Synthesis structure-activity relationships and biological evaluation of optimised terminally alkylated (bis)urea and (bis)thiourea polyamine analogues as antiplasmodial agents

The sustained control and elimination of malaria requires novel approaches to combat the emergence of drug resistance. Plasmodium falciparum causes the most lethal form of human malaria. Current therapeutics have shown decreased efficacy as a result of P. falciparum developing resistance to them. Consequently, novel antimalarial agents with new mechanisms of action are urgently needed to aid in the control and ultimate eradication of this disease and should display low resistance indices and high selectivity indices. Polyamines are involved in a variety of cellular functions including cell differentiation and proliferation and have been shown to be essential to malaria parasites in vitro. However, these analogues lacked drug-like properties, negating their use in malaria disease models in vivo. The objective of this study was to develop novel polyamine analogues based on a previous generation of compounds and to determine their antiplasmodial activity in vitro. Consequently, a novel series of (bis)urea and (bis)thiourea polyamine analogues were designed and synthesised with moderately high yields and purity. In silico evaluation of drug-likeness of these compounds indicated low oral bioavailability overall, although the predicted values were improved over the parent series. The antiplasmodial activity of the novel analogues indicated that halogenation generally decreases activity except for bromination, which did improve in vitro activity. Cheminformatics analysis enabled in-depth analysis of the structure-activity relationships (SAR) of this class of compounds, allowing structural features to be identified that are important for activity. Complementing the SAR with quantitative structure-activity relationships (QSAR) allowed the determination of a descriptor that weakly correlates with the analogues’ activities. The structural requirements for activity were found to be based on representations of the polyamine analogues molecular structures by means of circular atom neighbourhood’s. This work therefore contributed to the further development of the polyamine analogues as potential antimalarial drugs.Dissertation (MSc)--University of Pretoria, 2017.National Research Foundation (NRF)South African Research Chair (SARChI) programmeBiochemistryMScUnrestricte