Synthesis, biological activity and physicochemical properties evaluation of antiplasmodial pyrimido[1,2-a]benzimidazoles
type: CreativeWork
description: Malaria is an infectious disease which still causes high morbidity and mortality rates among the world's poorest populations, especially in tropical and sub-tropical regions. In 2020, 241 million malaria cases and 627 000 associated deaths were reported, with 94% of them on the African continent, according to the World Health Organization (WHO). The emergence of drug resistant strains of Plasmodium falciparum, the causative agent of the vast majority of malaria cases, has prompted the urgent need to develop new antimalarial drugs with novel modes of action and no cross resistance to existing medicines. Pyrido[1,2-a]benzimidazole (PBI) derivatives have been previously identified as antimalarial compounds with promising in vitro activity against Plasmodium falciparum and in vivo antimalarial efficacy. Unfortunately these compounds are beset by poor aqueous solubility and suboptimal in vivo pharmacokinetics (PK), which present barriers to in vivo efficacy improvement. Towards addressing these issues through improved physicochemical properties, in particular solubility, the related pyrimido[1,2-a]benzimidazole scaffold has been investigated within the context of this dissertation. A new series of compounds was designed and synthesized to expand the structureactivity relationship (SAR) scope and improve physicochemical properties, including aqueous solubility. To this end, the study was broadly diversified into three SAR series (SAR1, SAR2 and SAR3). In SAR1, various aliphatic amine side chains were explored. SAR2 analogues aimed at disrupting molecular planarity by increasing the dihedral angle and thereby potentially enhancing solubility through minimising intermolecular π-π stacking interactions. The design of SAR3 compounds was aimed at incorporating representative diverse lipophilic (π) and electronic (σ) Craig plot substituents and/or low molecular weight amide substituents in the C-3 position of the phenyl ring. Thirty-eight (38) derivatives were synthesized, char…
abstract: Malaria is an infectious disease which still causes high morbidity and mortality rates among the world's poorest populations, especially in tropical and sub-tropical regions. In 2020, 241 million malaria cases and 627 000 associated deaths were reported, with 94% of them on the African continent, according to the World Health Organization (WHO). The emergence of drug resistant strains of Plasmodium falciparum, the causative agent of the vast majority of malaria cases, has prompted the urgent need to develop new antimalarial drugs with novel modes of action and no cross resistance to existing medicines. Pyrido[1,2-a]benzimidazole (PBI) derivatives have been previously identified as antimalarial compounds with promising in vitro activity against Plasmodium falciparum and in vivo antimalarial efficacy. Unfortunately these compounds are beset by poor aqueous solubility and suboptimal in vivo pharmacokinetics (PK), which present barriers to in vivo efficacy improvement. Towards addressing these issues through improved physicochemical properties, in particular solubility, the related pyrimido[1,2-a]benzimidazole scaffold has been investigated within the context of this dissertation. A new series of compounds was designed and synthesized to expand the structureactivity relationship (SAR) scope and improve physicochemical properties, including aqueous solubility. To this end, the study was broadly diversified into three SAR series (SAR1, SAR2 and SAR3). In SAR1, various aliphatic amine side chains were explored. SAR2 analogues aimed at disrupting molecular planarity by increasing the dihedral angle and thereby potentially enhancing solubility through minimising intermolecular π-π stacking interactions. The design of SAR3 compounds was aimed at incorporating representative diverse lipophilic (π) and electronic (σ) Craig plot substituents and/or low molecular weight amide substituents in the C-3 position of the phenyl ring. Thirty-eight (38) derivatives were synthesized, char…
author: Disraeli, Chiara
keywords: Chemistry
date published: 2022
date modified: 2026-07-22T22:22:41Z
provider: University of Cape Town
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Department of Chemistry

PropertyValue
property ID: Handle
value: http://hdl.handle.net/11427/37196