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Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2).

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 - J. Med. Chem. (2012)

Bottom Line: 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(50)s 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.

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(50)s 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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Mono aryl quinolonesidentified as hits from high-throughput screenand initial SAR work.
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fig1: Mono aryl quinolonesidentified as hits from high-throughput screenand initial SAR work.

Mentions: Our initial studies focused on compounds with mono aryl groupsat the 2-position; however it became rapidly apparent that activity below500 nM against the 3D7 strain of P. falciparum wasnot possible. A progression toward the close HDQ analogues where alonger biaryl/phenoxy biaryl replaced the metabolically vulnerableHDQ-side chain improved both antimalarial and PfNDH2 activity. A seriesof structural modifications including the introduction of a methylsubstituent at the 3-position led to the generation of over 60 compoundsas exemplified by 2 (CK-2-68) with an activity of 31 nMagainst 3D7 and 16 nM against PfNDH2 (Figure 1). It was apparent from preliminary animal studies that ClogP neededto be reduced and aqueous solubility needed to be enhanced in orderto administer the drug in a suitable vehicle without the need fora pro-drug approach. Introduction of various heterocycles into thequinolone side chain led to the selection of a series of compoundscontaining a pyridine group within the side chain. Incorporation ofa pyridine group reduces ClogP, improves aqueous solubility, and allowsthe possibility of salt formation. Further strategies investigatedincluded the use of polar heterocycles in the side chain, use of protonatablegroups within the side chain, extending the terminal group using polarheterocycles and the placement of a polar group centrally in the sidechain with a lipophilic group at the terminal end.


Identification, design and biological evaluation of heterocyclic quinolones targeting Plasmodium falciparum type II NADH:quinone oxidoreductase (PfNDH2).

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 - J. Med. Chem. (2012)

Mono aryl quinolonesidentified as hits from high-throughput screenand initial SAR work.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351724&req=5

fig1: Mono aryl quinolonesidentified as hits from high-throughput screenand initial SAR work.
Mentions: Our initial studies focused on compounds with mono aryl groupsat the 2-position; however it became rapidly apparent that activity below500 nM against the 3D7 strain of P. falciparum wasnot possible. A progression toward the close HDQ analogues where alonger biaryl/phenoxy biaryl replaced the metabolically vulnerableHDQ-side chain improved both antimalarial and PfNDH2 activity. A seriesof structural modifications including the introduction of a methylsubstituent at the 3-position led to the generation of over 60 compoundsas exemplified by 2 (CK-2-68) with an activity of 31 nMagainst 3D7 and 16 nM against PfNDH2 (Figure 1). It was apparent from preliminary animal studies that ClogP neededto be reduced and aqueous solubility needed to be enhanced in orderto administer the drug in a suitable vehicle without the need fora pro-drug approach. Introduction of various heterocycles into thequinolone side chain led to the selection of a series of compoundscontaining a pyridine group within the side chain. Incorporation ofa pyridine group reduces ClogP, improves aqueous solubility, and allowsthe possibility of salt formation. Further strategies investigatedincluded the use of polar heterocycles in the side chain, use of protonatablegroups within the side chain, extending the terminal group using polarheterocycles and the placement of a polar group centrally in the sidechain with a lipophilic group at the terminal end.

Bottom Line: 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(50)s 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK.

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(50)s 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.

Show MeSH
Related in: MedlinePlus