A program was undertaken to identify hit compounds against
NADH:ubiquinone
oxidoreductase (PfNDH2), a dehydrogenase of the mitochondrial electron
transport chain of the malaria parasite Plasmodium falciparum. PfNDH2 has only one known inhibitor, hydroxy-2-dodecyl-4-(1H)-quinolone
(HDQ), and this was used along with a range of chemoinformatics methods
in the rational selection of 17 000 compounds for high-throughput
screening. Twelve distinct chemotypes were identified and briefly
examined leading to the selection of the quinolone core as the key
target for structure–activity relationship (SAR) development.
Extensive structural exploration led to the selection of 2-bisaryl
3-methyl quinolones as a series for further biological evaluation.
The lead compound within this series 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one
(CK-2-68) has antimalarial activity against the 3D7 strain of P. falciparum of 36 nM, is selective for PfNDH2 over other
respiratory enzymes (inhibitory IC50 against PfNDH2 of
16 nM), and demonstrates low cytotoxicity and high metabolic stability
in the presence of human liver microsomes. This lead compound and
its phosphate pro-drug have potent in vivo antimalarial activity after
oral administration, consistent with the target product profile of
a drug for the treatment of uncomplicated malaria. Other quinolones
presented (e.g., 6d, 6f, 14e) have the capacity to inhibit both PfNDH2 and P. falciparum cytochrome bc1, and studies to determine
the potential advantage of this dual-targeting effect are in progress.
SignificanceOnchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) are neglected tropical diseases that cause severe disability and affect more than 157 million people globally. Current control efforts are hindered by the lack of a safe macrofilaricidal drug that can eliminate the parasitic adult nematodes safely. A clinically validated approach for delivering macrofilaricidal activity is to target the Wolbachia bacterial endosymbiont of the causative nematodes. This first-in-class and highly potent and specific anti-Wolbachia preclinical candidate molecule, AWZ1066S, has the potential to significantly impact current global onchocerciasis and lymphatic filariasis elimination programs and reduce elimination time frames from decades to years.
Nematodes causing lymphatic filariasis and onchocerciasis rely on their bacterial endosymbiont, Wolbachia, for survival and fecundity, making Wolbachia a promising therapeutic target. Here we perform a high-throughput screen of AstraZeneca’s 1.3 million in-house compound library and identify 5 novel chemotypes with faster in vitro kill rates (<2 days) than existing anti-Wolbachia drugs that cure onchocerciasis and lymphatic filariasis. This industrial scale anthelmintic neglected tropical disease (NTD) screening campaign is the result of a partnership between the Anti-Wolbachia consortium (A∙WOL) and AstraZeneca. The campaign was informed throughout by rational prioritisation and triage of compounds using cheminformatics to balance chemical diversity and drug like properties reducing the chance of attrition from the outset. Ongoing development of these multiple chemotypes, all with superior time-kill kinetics than registered antibiotics with anti-Wolbachia activity, has the potential to improve upon the current therapeutic options and deliver improved, safer and more selective macrofilaricidal drugs.
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.
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