Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides

Ho Shin Kim; Diana Ortiz; Tara Man Kadayat; Corinne M. Fargo; Jared T. Hammill; Yizhe Chen; Amy L. Rice; Kristin L. Begley; Gaurav Shoeran; William Pistel; Phillip A. Yates; Marco A. Sanchez; Scott M. Landfear; R. Kiplin Guy

doi:10.1021/acs.jmedchem.3c00056

Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides

Ho Shin Kim, Diana Ortiz, Tara Man Kadayat, Corinne M. Fargo, Jared T. Hammill, Yizhe Chen, Amy L. Rice, Kristin L. Begley, Gaurav Shoeran, William Pistel, Phillip A. Yates, Marco A. Sanchez, Scott M. Landfear, R. Kiplin Guy

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

2 Scopus citations

Abstract

Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.

Original language	English (US)
Pages (from-to)	7374-7386
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	66
Issue number	11
DOIs	https://doi.org/10.1021/acs.jmedchem.3c00056
State	Published - Jun 8 2023

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Kim, H. S., Ortiz, D., Kadayat, T. M., Fargo, C. M., Hammill, J. T., Chen, Y., Rice, A. L., Begley, K. L., Shoeran, G., Pistel, W., Yates, P. A., Sanchez, M. A., Landfear, S. M., & Guy, R. K. (2023). Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides. Journal of Medicinal Chemistry, 66(11), 7374-7386. https://doi.org/10.1021/acs.jmedchem.3c00056

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title = "Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides",

abstract = "Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.",

author = "Kim, {Ho Shin} and Diana Ortiz and Kadayat, {Tara Man} and Fargo, {Corinne M.} and Hammill, {Jared T.} and Yizhe Chen and Rice, {Amy L.} and Begley, {Kristin L.} and Gaurav Shoeran and William Pistel and Yates, {Phillip A.} and Sanchez, {Marco A.} and Landfear, {Scott M.} and Guy, {R. Kiplin}",

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doi = "10.1021/acs.jmedchem.3c00056",

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AU - Kim, Ho Shin

AU - Ortiz, Diana

AU - Kadayat, Tara Man

AU - Fargo, Corinne M.

AU - Hammill, Jared T.

AU - Chen, Yizhe

AU - Rice, Amy L.

AU - Begley, Kristin L.

AU - Shoeran, Gaurav

AU - Pistel, William

AU - Yates, Phillip A.

AU - Sanchez, Marco A.

AU - Landfear, Scott M.

AU - Guy, R. Kiplin

PY - 2023/6/8

Y1 - 2023/6/8

N2 - Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.

AB - Leishmaniasis, a neglected tropical disease caused by Leishmania species parasites, annually affects over 1 million individuals worldwide. Treatment options for leishmaniasis are limited due to high cost, severe adverse effects, poor efficacy, difficulty of use, and emerging drug resistance to all approved therapies. We discovered 2,4,5-trisubstituted benzamides (4) that possess potent antileishmanial activity but poor aqueous solubility. Herein, we disclose our optimization of the physicochemical and metabolic properties of 2,4,5-trisubstituted benzamide that retains potency. Extensive structure-activity and structure-property relationship studies allowed selection of early leads with suitable potency, microsomal stability, and improved solubility for progression. Early lead 79 exhibited an 80% oral bioavailability and potently blocked proliferation of Leishmania in murine models. These benzamide early leads are suitable for development as orally available antileishmanial drugs.

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Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides

Abstract

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