DISCOVERY OF MULTISTAGE ANTIMALARIALS: SYNERGISTIC FUSION OF PRIVILEGED BIOACTIVE SCAFFOLDS TRIGGERS GROWTH INHIBITION OF MALARIA PARASITE PLASMODIUM FALCIPARUM

Brijesh Rathi

Department of Chemistry, Massachusetts Institute of Technology, Massachusetts Avenue, Cambridge MA 02139, USA

Abstract

Despite the substantial progress over the time, malaria remains a major public health fear and causing hundreds of thousands of deaths in large areas of the world. Resistance to the available antimalarial chemotherapeutics increases additional burden to the global public health. In the search for new drug molecules, we present synergistic blending of high-valued heterocycles with phthalimide and hydroxyethylamine scaffolds that exhibited significant growth inhibition of malaria parasite in culture and Plasmodium berghei infection in mouse model. Several hit molecules with less cytotoxicity were evaluated as noteworthy multistage growth inhibition (blood stage and liver stage) of the parasite in low submicromolar inhibitory concentrations. Structure-activity analysis specified the significance of amino acid linkers for obtaining the maximal antimalarial activity. In addition, hit molecules displayed synergistic interactions with chloroquine and dihydroartemisinin in culture and P. berghei infected mice model. To gain greater insight into the target identification, we screened these molecules against several known molecular drug target(s) and hydroxyethylamine based molecules inhibited the activity of plasmepsins (II and IV), enzymes found in the digestive vacuole of the plasmodium parasite. The multistage antimalarial profile of such blended molecules encourages their potential task as novel antimalarial agents, either as standalone or combination therapies.

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