title: Antiprotozoal activity and DNA binding of N-substituted N-phenylbenzamide and 1,3-diphenylurea bisguanidines.
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.
authors.affiliation: Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Ríos Martínez
authors.affiliation: Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Lagartera
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland; University of Basel, Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain. Electronic address: dardonville@iqm.csic.es.
authors.forename: Christophe
authors.initials: C
authors.lastname: Dardonville
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology*; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000977:Antiparasitic Agents; D001549:Benzamides; D006146:Guanidines; D014508:Urea; D004247:DNA
keywords: Guanidine; Minor groove binder; Parasite chemotherapy; Plasmodium falciparum; Trypanosoma brucei; surface plasmon resonance (SPR) biosensor