Synthesis, pharmacological and solubility evaluation of antiplasmodial pyrido[1,2-a]benzimidazoles with cyclic and functionalized amine side chain substituents

Master Thesis


Permanent link to this Item
Journal Title
Link to Journal
Journal ISSN
Volume Title

University of Cape Town

Malaria continues to cause significant morbidity and mortality globally, especially in sub-Saharan Africa where the disease is endemic. Widespread resistance by Plasmodium parasites to chloroquine and sulphadoxine-pyrimethamine, once mainstays of malaria treatment, has further set back control efforts. Recent reports of emerging resistance to ACTs, the current first-line antimalarial drugs, present an even grimmer picture in regard to future control and eradication of malaria. Moreover, antimalarial medications in current clinical use are fraught with challenges of high cost, low availability and undesirable adverse effects associated with their use. This cocktail of factors calls for accelerated research efforts to identify novel, safe and efficacious agents for treatment of malaria. Pyrido[1,2-a]benzimidazoles (PBIs) have previously been shown to possess potent antiplasmodial activity, but their in vivo antimalarial activity is limited by poor oral bioavailability arising from low aqueous solubility. The mechanism of action of PBI antimalarials remains unknown. In an attempt to address these initial limitations associated with PBIs, and shed light on potential contributing mechanisms of action, PBI analogues containing aliphatic cyclic and functionalized amine side chain substituents bearing polar, hydrogen-bonding groups were synthesized and evaluated for pharmacological and beta-hematin inhibition activity. The functionalized and cyclic amine side chain substituents were envisaged to improve aqueous solubility of the new analogues while maintaining or improving antiplasmodial activity and metabolic stability. Aminopiperidine-based compounds were found to possess the most potent antiplasmodial and beta-hematin inhibition activity coupled with moderate to high turbidimetric solubility. Analogues with pyrrolidine and piperazine groups showed only moderate activity in the in vitro assays, and also showed lower solubility compared to the piperidines. Azetidine and cyclohexylamine substitution led to compounds with moderate to poor in vitro activity and solubility. Substitution with highly polar functions and reduced basicity of the second amino group on the cyclic amine moiety were found to be detrimental to both activity and solubility. Minimal substitution on the PBI core was also carried out, where dichloro groups were found to improve both antiplasmodial and beta-hematin inhibition activity, as well as microsomal metabolic stability. These analogues, however, showed increased cytotoxicity compared to their unsubstituted counterparts. Salt screening was also attempted for one of the frontrunner analogues, resulting in a total of five salts. All but one of the salts were moderately soluble in the kinetic solubility assay, as was the free base form of the compound. Two of the five salts showed higher solubility than the free base.