Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues

Malaria is a major cause of morbidity and mortality globally, resulting in over 200 million cases and 650, 000 deaths in 2010 according to the 2012 WHO Malaria Report. Furthermore, malaria endemicity is associated with poor economic growth. One of the greatest challenges facing malaria chemotherapy is the emergence of Plasmodium strains resistant to all known clinically used antimalarials. This underscores the need for the development of new drugs that retain efficacy against the resistant parasites. In this study, analogue-based drug design was employed as a form of drug ‘rescue’ in the development of novel potential antimalarials. The main aim was to design and synthesize analogues of the 4-aminoquinoline drug amodiaquine with potentially improved safety and efficacy profiles using prior knowledge of the drug metabolism and pharmacokinetics (DMPK), toxicity and efficacy profile of the drug. A representative set of compounds in four different series was synthesized in which the 4-aminoquinoline ring was coupled with benzothiazole, benzimidazole, benzoxazole and pyridyl rings bearing different aliphatic amines and diamines. The chemistry involved aromatic nucleophilic substitution reactions and hydrogenation of nitro aromatic compounds. Benzothiazole and benzoxazole analogues with a tertiary protonatable nitrogen were found to possess potent antiplasmodial activity against the drug resistant W2 and K1 Plasmodium falciparum strains.

Grantor dc:publisher.institution

Department of Chemistry

Year dc:date.issued

2014

Author dc:creator

• Ongarora, Dennis Sure Bagwasi

Advisors dc:contributor.advisor

• Chibale, Kelly
• Masimirembwa, Collen

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/9309

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/9309