title: Inhibition of the in vitro growth of Plasmodium falciparum by acyclic nucleoside phosphonates.
abstract: Forty-eight acyclic nucleoside phosphonates (putative prodrugs of acyclic nucleoside triphosphate inhibitors of DNA replication) have been evaluated for in vitro antiplasmodial activity. Only certain purine derivatives with a hydroxyl group attached to the acyclic sugar moiety displayed antiplasmodial activity. The two most active analogs were (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA, IC50=0.18+/-0.07 microM) and (S)-3-deaza-HPMPA (IC50=0.29+/-0.08 microM). Their cyclic derivatives, containing an ester bond between the phosphonate and the hydroxyl group, were slightly less active. All tested compounds that lacked the hydroxyl group, including potent antiretrovirus analogs such as 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and the (S)-HPMPA derivatives (R)-PMPA and (S)-FPMPA, did not show any activity, even at very high concentrations ( >250 microM). Similarly, pyrimidine analogs of (S)-HPMPA, such as (S)-HPMPT, (S)-HPMPU and the anti-herpesvirus analog (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine ((S)-HPMPC), were devoid of any antiplasmodial activity. In addition, 11 acyclic nucleoside (non-phosphorylated) analogs--which in contrast to the acyclic nucleoside phosphonates require the presence of a monophosphorylating enzyme for the first activation step--were tested. None of them inhibited the growth of the parasite. In short three chemical entities seem to be imperative for antiplasmodial activity: a purine base, a hydroxyl group in the acyclic side chain and a phosphonate group terminating this chain.
authors.affiliation: Institute of Infectious Diseases and Immunology, Department of Parasitology and Tropical Veterinary Medicine, Faculty of Veterinary Medicine, University of Utrecht, The Netherlands.
authors.forename: L J
authors.initials: LJ
authors.lastname: Smeijsters
authors.forename: F F
authors.initials: FF
authors.lastname: Franssen
authors.forename: L
authors.initials: L
authors.lastname: Naesens
authors.forename: E
authors.initials: E
authors.lastname: de Vries
authors.forename: A
authors.initials: A
authors.lastname: Holý
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: E
authors.initials: E
authors.lastname: de Clercq
authors.forename: J P
authors.initials: JP
authors.lastname: Overdulve
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000469:parasitology; D015774:Ganciclovir / Q000494:pharmacology; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C072574:cyclic-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine; D003596:Cytosine; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine; D000077404:Cidofovir; D015774:Ganciclovir