VOL. 57 NO. 6, JUNE 2004
pp. 400 — 402
In Vitro and In Vivo Antimalarial Activities of
In vitro activities against Plasmodium falciparum strains a Carbohydrate Antibiotic, Prumycin, against
K1 (drug-resistant) and FCR3 (drug-sensitive), and cytotoxicity against human diploid embryonic cell line Drug-resistant Strains of Plasmodia
MRC-5, were measured as described previously1). Rodent malaria-derived strains for in vivo 4-days suppressive testing, P. berghei N (drug-sensitive) and P. yoelii ssp. NS In the course of our program to discover antimalarial (chloroquine-resistant) were used to assess in vivo efficacy antibiotics active against drug-resistant parasites, by as reported previously1,2). Prumycin was dissolved in water, screening soil microorganisms and antibiotic library of the while other test compounds were solubilized in 10% Kitasato Institute for Life Sciences, we previously reported DMSO-Tween 80 aqueous solution. The formulated on various microbial metabolites exhibiting potent samples were administered subcutaneously (s.c.) to mice antimalarial properties1ϳ4). Now, we find that prumycin5ϳ7), two hours after infection with parasites (Day 0), and then a compound in the antibiotic library of our institute, has once a day for 3 days (Days 1ϳ3). On the day after the last potent and moderately selective antimalarial activity in vitro treatment (Day 4), thin blood films were made from the tail and in vivo. We report here the antimalarial profiles of blood of the mice, and the parasitaemia was determined as prumycin and its derivatives (Fig. 1) in comparison with those of clinically used antimalarial drugs, and also present Table 1 shows the in vitro antimalarial activities of some conclusions on structure-activity relationships.
prumycin, its derivatives and some standard antimalarial Prumycin was purified from the cultured broth of drugs. Prumycin and a -prumycin had similar activity to Streptomyces sp. strain No. F-10285,6). The derivatives choroquine against the drug-resistant K1 strain of P. (2ϳ4) were synthesized according to our previous report7).
falciparum, but were less potent than the clinically used Benzyl 4-amino-2-(benzyloxycarbonyl) amino-2,4- antimalarials artemether, artemisinin and artesunate.
dideoxy-a -L-arabinopyraside (5) was a generous gift of
Furthermore, prumycin and a -prumycin showed similar Nippon Kayaku Co. LTD., (Japan). The compounds (6ϳ8)
activities against the drug-sensitive FCR3 strain of P. were prepared from 5 with the protected amino acids
(DCC, CH Cl , r.t.), followed by deprotections.
3ϳ8) against the K1 strain were Ͼ12.5 mg/ml.
Structures of prumycin and its derivatives.
VOL. 57 NO. 6
derivatives and the antimalarial drugs against K1 activities of prumycin, artemether, artesunate and and FCR3 strains of Plasmodium falciparum.
chloroquine against P. berghei N and P. yoelii ssp.
We then investigated the cytotoxicities of prumycin and a - It is known that prumycin has inhibitory activities against prumycin against MRC-5 cells and found them to be, phytopathogenic fungi such as Sclerotinia sclerotiorum and respectively, 3.6 and 1.2 m g/ml. Prumycin and a -prumycin Botorytis cineria5,6), and against tumor cells8ϳ11), and that showed moderate to low selectivity indexes, with ratios in its mode of anti-fungal action in growing cells of B. cineria the ranges of 22.5ϳ3.5 and 21.3ϳ8.6 for the MRC-5 involves selective inhibition of protein synthesis12).
cells/K1 strain and MRC-5 cells/FCR3 strain, respectively.
Furthermore, we previously reported that it inhibits both The lack of antimalarial activity of prumycin derivatives protein synthesis and DNA synthesis in cultured HeLa S3 (3ϳ8) in comparison to prumycin provides interesting
cells8). However, the finding of the antimalarial activities of information on structure-activity relationships. Thus prumycin and its derivative is novel and the above data are introduction of a methyl group on the hydroxyl (to give 3)
the first report of such properties.
and acetylating the two primary amino groups (resulting in 4) destroys activity. Furthermore, replacement of the
in mice) of prumycin were 144 and 155 mg/kg, respectively.
