Antiprotozoal activity and DNA binding of N-substituted N-phenylbenzamide and 1,3-diphenylurea bisguanidines
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 2713846
Author(s) Ríos Martínez, Carlos H.; Lagartera, Laura; Kaiser, Marcel; Dardonville, Christophe
Author(s) at UniBasel Kaiser, Marcel
Year 2014
Title Antiprotozoal activity and DNA binding of N-substituted N-phenylbenzamide and 1,3-diphenylurea bisguanidines
Journal European journal of medicinal chemistry
Volume 81
Pages / Article-Number 481-491
Keywords Trypanosoma brucei, Plasmodium falciparum, Parasite chemotherapy, Guanidine, Minor groove binder, surface plasmon resonance (SPR) biosensor
Abstract Two series of N-alkyl, N-alkoxy, and N-hydroxy bisguanidines derived from the N-phenylbenzamide and 1,3-diphenylurea scaffolds were synthesised in three steps from the corresponding 4-amino-N-(4-aminophenyl)benzamide and 1,3-bis(4-aminophenyl)urea, respectively. All of the new compounds were evaluated in vitro against T. b. rhodesiense (STIB900) trypomastigotes and Plasmodium falciparum NF54 parasites (erythrocytic stage). N-alkoxy and N-hydroxy derivatives showed weak micromolar range IC50 values against T. b. rhodesiense and P. falciparum whereas the N-alkyl analogues displayed submicromolar and low nanomolar IC50 values against P. falciparum and Trypanosoma brucei, respectively. Two compounds, 4-(2-ethylguanidino)-N-(4-(2-ethylguanidino)phenyl)benzamide dihydrochloride (7b) and 4-(2-isopropylguanidino)-N-(4-(2-isopropylguanidino)phenyl)benzamide dihydrochloride (7c), which showed favourable drug-like properties and in vivo efficacy (100% cures) in the STIB900 mouse model of acute human African trypanosomiasis represent interesting leads for further in vivo studies. The binding of these compounds to AT-rich DNA was confirmed by surface plasmon resonance (SPR) biosensor experiments.
Publisher Elsevier
ISSN/ISBN 0223-5234
edoc-URL http://edoc.unibas.ch/dok/A6298953
Full Text on edoc No
Digital Object Identifier DOI 10.1016/j.ejmech.2014.04.083
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/24865793
Document type (ISI) Article
 
   

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