Design and Synthesis of Malarial Aspartic Protease Inhibitors

• Main Author: Ersmark, Karolina
• Format: Doctoral Thesis
• Language: English
• Published: Uppsala universitet, Institutionen för läkemedelskemi 2005
• Subjects: Pharmaceutical chemistry; malaria; plasmepsin; aspartic protease; protease inhibitor; macrocycle; Farmaceutisk kemi
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4833; http://nbn-resolving.de/urn:isbn:91-554-6177-8

Malaria is one of the major public health problems in the world. Approximately 500 million people are afflicted and almost 3 million people die from the disease each year. Of the four causative species Plasmodium falciparum is the most lethal. Due to the rapid spread of parasite resistance there is an urgent need for new antimalarial drugs with novel mechanisms of action. Several promising targets for drug intervention have been revealed. This thesis addresses the parasitic aspartic proteases termed plasmepsins (Plm), which are considered crucial to the hemoglobin catabolism essential for parasite survival. The overall aim was to identify inhibitors of the P. falciparum Plm I, II, and IV. More specific objectives were to attain activity against P. falciparum in infected erythrocytes and selectivity versus the most homologous human aspartic protease cathepsin D (Cat D). To guide the design process the linear interaction energy (LIE) method was employed in combination with molecular dynamics. Initial investigations of the stereochemical requirements for inhibition resulted in identification of an L-mannitol derived scaffold encompassing a 1,2-dihydroxyethylene transition state isostere with affinity for Plm II. Further modifications of this scaffold provided inhibitors of all three target plasmepsins (Plm I, II, and IV). Apart from the stereochemical analysis three major kinds of manipulation were explored: a) P1/P1′ and P2/P2′ side chain alterations, b) replacement of amide bonds by diacylhydrazine, 1,3,4-oxadiazole, and 1,2,4-triazole, and c) macrocyclization. Several inhibitors of Plm I and II with Ki values below 10 nM were discovered and one Plm IV selective inhibitor comprising two oxadiazole rings was found which represents the most potent non-peptide Plm IV inhibitor (Ki = 35 nM) reported to date. Some of the identified plasmepsin inhibitors demonstrated significant activity against P. falciparum in infected erythrocytes and all inhibitors showed a considerable selectivity for the plasmepsins over the human Cat D.