Aigialomycins A-E (2-6), new 14-membered resorcylic macrolides, were isolated together with a known hypothemycin (1) from the mangrove fungus, Aigialus parvus BCC 5311. Structures of these compounds, including absolute configuration, were elucidated by spectroscopic methods, chemical conversions, and X-ray crystallographic analysis. Hypothemycin and aigialomycin D (5) exhibited in vitro antimalarial activity with IC(50) values of 2.2 and 6.6 microg/mL, respectively, while other analogues were inactive. Cytotoxicities of these compounds were also evaluated.

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Pyrimethamine (Pyr) targets dihydrofolate reductase of Plasmodium vivax (PvDHFR) as well as other malarial parasites, but its use as antimalarial is hampered by the widespread high resistance. Comparison of the crystal structures of PvDHFR from wild-type and the Pyr-resistant (SP21, Ser-58 3 Arg ؉ Ser-117 3 Asn) strain as complexes with NADPH and Pyr or its analog lacking p-Cl (Pyr20) clearly shows that the steric conflict arising from the side chain of Asn-117 in the mutant enzyme, accompanied by the loss of binding to Ser-120, is mainly responsible for the reduction in binding of Pyr. Pyr20 still effectively inhibits both the wild-type and SP21 proteins, and the x-ray structures of these complexes show how Pyr20 fits into both active sites without steric strain. These structural insights suggest a general approach for developing new generations of antimalarial DHFR inhibitors that, by only occupying substrate space of the active site, would retain binding affinity with the mutant enzymes.drug resistance ͉ malaria ͉ antifolates A major share of the global malaria burden, with an estimated 80 million cases annually, is caused by Plasmodium vivax (Pv) (1, 2). The problem has recently been worsened by emergence of resistance of the parasite to chloroquine (3-6). Pyrimethamine (Pyr) and other antifolates are generally not used against vivax malaria, because of the resistance of the parasite, which has commonly been considered to be inherent (7). It recently has been shown, however, that wild-type (WT) P. vivax dihydrofolate reductase (PvDHFR), the target of antifolates, is susceptible to inhibition by Pyr and other antifolates (8-11), whereas for the mutant parasites, of which the common one is the double mutant (SP21, Ser-58 3 Arg ϩ Ser-117 3 Asn), the affinities for binding with the antifolates are much reduced, rendering them ineffective. A similar, but less severe, situation was shown for Plasmodium falciparum (Pf), in which the homologous double mutant (K1, Cys-59 3 Arg ϩ Ser-108 3 Asn) PfDHFR has reduced affinities for the antifolates (12-14). In the case of P. falciparum, there was only a moderate reduction in affinity (50-to 90-fold) relative to the WT enzyme, and a moderate level of resistance ensued, which was augmented by further mutations at other sites (14-17). The crystal structures of the bifunctional enzyme dihydrofolate reductase (DHFR)-thymidylate synthase (TS) of P. falciparum (PfDHFR-TS) revealed basic structural features of Plasmodial DHFR-TS, including the insert regions and the junction region (18).Comparison of the structures of the WT and mutant forms of PfDHFR-TS demonstrates that Pyr is involved in steric conflict with the side chain of Asn-108, resulting in antifolate resistance (13,19,20). However, the steric conflict did not appear to result in major displacement of Pyr in the active site of P. falciparum. In contrast, analogous mutations in P. vivax resulted in relatively larger reduction in binding affinity of Pyr. Because the crystal structure of PvDHFR, either of the WT or the SP21...