated for in vitro toxicity, plasma protein binding, pharmacokinetics (PK), and a mouse model of methicillin-resistant Staphylococcus aureus (MRSA) infection. Oxadiazole 72c shows potent in vitro antibacterial activity, exhibits low clearance, a high volume of distribution, and 41% oral bioavailability, and shows efficacy in mouse models of MRSA infection.

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KW - oxadiazoles

KW - penicillin-binding proteins

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Structure-Activity Relationship for the Oxadiazole Class of Antibacterials

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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