FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W127130454> ?p ?o ?g. }

• W127130454 abstract "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." @default.
• W127130454 created "2016-06-24" @default.
• W127130454 creator A5045864068 @default.
• W127130454 date "2005-01-01" @default.
• W127130454 modified "2023-09-27" @default.
• W127130454 title "Design and Synthesis of Malarial Aspartic Protease Inhibitors" @default.
• W127130454 cites W105760458 @default.
• W127130454 cites W1522940126 @default.
• W127130454 cites W1579211574 @default.
• W127130454 cites W1583083824 @default.
• W127130454 cites W1595041541 @default.
• W127130454 cites W188321583 @default.
• W127130454 cites W1952065778 @default.
• W127130454 cites W1954728452 @default.
• W127130454 cites W1963545039 @default.
• W127130454 cites W1966363887 @default.
• W127130454 cites W1966416038 @default.
• W127130454 cites W1967574410 @default.
• W127130454 cites W1968482666 @default.
• W127130454 cites W1969605542 @default.
• W127130454 cites W1972959613 @default.
• W127130454 cites W1973858938 @default.
• W127130454 cites W1977648979 @default.
• W127130454 cites W1977928473 @default.
• W127130454 cites W1979196526 @default.
• W127130454 cites W1979849071 @default.
• W127130454 cites W1979999135 @default.
• W127130454 cites W1982809233 @default.
• W127130454 cites W1985469117 @default.
• W127130454 cites W1985768828 @default.
• W127130454 cites W1987776161 @default.
• W127130454 cites W1991230641 @default.
• W127130454 cites W1991489244 @default.
• W127130454 cites W1992636402 @default.
• W127130454 cites W1992733039 @default.
• W127130454 cites W1992787746 @default.
• W127130454 cites W1992850824 @default.
• W127130454 cites W1994144656 @default.
• W127130454 cites W1996665221 @default.
• W127130454 cites W2001304056 @default.
• W127130454 cites W2006700420 @default.
• W127130454 cites W2008590973 @default.
• W127130454 cites W2010004274 @default.
• W127130454 cites W2011072417 @default.
• W127130454 cites W2014862126 @default.
• W127130454 cites W2017389884 @default.
• W127130454 cites W2019251747 @default.
• W127130454 cites W2020097124 @default.
• W127130454 cites W2020474231 @default.
• W127130454 cites W2023486113 @default.
• W127130454 cites W2025023416 @default.
• W127130454 cites W2028695808 @default.
• W127130454 cites W2041725303 @default.
• W127130454 cites W2041769371 @default.
• W127130454 cites W2043293105 @default.
• W127130454 cites W2052137707 @default.
• W127130454 cites W2052696994 @default.
• W127130454 cites W2054902458 @default.
• W127130454 cites W2058479841 @default.
• W127130454 cites W2059535228 @default.
• W127130454 cites W2061343703 @default.
• W127130454 cites W2062253359 @default.
• W127130454 cites W2064855181 @default.
• W127130454 cites W2065552859 @default.
• W127130454 cites W2068403499 @default.
• W127130454 cites W2073963375 @default.
• W127130454 cites W2074183668 @default.
• W127130454 cites W2074494791 @default.
• W127130454 cites W2076247413 @default.
• W127130454 cites W2076639392 @default.
• W127130454 cites W2077158554 @default.
• W127130454 cites W2077524973 @default.
• W127130454 cites W2078127009 @default.
• W127130454 cites W2081609898 @default.
• W127130454 cites W2083758589 @default.
• W127130454 cites W2084220260 @default.
• W127130454 cites W2085313140 @default.
• W127130454 cites W2089672336 @default.
• W127130454 cites W2090632234 @default.
• W127130454 cites W2091379422 @default.
• W127130454 cites W2093094597 @default.
• W127130454 cites W2094568831 @default.
• W127130454 cites W2097808534 @default.
• W127130454 cites W2098166392 @default.
• W127130454 cites W2098184601 @default.
• W127130454 cites W2100544217 @default.
• W127130454 cites W2112941164 @default.
• W127130454 cites W2114722238 @default.
• W127130454 cites W2116688431 @default.
• W127130454 cites W2117936709 @default.
• W127130454 cites W2123529526 @default.
• W127130454 cites W2127073449 @default.
• W127130454 cites W2128791868 @default.
• W127130454 cites W2128827201 @default.
• W127130454 cites W2135192999 @default.
• W127130454 cites W2143856302 @default.
• W127130454 cites W2146499272 @default.
• W127130454 cites W2150639711 @default.
• W127130454 cites W2159367911 @default.
• W127130454 cites W2163385165 @default.

• next