Lead optimization of 3-carboxyl-4(1 H)-quinolones to deliver orally bioavailable antimalarials

Yiqun Zhang; Julie A. Clark; Michele C. Connelly; Fangyi Zhu; Jaeki Min; W. Armand Guiguemde; Anupam Pradhan; Lalitha Iyer; Anna Furimsky; Jason Gow; Toufan Parman; Farah El Mazouni; Margaret A. Phillips; Dennis E. Kyle; Jon Mirsalis; R. Kiplin Guy

doi:10.1021/jm201642z

Lead optimization of 3-carboxyl-4(1 H)-quinolones to deliver orally bioavailable antimalarials

Yiqun Zhang, Julie A. Clark, Michele C. Connelly, Fangyi Zhu, Jaeki Min, W. Armand Guiguemde, Anupam Pradhan, Lalitha Iyer, Anna Furimsky, Jason Gow, Toufan Parman, Farah El Mazouni, Margaret A. Phillips, Dennis E. Kyle, Jon Mirsalis, R. Kiplin Guy

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75 Scopus citations

Abstract

Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.

Original language	English (US)
Pages (from-to)	4205-4219
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	9
DOIs	https://doi.org/10.1021/jm201642z
State	Published - May 10 2012

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Zhang, Y., Clark, J. A., Connelly, M. C., Zhu, F., Min, J., Guiguemde, W. A., Pradhan, A., Iyer, L., Furimsky, A., Gow, J., Parman, T., El Mazouni, F., Phillips, M. A., Kyle, D. E., Mirsalis, J., & Guy, R. K. (2012). Lead optimization of 3-carboxyl-4(1 H)-quinolones to deliver orally bioavailable antimalarials. Journal of Medicinal Chemistry, 55(9), 4205-4219. https://doi.org/10.1021/jm201642z

Zhang, Y, Clark, JA, Connelly, MC, Zhu, F, Min, J, Guiguemde, WA, Pradhan, A, Iyer, L, Furimsky, A, Gow, J, Parman, T, El Mazouni, F, Phillips, MA, Kyle, DE, Mirsalis, J & Guy, RK 2012, 'Lead optimization of 3-carboxyl-4(1 H)-quinolones to deliver orally bioavailable antimalarials', Journal of Medicinal Chemistry, vol. 55, no. 9, pp. 4205-4219. https://doi.org/10.1021/jm201642z

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abstract = "Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.",

author = "Yiqun Zhang and Clark, {Julie A.} and Connelly, {Michele C.} and Fangyi Zhu and Jaeki Min and Guiguemde, {W. Armand} and Anupam Pradhan and Lalitha Iyer and Anna Furimsky and Jason Gow and Toufan Parman and {El Mazouni}, Farah and Phillips, {Margaret A.} and Kyle, {Dennis E.} and Jon Mirsalis and Guy, {R. Kiplin}",

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doi = "10.1021/jm201642z",

language = "English (US)",

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AU - Zhang, Yiqun

AU - Clark, Julie A.

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AU - Zhu, Fangyi

AU - Min, Jaeki

AU - Guiguemde, W. Armand

AU - Pradhan, Anupam

AU - Iyer, Lalitha

AU - Furimsky, Anna

AU - Gow, Jason

AU - Parman, Toufan

AU - El Mazouni, Farah

AU - Phillips, Margaret A.

AU - Kyle, Dennis E.

AU - Mirsalis, Jon

AU - Guy, R. Kiplin

PY - 2012/5/10

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AB - Malaria is a protozoal parasitic disease that is widespread in tropical and subtropical regions of Africa, Asia, and the Americas and causes more than 800,000 deaths per year. The continuing emergence of multidrug-resistant Plasmodium falciparum drives the ongoing need for the development of new and effective antimalarial drugs. Our previous work has explored the preliminary structural optimization of 4(1H)-quinolone ester derivatives, a new series of antimalarials related to the endochins. Herein, we report the lead optimization of 4(1H)-quinolones with a focus on improving both antimalarial potency and bioavailability. These studies led to the development of orally efficacious antimalarials including quinolone analogue 20g, a promising candidate for further optimization.

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Lead optimization of 3-carboxyl-4(1 H)-quinolones to deliver orally bioavailable antimalarials

Abstract

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