title: From medicinal chemistry optimisation of antimalarial 2-aryl quinolones to synthesis and application of endoperoxide activity-based protein profiling probes
Creators: name: Charoensutthivarakul, Sitthivut
Publisher: name: University of Liverpool Repository
Year: 2015

description: Malaria is one of the most prevalent and deadliest parasitic diseases affecting various systems of the body and leading to death. Resistance against antimalarial treatment is a major threat in controlling and eliminating malaria. New drugs are urgently needed especially when artemisinin resistance has emerged. The mitochondrial electron transport chain of Plasmodium falciparum is an attractive target for chemotherapy. Two enzymes in the pathway - Pfbc1 and PfNDH2 - are druggable target enzymes. The dual inhibition of both enzymes can be seen in 2-aryl quinolone pharmacophore giving added therapeutic benefit. The development from this series leads to the potent lead compounds including SL-2-25 and PG227. In Chapter III, following the hit-to-lead optimisation of SL-2-25, a 5-7 step synthesis of a library of 2-aryl quinolones has been described. In vitro antimalarial assessment of these quinolones revealed the advantages of the 7-methoxy moiety. The potency increases 3-8 folds when the 7-OMe group is attached. Further lead modification led to a more flexible quinolone 61i retaining high potency against the 3D7 strain of P. falciparum. This structure also possesses no cross resistance, greater aqueous solubility and low potential for cardiotoxicity. Following a similar study on related quinolones, 3,4-dichlorophenyl analogues were briefly investigated. This led to the discovery of 61o possessing an outstanding potency against 3D7 strain of P. falciparum of 18 nM. It also shows low cardiotoxicity when compare to other quinolones. 61u featuring 6-Cl and 7-OMe substitution was identified with an in vitro IC50 potency of 9 nM against Plasmodium. In silico molecular modelling based on the yeast bc1 protein complex shows that all quinolones bind tightly to the target protein with essential interactions in place. PG227 (69) exhibits outstanding pharmacological properties amongst the series of quinolones. Its original synthesis suffers from reproducibility and low overall yields. 69 can be made in a multi-gram scale using an alternative method for cyclisation. The 5-step synthesis of PG227 can be achieved from commercially available starting materials involving the synthesis of β-keto ester intermediate, the Conrad-Limpach cyclisation and chlorination using NCS. The overall yield was 7%. Artemisinin combination therapy (ACT) is used as the first line treatment in most of the malarial endemic areas. The emerged artemisinin resistance requires greater understanding of drug action. In Chapter V, activity-based protein profiling (ABPP) was employed to identify the molecular target of artemisinin for the first time. The novel “tag-free” ABPP proteomic technique is introduced based on the click chemistry between a chemical probe and a reporter tag. The synthesis of the artemisinin-based ABPP chemical probes was achieved. The peroxide-containing probes show an excellent in vitro potency against the 3D7 malaria parasite. The preliminary result reveals that active probe 99 can perform well in protein pull down resulting in 45 different proteins being identified.