Identification, design and biological evaluation of heterocyclic quinolones targeting plasmodium falciparum Type II NADH:Quinone oxidoreductase (PfNDH2)

Suet C. Leung; Peter Gibbons; Richard Amewu; Gemma L. Nixon; Chandrakala Pidathala; W. David Hong; Bénédicte Pacorel; Neil G. Berry; Raman Sharma; Paul A. Stocks; Abhishek Srivastava; Alison E. Shone; Sitthivut Charoensutthivarakul; Lee Taylor; Olivier Berger; Alison Mbekeani; Alasdair Hill; Nicholas E. Fisher; Ashley J. Warman; Giancarlo A. Biagini; Stephen A. Ward; Paul M. O'Neill

doi:10.1021/jm201184h

Identification, design and biological evaluation of heterocyclic quinolones targeting plasmodium falciparum Type II NADH:Quinone oxidoreductase (PfNDH2)

Suet C. Leung, Peter Gibbons, Richard Amewu, Gemma L. Nixon, Chandrakala Pidathala, W. David Hong, Bénédicte Pacorel, Neil G. Berry, Raman Sharma, Paul A. Stocks, Abhishek Srivastava, Alison E. Shone, Sitthivut Charoensutthivarakul, Lee Taylor, Olivier Berger, Alison Mbekeani, Alasdair Hill, Nicholas E. Fisher, Ashley J. Warman, Giancarlo A. BiaginiStephen A. Ward, Paul M. O'Neill

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51 Citations (Scopus)

Abstract

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC ₅₀s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC ₅₀ = 15 nM PfNDH2; IC ₅₀ = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED ₅₀/ED ₉₀ of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc ₁ complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.

Original language	English
Pages (from-to)	1844-1857
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	5
DOIs	https://doi.org/10.1021/jm201184h
Publication status	Published - 8 Mar 2012
Externally published	Yes

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Leung, S. C., Gibbons, P., Amewu, R., Nixon, G. L., Pidathala, C., Hong, W. D., Pacorel, B., Berry, N. G., Sharma, R., Stocks, P. A., Srivastava, A., Shone, A. E., Charoensutthivarakul, S., Taylor, L., Berger, O., Mbekeani, A., Hill, A., Fisher, N. E., Warman, A. J., ... O'Neill, P. M. (2012). Identification, design and biological evaluation of heterocyclic quinolones targeting plasmodium falciparum Type II NADH:Quinone oxidoreductase (PfNDH2). Journal of Medicinal Chemistry, 55(5), 1844-1857. https://doi.org/10.1021/jm201184h

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title = "Identification, design and biological evaluation of heterocyclic quinolones targeting plasmodium falciparum Type II NADH:Quinone oxidoreductase (PfNDH2)",

abstract = "Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC 50s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC 50 = 15 nM PfNDH2; IC 50 = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED 50/ED 90 of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc 1 complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.",

author = "Leung, {Suet C.} and Peter Gibbons and Richard Amewu and Nixon, {Gemma L.} and Chandrakala Pidathala and Hong, {W. David} and B{\'e}n{\'e}dicte Pacorel and Berry, {Neil G.} and Raman Sharma and Stocks, {Paul A.} and Abhishek Srivastava and Shone, {Alison E.} and Sitthivut Charoensutthivarakul and Lee Taylor and Olivier Berger and Alison Mbekeani and Alasdair Hill and Fisher, {Nicholas E.} and Warman, {Ashley J.} and Biagini, {Giancarlo A.} and Ward, {Stephen A.} and O'Neill, {Paul M.}",

year = "2012",

month = mar,

day = "8",

doi = "10.1021/jm201184h",

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Leung, SC, Gibbons, P, Amewu, R, Nixon, GL, Pidathala, C, Hong, WD, Pacorel, B, Berry, NG, Sharma, R, Stocks, PA, Srivastava, A, Shone, AE, Charoensutthivarakul, S, Taylor, L, Berger, O, Mbekeani, A, Hill, A, Fisher, NE, Warman, AJ, Biagini, GA, Ward, SA & O'Neill, PM 2012, 'Identification, design and biological evaluation of heterocyclic quinolones targeting plasmodium falciparum Type II NADH:Quinone oxidoreductase (PfNDH2)', Journal of Medicinal Chemistry, vol. 55, no. 5, pp. 1844-1857. https://doi.org/10.1021/jm201184h

TY - JOUR

T1 - Identification, design and biological evaluation of heterocyclic quinolones targeting plasmodium falciparum Type II NADH:Quinone oxidoreductase (PfNDH2)

AU - Leung, Suet C.

AU - Gibbons, Peter

AU - Amewu, Richard

AU - Nixon, Gemma L.

AU - Pidathala, Chandrakala

AU - Hong, W. David

AU - Pacorel, Bénédicte

AU - Berry, Neil G.

AU - Sharma, Raman

AU - Stocks, Paul A.

AU - Srivastava, Abhishek

AU - Shone, Alison E.

AU - Charoensutthivarakul, Sitthivut

AU - Taylor, Lee

AU - Berger, Olivier

AU - Mbekeani, Alison

AU - Hill, Alasdair

AU - Fisher, Nicholas E.

AU - Warman, Ashley J.

AU - Biagini, Giancarlo A.

AU - Ward, Stephen A.

AU - O'Neill, Paul M.

PY - 2012/3/8

Y1 - 2012/3/8

N2 - Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC 50s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC 50 = 15 nM PfNDH2; IC 50 = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED 50/ED 90 of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc 1 complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.

AB - Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC 50s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC 50 = 15 nM PfNDH2; IC 50 = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED 50/ED 90 of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc 1 complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.

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ER -

Identification, design and biological evaluation of heterocyclic quinolones targeting plasmodium falciparum Type II NADH:Quinone oxidoreductase (PfNDH2)

Abstract

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