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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