Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties

W. David Hong; Suet C. Leung; Kangsa Amporndanai; Jill Davies; Richard S. Priestley; Gemma L. Nixon; Neil G. Berry; S. Samar Hasnain; Svetlana Antonyuk; Steve Ward; Giancarlo Biagini; Paul M. O'Neill

doi:10.1021/acsmedchemlett.8b00371

Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties

W. David Hong, Suet C. Leung, Kangsa Amporndanai, Jill Davies, Richard S. Priestley, Gemma L. Nixon, Neil G. Berry, S. Samar Hasnain, Svetlana Antonyuk, Steve Ward, Giancarlo Biagini, Paul M. O'Neill

Tropical Disease Biology

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

32 Citations (Scopus)

Abstract

A series of 2-pyrazolyl quinolones has been designed and synthesized in 5–7 steps to optimize for both in vitro antimalarial potency and various in vitro drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC50 (concentration of drug required to achieve half maximal growth suppression) values in the range of 15–33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptable safety margin through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Qi site of the parasite bc1 complex, which is supported by crystallographic studies of bovine cytochrome bc1 complex.

Original language	English
Pages (from-to)	1205-1210
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	12
DOIs	https://doi.org/10.1021/acsmedchemlett.8b00371
Publication status	Published - 19 Oct 2018

Keywords

antimalarial
atovaquone
cytochrome bc
drug resistance
Plasmodium falciparum
Quinolone

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10.1021/acsmedchemlett.8b00371

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David Hong, W., Leung, S. C., Amporndanai, K., Davies, J., Priestley, R. S., Nixon, G. L., Berry, N. G., Samar Hasnain, S., Antonyuk, S., Ward, S., Biagini, G., & O'Neill, P. M. (2018). Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties. ACS Medicinal Chemistry Letters, 9(12), 1205-1210. https://doi.org/10.1021/acsmedchemlett.8b00371

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title = "Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties",

abstract = "A series of 2-pyrazolyl quinolones has been designed and synthesized in 5–7 steps to optimize for both in vitro antimalarial potency and various in vitro drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC50 (concentration of drug required to achieve half maximal growth suppression) values in the range of 15–33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptable safety margin through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Qi site of the parasite bc1 complex, which is supported by crystallographic studies of bovine cytochrome bc1 complex.",

keywords = "antimalarial, atovaquone, cytochrome bc, drug resistance, Plasmodium falciparum, Quinolone",

author = "\{David Hong\}, W. and Leung, \{Suet C.\} and Kangsa Amporndanai and Jill Davies and Priestley, \{Richard S.\} and Nixon, \{Gemma L.\} and Berry, \{Neil G.\} and \{Samar Hasnain\}, S. and Svetlana Antonyuk and Steve Ward and Giancarlo Biagini and O'Neill, \{Paul M.\}",

year = "2018",

month = oct,

day = "19",

doi = "10.1021/acsmedchemlett.8b00371",

language = "English",

volume = "9",

pages = "1205--1210",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

number = "12",

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David Hong, W, Leung, SC, Amporndanai, K, Davies, J, Priestley, RS, Nixon, GL, Berry, NG, Samar Hasnain, S, Antonyuk, S, Ward, S , Biagini, G & O'Neill, PM 2018, 'Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties', ACS Medicinal Chemistry Letters, vol. 9, no. 12, pp. 1205-1210. https://doi.org/10.1021/acsmedchemlett.8b00371

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T1 - Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties

AU - David Hong, W.

AU - Leung, Suet C.

AU - Amporndanai, Kangsa

AU - Davies, Jill

AU - Priestley, Richard S.

AU - Nixon, Gemma L.

AU - Berry, Neil G.

AU - Samar Hasnain, S.

AU - Antonyuk, Svetlana

AU - Ward, Steve

AU - Biagini, Giancarlo

AU - O'Neill, Paul M.

PY - 2018/10/19

Y1 - 2018/10/19

N2 - A series of 2-pyrazolyl quinolones has been designed and synthesized in 5–7 steps to optimize for both in vitro antimalarial potency and various in vitro drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC50 (concentration of drug required to achieve half maximal growth suppression) values in the range of 15–33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptable safety margin through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Qi site of the parasite bc1 complex, which is supported by crystallographic studies of bovine cytochrome bc1 complex.

AB - A series of 2-pyrazolyl quinolones has been designed and synthesized in 5–7 steps to optimize for both in vitro antimalarial potency and various in vitro drug metabolism and pharmacokinetics (DMPK) features. The most potent compounds display no cross-resistance with multidrug resistant parasite strains (W2) compared to drug sensitive strains (3D7), with IC50 (concentration of drug required to achieve half maximal growth suppression) values in the range of 15–33 nM. Furthermore, members of the series retain moderate activity against the atovaquone-resistant parasite isolate (TM90C2B). The described 2-pyrazoyl series displays improved DMPK properties, including improved aqueous solubility compared to previously reported quinolone series and acceptable safety margin through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Qi site of the parasite bc1 complex, which is supported by crystallographic studies of bovine cytochrome bc1 complex.

KW - antimalarial

KW - atovaquone

KW - cytochrome bc

KW - drug resistance

KW - Plasmodium falciparum

KW - Quinolone

U2 - 10.1021/acsmedchemlett.8b00371

DO - 10.1021/acsmedchemlett.8b00371

M3 - Article

SN - 1948-5875

VL - 9

SP - 1205

EP - 1210

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 12

ER -

Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties

Abstract

Keywords

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