Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting <i>Plasmodium falciparum</i> Type II NADH:Quinone Oxidoreductase (PfNDH2)

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite <i>Plasmodium falciparum</i>, 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 (<b>8b</b>). <b>8b</b> has IC₅₀s in the nanomolar range versus both the enzyme and whole cell <i>P. falciparum</i> (IC₅₀ = 15 nM PfNDH2; IC₅₀ = 54 nM (3D7 strain of <i>P. falciparum</i>) with notable oral activity of ED₅₀/ED₉₀ of 1.87/4.72 mg/kg versus <i>Plasmodium berghei</i> (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the <i>bc</i>₁ complex of <i>P. falciparum</i> 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 of Novel Antimalarial Chemotypes via Chemoinformatic Compound Selection Methods for a High-Throughput Screening Program against the Novel Malarial Target, PfNDH2: Increasing Hit Rate via Virtual Screening Methods

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ∼17000 compounds were selected from a commercial library of ∼750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC₅₀ values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria