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 IC50s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC50 = 15 nM PfNDH2; IC50 = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED50/ED90 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 bc1 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.

Identification and Validation of Novel Drug Targets for the Treatment of Plasmodium falciparum Malaria: New Insights

“…This approach led to the selection of the quinolone core as the key target for SAR, followed by the selection of CK-2-68 as a lead for further development [81,106]. Structural alterations aiming to improve the inhibitory activity and aqueous solubility led to the [107]. SL-2-25, as other quinolones in this study, had the ability to inhibit both PfNDH2 and cytochrome bc1 at low nanomolar range, the same dual inhibition previously observed for HDQ.…”

2-Pyridylquinolone antimalarials with improved antimalarial activity and physicochemical properties

“…Since effective dual inhibition of these proteins can be observed with the 2-aryl and 2-pyridylquinolone pharmacophore 14a a number of inhibitors based on this structure have been identified. Two such lead compounds are CK-2-68 and SL-2-25 (1) -both of which confer potent nanomolar activity against asexual and liver stages of P. falciparum 15,16 ( Figure 1). Here, we describe further modifications of the quinolone A-ring and 2-pyridyl side chain with the aim of reducing lipophilicity in an attempt to provide compounds with improved activity/solubility profiles.…”

Recent advances in malaria drug discovery

“…Data are reported for primaquine, 40 ato-vaquone, 41,42 proguanil, 43 and its active metabolite cycloguanil. 44 …”

“…A succession of in silico screens, HTS, and medicinal chemistry activities led to CK-2-25 ( 95 , Scheme 25 ), which is specific for PfNDH2 over bc 1 , and is potent in mouse, with an ED 50 = 1.8 mg/kg. 42,165 …”