Investigations on the antimalarial activity of alkoxylated and hydroxylated chalcones

Abstract

The focus of this thesis is the investigation of the antimalarial activities of oxygenated chalcones. A series of 102 chalcones, distinguished by their B ring substitution patterns as alkoxylated or hydroxylated members, were synthesized and evaluated for in vitro antimalarial activity against Plasmodium falciparum K1. Cytotoxicity tests indicated that the chalcones specifically target Plasmodium. Active members were tested in vivo against P. berghei infected mice. Significant correlations between in vitro antimalarial activity and physicochemical properties of the active chalcones led to a proposed quantitative structure-activity relationship model with good predictive ability. Investigations were also made to establish the structural requirements of antimalarial and antileishmanial chalcones. The effects of chalcones on the degradation of hemoglobin were investigated. Several chalcones demonstrated binding to hematin and inhibition of plasmodial cysteine protease. Unfortunately, there was no consistent correlation to antimalarial activity and the mode of action of these compounds in malaria remains an open question.