In vitro and in vivo antimalarial activities of a carbohydrate antibiotic, prumycin, against drug-resistant strains of Plasmodia.

Sir: In the course of our program to discover antimalarial antibiotics active against drug-resistant parasites, by screening soil microorganisms and antibiotic library of the Kitasato Institute for Life Sciences, we previously reported on various microbial metabolites exhibiting potent antimalarial properties . Now, we find that prumycin , a compound in the antibiotic library of our institute, has potent and moderately selective antimalarial activity in vitro and in vivo. We report here the antimalarial profiles of prumycin and its derivatives (Fig. 1) in comparison with those of clinically used antimalarial drugs, and also present some conclusions on structure-activity relationships. Prumycin was purified from the cultured broth of Streptomyces sp. strain No. F-1028. The derivatives (2 4) were synthesized according to our previous report. Benzyl 4-amino-2-(benzyloxycarbonyl) amino-2,4dideoxy-a-L-arabinopyraside (5) was a generous gift of Nippon Kayaku Co. LTD., (Japan). The compounds (6 8) were prepared from 5 with the protected amino acids (DCC, CH2Cl2, r.t.), followed by deprotections. In vitro activities against Plasmodium falciparum strains K1 (drug-resistant) and FCR3 (drug-sensitive), and cytotoxicity against human diploid embryonic cell line MRC-5, were measured as described previously. Rodent malaria-derived strains for in vivo 4-days suppressive testing, P. berghei N (drug-sensitive) and P. yoelii ssp. NS (chloroquine-resistant) were used to assess in vivo efficacy as reported previously. Prumycin was dissolved in water, while other test compounds were solubilized in 10% DMSO-Tween 80 aqueous solution. The formulated samples were administered subcutaneously (s.c.) to mice two hours after infection with parasites (Day 0), and then once a day for 3 days (Days 1 3). On the day after the last treatment (Day 4), thin blood films were made from the tail blood of the mice, and the parasitaemia was determined as described previously. Table 1 shows the in vitro antimalarial activities of prumycin, its derivatives and some standard antimalarial drugs. Prumycin and a-prumycin had similar activity to choroquine against the drug-resistant K1 strain of P. falciparum, but were less potent than the clinically used antimalarials artemether, artemisinin and artesunate. Furthermore, prumycin and a-prumycin showed similar activities against the drug-sensitive FCR3 strain of P. falciparum. However, the IC50 values of prumycin derivatives (3 8) against the K1 strain were 12.5 mg/ml. VOL. 57 NO. 6, JUNE 2004 THE JOURNAL OF ANTIBIOTICS pp. 400 — 402