Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent

Ricardo Gallardo-Macias; Pradeep Kumar; Mark Jaskowski; Todd Richmann; Riju Shrestha; Riccardo Russo; Eric Singleton; Matthew D. Zimmerman; Hsin Pin Ho; Véronique Dartois; Nancy Connell; David Alland; Joel S. Freundlich

doi:10.1016/j.bmcl.2018.12.053

Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent

Ricardo Gallardo-Macias, Pradeep Kumar, Mark Jaskowski, Todd Richmann, Riju Shrestha, Riccardo Russo, Eric Singleton, Matthew D. Zimmerman, Hsin Pin Ho, Véronique Dartois, Nancy Connell, David Alland, Joel S. Freundlich

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

2 Scopus citations

Abstract

The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019–0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC₅₀ = 40–>120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC₅₀ > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.

Original language	English (US)
Pages (from-to)	601-606
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.bmcl.2018.12.053
State	Published - Feb 15 2019
Externally published	Yes

Keywords

Benzamide
Mycobacterium tuberculosis
Nitrofuran
α α-Dimethyl

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2018.12.053

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Gallardo-Macias, R., Kumar, P., Jaskowski, M., Richmann, T., Shrestha, R., Russo, R., Singleton, E., Zimmerman, M. D., Ho, H. P., Dartois, V., Connell, N., Alland, D., & Freundlich, J. S. (2019). Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent. Bioorganic and Medicinal Chemistry Letters, 29(4), 601-606. https://doi.org/10.1016/j.bmcl.2018.12.053

Gallardo-Macias, R, Kumar, P, Jaskowski, M, Richmann, T, Shrestha, R, Russo, R, Singleton, E, Zimmerman, MD, Ho, HP, Dartois, V, Connell, N, Alland, D & Freundlich, JS 2019, 'Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent', Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 4, pp. 601-606. https://doi.org/10.1016/j.bmcl.2018.12.053

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title = "Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent",

abstract = "The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019–0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC50 = 40–>120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC50 > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.",

keywords = "Benzamide, Mycobacterium tuberculosis, Nitrofuran, α α-Dimethyl",

author = "Ricardo Gallardo-Macias and Pradeep Kumar and Mark Jaskowski and Todd Richmann and Riju Shrestha and Riccardo Russo and Eric Singleton and Zimmerman, {Matthew D.} and Ho, {Hsin Pin} and V{\'e}ronique Dartois and Nancy Connell and David Alland and Freundlich, {Joel S.}",

note = "Funding Information: The authors gratefully acknowledge support from NIH grants R33AI11167 , R21AI111647 , and U19AI109713 . Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

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AU - Richmann, Todd

AU - Shrestha, Riju

AU - Russo, Riccardo

AU - Singleton, Eric

AU - Zimmerman, Matthew D.

AU - Ho, Hsin Pin

AU - Dartois, Véronique

AU - Connell, Nancy

AU - Alland, David

AU - Freundlich, Joel S.

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AB - The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019–0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC50 = 40–>120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC50 > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.

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Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent

Abstract

Keywords

ASJC Scopus subject areas

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