ADENOSINE-ANALOGS AS ANTIMETABOLITES AGAINST PLASMODIUM-FALCIPARUM MALARIA

Analogues of purine nucleosides and deoxynucleosides were tested for t oxicity against the intraerythrocytic parasite Plasmodium falciparum i n vitro culture. Sangivamycin (7-deaza-7-amido-adenosine) (IC37 of 0.3 muM), tubercidin (7-deaza-adenosine) (IC37 of 0.7 muM), 6-methylamino -deoxyadenosine (IC37 Of 10 muM), 8-aza-2-amino-deoxy-adenosine (IC37 of 11 muM) and 2-chloro-adenosine (IC37 of 11 muM) were found to be th e most toxic towards the parasite. Structure-activity analysis suggest ed that alteration of the purine ring at the 7 or 8 position significa ntly increased the toxicity of the compound against P. falciparum. Ana lysis by HPLC of parasite lysates which had been subjected to the cyto toxic compounds confirmed that alterations in the flux of the purine s alvage pathways of the parasite had occurred. Comparison of the toxici ty of these compounds against P. falciparum with the toxicity against a similar intraerythrocytic parasite, Babesia bovis, or human melanoma cell lines indicated a differential toxicity, in that many of the com pounds toxic towards P. falciparum were relatively non-toxic towards h uman melanoma cell lines or B. bovis and vice versa. The mechanism of toxicity of the deoxyadenosine and adenosine analogues, whose normal m etabolism involves transport, metabolism and incorporation into nuclei c acids appears to vary significantly between P. falciparum, B. bovis and mammalian cells.