title: Synthesis and antiprotozoal activity of pyridyl analogues of pentamidine.
abstract: A series of novel pyridyl analogues 1-18 of antiprotozoal drug 1,5-bis(4-amidinophenoxy)pentane (pentamidine) has been synthesized and tested for in vitro activities against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani, and for cytotoxicity against mammalian cells. Antiprotozoal properties of compounds 1-18 depended on the placement of cationic moieties on the pyridine rings as well as the nature of substituents on the amidine groups. Diamidine 6 with cationic moieties adjacent to pyridine nitrogen atoms was the most promising compound in the series showing superior in vitro activities against T. brucei rhodesiense, P. falciparum, and L. donovani compared to pentamidine. An oral prodrug of diamidine 6, diamidoxime 9, administered at 25 mg/kg daily for 4 days, exhibited excellent antitrypanosomal efficacy in vivo curing all infected animals in the STIB900 acute mouse model of trypanosomiasis.
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina 27599-7525, USA.
authors.forename: Svetlana M
authors.initials: SM
authors.lastname: Bakunova
authors.forename: Stanislav A
authors.initials: SA
authors.lastname: Bakunov
authors.forename: Tanja
authors.initials: T
authors.lastname: Wenzler
authors.forename: Todd
authors.initials: T
authors.lastname: Barszcz
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D010963:Plasmodium falciparum / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D011725:Pyridines; D010419:Pentamidine