Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei

Jong Yeon Hwang; David C. Smithson; Gloria Holbrook; Fangyi Zhu; Michele C. Connelly; Marcel Kaiser; Reto Brun; R. Kiplin Guy

doi:10.1016/j.bmcl.2013.05.049

Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei

Jong Yeon Hwang, David C. Smithson, Gloria Holbrook, Fangyi Zhu, Michele C. Connelly, Marcel Kaiser, Reto Brun, R. Kiplin Guy

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

12 Scopus citations

Abstract

We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC₅₀ = 120 nM for Trypanosoma b. brucei, 18 nM for Trypanosoma b. rhodesiense, and 38 nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC₅₀ > 25 μM for HepG2, HEK293, Raji, and BJ cell lines) and also had good stability in microsomal models (t_1/2 > 4 h in both human and mouse). Overall these properties indicate the compound 7d and its analogs are worth further exploration as potential leads for HAT.

Original language	English
Pages (from-to)	4127-4131
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	14
DOIs	https://doi.org/10.1016/j.bmcl.2013.05.049
State	Published - Jul 15 2013

Bibliographical note

Funding Information:
This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children’s Research Hospital .

Funding

This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children’s Research Hospital .

Funders	Funder number
St. Jude Children's Research Hospital
American Lebanese Syrian Associated Charities

Keywords

Drug discovery
Parasitology
Trypanosomes

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.2013.05.049

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title = "Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei",

abstract = "We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC50 = 120 nM for Trypanosoma b. brucei, 18 nM for Trypanosoma b. rhodesiense, and 38 nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC50 > 25 μM for HepG2, HEK293, Raji, and BJ cell lines) and also had good stability in microsomal models (t1/2 > 4 h in both human and mouse). Overall these properties indicate the compound 7d and its analogs are worth further exploration as potential leads for HAT.",

keywords = "Drug discovery, Parasitology, Trypanosomes",

author = "Hwang, {Jong Yeon} and Smithson, {David C.} and Gloria Holbrook and Fangyi Zhu and Connelly, {Michele C.} and Marcel Kaiser and Reto Brun and {Kiplin Guy}, R.",

note = "Funding Information: This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children{\textquoteright}s Research Hospital . ",

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doi = "10.1016/j.bmcl.2013.05.049",

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AU - Hwang, Jong Yeon

AU - Smithson, David C.

AU - Holbrook, Gloria

AU - Zhu, Fangyi

AU - Connelly, Michele C.

AU - Kaiser, Marcel

AU - Brun, Reto

AU - Kiplin Guy, R.

N1 - Funding Information: This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children’s Research Hospital .

PY - 2013/7/15

Y1 - 2013/7/15

N2 - We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC50 = 120 nM for Trypanosoma b. brucei, 18 nM for Trypanosoma b. rhodesiense, and 38 nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC50 > 25 μM for HepG2, HEK293, Raji, and BJ cell lines) and also had good stability in microsomal models (t1/2 > 4 h in both human and mouse). Overall these properties indicate the compound 7d and its analogs are worth further exploration as potential leads for HAT.

AB - We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC50 = 120 nM for Trypanosoma b. brucei, 18 nM for Trypanosoma b. rhodesiense, and 38 nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC50 > 25 μM for HepG2, HEK293, Raji, and BJ cell lines) and also had good stability in microsomal models (t1/2 > 4 h in both human and mouse). Overall these properties indicate the compound 7d and its analogs are worth further exploration as potential leads for HAT.

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KW - Trypanosomes

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Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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