Inhibition of the in vitro growth of Plasmodium falciparum by acyclic nucleoside phosphonates

Fortyeight acyclic nucleoside phosphonates (putative prodrugs of acyclic nu cleoside triphosphate inhibitors of DNA replication) have been evaluated fo r in vitro antiplasmodial activity. Only certain purine derivatives with a hydroxyl group attached to the acyclic sugar moiety displayed antiplasmodia l activity. The two most active analogs were (S)-9-(3-hydroxy-2-phosphonylm ethoxypropyl)adenine ((S)-HPMPA, IC50 = 0.18 +/- 0.07 mu M) and (S)-3-deaza -HPMPA (IC50 = 0.29 +/- 0.08 mu M). Their cyclic derivatives, containing an ester bond between the phosphonate and the hydroxyl group, were slightly l ess 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 an y activity, even at very high concentrations (> 250 mu M). Similarly, pyrim idine analogs of (S)-HPMPA, such as (S)-HPMPT, (S)-HPMPU and the anti-herpe svirus analog (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine ((S)-HPMP C), were devoid of any antiplasmodial activity. In addition, 11 acyclic nuc leoside (non-phosphorylated) analogs-which in contrast to the acyclic nucle oside phosphonates require the presence of a monophosphorylating enzyme for the first activation step-were tested. None of them inhibited the growth o f the parasite. In short three chemical entities seem to be imperative for antiplasmodial activity: a purine base, a hydroxyl group in the acyclic sid e chain and a phosphonate group terminating this chain. (C) 1999 Elsevier S cience B.V. and International Society of Chemotherapy. All rights reserved.