L-alanine group on the amino moiety at C-4 with, However, we did observe toxicity (loss of weight, mortality) respectively, L-glycine (6), L-proline (7), and L-isoleucine
when the compound was delivered by the s.c. route (8) also destroys activity. These results suggest that a free
at Ͼ30 mg/kgϫ4. These effects are being investigated anomer at C-1, amino groups at C-2, and the methyl group at L-alanine all play an important role in the antimalarial The above results reveal that prumycin is a promising lead compound for a new type of antimalarial drug. Further Further studies are necessary to extend the structure- investigation of the antimalarial potential of prumycin is in activity relationships of prumycin-related antimalarial Table 2 shows a preliminary comparison of the in vivo subcutaneous antimalarial activities of prumycin and the standard antimalarial drugs. Prumycin had moderate This work was supported, in part, by funds from the activity against both rodent malaria-derived P. berghei N UNICEF/UNDP/World Bank/WHO Special Program forResearch and Training in Tropical Diseases (grants ID and P. yoelii ssp. NS, but was less effective than the A10124), and Grants-in-Aid for Scientific Research (A) from clinically used antimalarials artemether and artesunate. the Ministry of Education, Culture, Sports, Science and value of prumycin (27.8 mg/kg) against the Technology, Japan. A part of work was supported by The 21st chloroquine-resistant strain (P. yoelii ssp. NS) was much Century COE program, the Ministry of Education, Culture,Sports, Science and Technology, Japan. We are grateful to Dr.
lower than that of chloroquine (Ͼ100 mg/kg), and was THE JOURNAL OF ANTIBIOTICS
JUNE 2004
K. HATA, JPMW Coordination Center, for valuable discussion.
the microbial metabolites. J. Antibiotics 56: 322ϳ324, We also thank Mr. Y. KATO and Ms. M. SUZUKI, the Kitasato Institute, for the antimalarial assay, Dr. J. NAMATAME, Kitasato OTOGURO, K.; H. UI, A. ISHIYAMA, M. KOBAYASHI, H.
Institute for Life Sciences, Kitasato University, for technical TOGASHI, Y. TAKAHASHI, R. MASUMA, H. TANAKA, H.
¯ MURA: In vitro and in vivo antimalarial activities of a non-glycoside 18-member macrolide antibiotic, borrelidin, against drug-resistant strains of Plasmodia. J. Antibiotics 56: 727ϳ729, 2003 ¯ MURA, M. KATAGIRI, K. ATSUMI, J. AWAYA, S. HIGASHIKAWA, K. YASUI, H. TERADA & S. KUYAMA: A new antifungal antibiotic, prumycin. J. Antibiotics 24: ¯ MURA, S.; M. KATAGIRI, J. AWAYA, K. ATSUMI, R. O¯IWA, T. HATA, S. HIGASHIKAWA, K. YASUI, H. TERADA & S.
KUYAMA: Production and isolation of a new antifungal antibiotic, prumycin, and taxonomic studies ofStreptomyces sp., strain No. F-1028. Agr. Biol. Chem.
Research Center for Tropical Diseases, The Kitasato Institute, † Kitasato Institute for Life Sciences, Kitasato University, ¯ MURA, S.; M. KATAGIRI, K. ATSUMI, T. HATA, A. A.
5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan JAKUBOWSKI, E. B. SPRINGS & M. TISHILER: Structure ofprumycin. J. Chem. Soc., Perkin Trans. I. 1974: OKUBO, S.; N. NAKAMURA, K. ITO, H. MARUMO, M.
TANAKA & S. O ¯ MURA: Antitumor activity of prumycin. J.
of prumycin. II. Studies on distribution and excretion ofprumycin. J. Antibiotics 33: 221ϳ225, 1980 OTOGURO, K.; A. KOHANA, C. MANABE, A. ISHIYAMA, OKUBO, S.; N. NAKAMURA, M. MORIMOTO, K. MINEURA, antimalarial activities of polyether antibiotic, X-206. J.
of prumycin. III. Mode of action of prumycin on Hela S-3 cells. J. Antibiotics 33: 226ϳ230, 1980 OTOGURO, K.; A. ISHIYAMA, H. UI, M. KOBAYASHI, OKUBO, S.; M. MORIMOTO, K. MINEURA, H. MARUMO & C. MANABE, G. YAN, Y. TAKAHASHI, H. TANAKA, H.
¯ MURA: Studies on antitumor activity of prumycin. IV.
¯ MURA: In vitro and in vivo antimalarial Effect of prumycin on mouse immune system. J.
activities of the monoglycoside polyether antibiotic, K- 41 against drug resistant strains of Plasmodia. J.
The mechanism of prumycin action. J. Antibiotics 27: OTOGURO, K.; H. UI, A. ISHIYAMA, N. ARAI, M.
YAMADA & S. O ¯ MURA: In vitro antimalarial activities of * Corresponding author: otoguro@lisci.kitasato-u.ac.jp

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