Amodia Research Paper

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4.1.2.1.2. Artemisinin-based combinations
Artemisinin (1) based combination therapy has different characteristics and mode of action. It has several advantages as fast reduction of the parasite growth, rapid clearance of symptoms, effective action against multidrug-resistant Plasmodium falciparum, blocks transmission of gametocytes and delay the development of resistance. The derivatives usually have short half-life. If combined with other drugs with longer half-life, it increases the efficacy by reduction of multiple dose regiments and slows down its parasite resistance.[47b] The resistance of artemisinin is associated essentially with pfmdr1 Tyr86. Ser1034, Asn1042 and Asp1246 are also associate with this resistance.[49] Several combinations
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4.12 – Development and optimization of p-aminoquinoline derivatives [Adapted from [47b]]
Ferroquine (72) is the first organometallic drug which has a ferrocenyl group covalently linked to a chloroquine by its tertiary amine side chain. This drug overcomes the resistance problem of P. falciparum and has high potency for P. vivax, by targeting of lipids, inhibition the formation of hemozoin and generation of reactive oxygen species.[58]
Amodiaquine (62) is another potent quinoline derivative. Its p-hydroxyanilino moiety suffers enzymatic oxidation to quinone imine, a reactive metabolite. To overcome this problem, O’Neill group developed a series of isomers by interchange the hydroxyl group and the mannich side chain, which originated the GSK369796 (81) that entered in phase I of clinical trials.[59]
Other quinoline derivatives such as 8-aminoquinoline (82) (Fig. 4.13) has a potent antimalarial activity including potency to fight against relapsing. Tafenoquine (83) is an example of this class with a long half-life, high activity and low toxicity. Because of its features, it is currently in the late phase of clinical trials. Bulaquine (84), other 8-aminoquinoline derivative with anti-relapsing activity for P. vivax, has finished the phase
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falciparum.

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