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Development of Benzophenone‐Based Farnesyltransferase Inhibitors as Novel Antimalarials
Author(s) -
Kohring Katja,
Wiesner Jochen,
Altenkämper Mirko,
Sakowski Jacek,
Silber Katrin,
Hillebrecht Alexander,
Haebel Peter,
Dahse HansMartin,
Ortmann Regina,
Jomaa Hassan,
Klebe Gerhard,
Schlitzer Martin
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800043
Subject(s) - farnesyltransferase , plasmodium falciparum , in vivo , moiety , benzophenone , farnesyltransferase inhibitor , antimalarial agent , pharmacology , chemistry , farnesyl diphosphate farnesyltransferase , in vitro , docking (animal) , malaria , biochemistry , stereochemistry , biology , enzyme , medicine , immunology , prenylation , microbiology and biotechnology , nursing , photochemistry
The development of farnesyltransferase inhibitors directed against Plasmodium falciparum is a strategy towards new drugs against malaria. Previously, we described benzophenone‐based farnesyltransferase inhibitors with high in vitro antimalarial activity but no in vivo activity. Through the introduction of a methylpiperazinyl moiety, farnesyltransferase inhibitors with in vivo antimalarial activity were obtained. Subsequently, a structure‐based design approach was chosen to further improve the antimalarial activity of this type of inhibitor. As no crystal structure of the farnesyltransferase of the target organism is available, homology modeling was used to reveal differences between the active sites of the rat/human and the P. falciparum farnesyltransferase. Based on flexible docking data, the piperazinyl moiety was replaced by a N,N,N ′‐trimethylethylenediamine moiety. This resulted in an inhibitor with significantly improved in vitro and in vivo antimalarial activity. Furthermore, this inhibitor displayed a notable increase in selectivity towards malaria parasites relative to human cells.