FigsharePub Date : 2016-05-05DOI: 10.1021/jm040884n.s001
Per-Ola Johansson (2678443), Jimmy Lindberg (846939), Michael J. Blackman (192013), Ingemar Kvarnström (2678440), Lotta Vrang (1284522), Elizabeth Hamelink (2669875), Anders Hallberg (585061), Åsa Rosenquist (1284525), Bertil Samuelsson (1303401)
{"title":"Design and Synthesis of Potent Inhibitors of Plasmepsin I and II: X-ray CrystalnStructure of Inhibitor in Complex with Plasmepsin II","authors":"Per-Ola Johansson (2678443), Jimmy Lindberg (846939), Michael J. Blackman (192013), Ingemar Kvarnström (2678440), Lotta Vrang (1284522), Elizabeth Hamelink (2669875), Anders Hallberg (585061), Åsa Rosenquist (1284525), Bertil Samuelsson (1303401)","doi":"10.1021/jm040884n.s001","DOIUrl":"https://doi.org/10.1021/jm040884n.s001","url":null,"abstract":"New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, fromnthe deadliest malaria parasite <i>Plasmodium falciparum</i>, have been synthesized utilizing Suzukincoupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors.nThe enzyme inhibition activity has been improved up to eight times by identifying P1nsubstituents that effectively bind to the continuous S1−S3 crevice of Plasmepsin I and II. Bynreplacement of the bromo atom in the P1 <i>p</i>-bromobenzyloxy-substituted inhibitors with differentnaryl substituents, several inhibitors exhibiting <i>K</i><sub>i</sub> values in the low nanomolar range for bothnPlm I and II have been identified. Some of these inhibitors are also effective in attenuatingnparasite growth in red blood cells, with the best inhibitors, compounds <b>2</b> and <b>4</b>, displayingn70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partiallynguided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitorn<b>1</b> in complex with plasmepsin II.","PeriodicalId":523306,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147913744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}