Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment
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Johansson , N G , Turku , A , Vidilaseris , K , Dreano , L , Khattab , A , Ayuso Perez , D , Wilkinson , A , Zhang , Y , Tamminen , M , Grazhdankin , E , Kiriazis , A , Fishwick , C W G , Meri , S , Yli-Kauhaluoma , J , Goldman , A , Boije af Gennäs , G & Xhaard , H 2020 , ' Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment ' , ACS Medicinal Chemistry Letters , vol. 11 , no. 4 , pp. 605-610 . https://doi.org/10.1021/acsmedchemlett.9b00537
| Title: | Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment |
| Author: | Johansson, Niklas G; Turku, Ainoleena; Vidilaseris, Keni; Dreano, Loic; Khattab, Ayman; Ayuso Perez, Daniel; Wilkinson, Aaron; Zhang, Yuezhou; Tamminen, Matti; Grazhdankin, Evgeni; Kiriazis, Alexandros; Fishwick, Colin W. G.; Meri, Seppo; Yli-Kauhaluoma, Jari; Goldman, Adrian; Boije af Gennäs, Gustav; Xhaard, Henri |
| Contributor organization: | Pharmaceutical Design and Discovery group Division of Pharmaceutical Chemistry and Technology Drug Research Program Molecular and Integrative Biosciences Research Programme Staff Services TRIMM - Translational Immunology Research Program HUSLAB Seppo Meri / Principal Investigator Department of Bacteriology and Immunology Jari Yli-Kauhaluoma / Principal Investigator University Management Biochemistry and Biotechnology Computational Adme Henri Xhaard / Principal Investigator Division of Pharmaceutical Biosciences |
| Date: | 2020-04-09 |
| Language: | eng |
| Number of pages: | 6 |
| Belongs to series: | ACS Medicinal Chemistry Letters |
| ISSN: | 1948-5875 |
| DOI: | https://doi.org/10.1021/acsmedchemlett.9b00537 |
| URI: | http://hdl.handle.net/10138/314686 |
| Abstract: | Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of small mPPase inhibitors with 6-10 mu M IC50 values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth. |
| Subject: |
ACIDOCALCISOMES
BISPHOSPHONATES Membrane-bound pyrophosphatase PUMPING PYROPHOSPHATASES TARGET TRYPANOSOMA-BRUCEI drug design isoxazoles protozoan diseases 317 Pharmacy |
| Peer reviewed: | Yes |
| Rights: | cc_by |
| Usage restriction: | openAccess |
| Self-archived version: | publishedVersion |
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