Nafuredin

Discovery, producing organism and structure (1-4)

Nafuredin was isolated from a culture broth of the fungal strain FT-0554 and recognized as an inhibitor of helminth NADH-fumarate reductase. Its target was revealed to be complex I (NADH-quinone oxidoreductase), and it was identified as a selective inhibitor of helminth complex I. Nafuredin showed anthelmintic activity against Haemonchus contortus in in vivo studies. The structure of nafuredin was elucidated as β,γ-epoxy-δ-lactone with a branched side chain, and its absolute configuration was revealed synthetically. Nafuredin is biosynthesized from a nonaketide and four methionines (branched methyl carbons) (2).

Physical data

White powder. C₂₂H₃₂O₄; mol wt 360.50. Sol. in DMSO, EtOH, EtOAc, CHCl₃. Insol. in H₂O, hexane.

Biological activity (1,4)

1) Effects on electron transport enzymes

Many adult parasites live in low oxygen environments. Such organisms generate ATP differently from aerobic mammals. Anaerobic parasites fix CO₂ to phosphoenolpyruvate producing oxaloacetate, which is converted into malate and transported to the mitochondria. Malate is then converted to fumarate, and reduced to succinate by complex II which uses NADH as a reducing agent. This system, composed of complexes I and II, is called NADHfumarate reductase. The quinone used in this system is not ubiquinone but rhodoquinone. In a screening of NADH-fumarate reductase inhibitors for new anthelmintics, we found nafuredin and atpenin.

2) Kinetic analysis of nafuredin inhibition of A. suum complex I
The inhibition is non-competitive with NADH (Ki=8.1 nM) and competitive with rhodoquinone (Ki=8.3 nM).

3) Effect on Haemonchus contortus infected sheep

4) Toxicity
There were no signs of side effects or reduction of body weight during the testing period in either sheep (2 mg/kg p.o.) or mice (50 mg/kg p.o. and i.p.).

5) Antimicrobial activity (10 μg/6 mm disc, paper disc method)

References

1. [768] S. Ōmura et al., Proc. Natl. Acad. Sci. USA, 98, 60–62 (2001)
2. [772] H. Ui et al., J. Antibiot., 54, 234–238 (2001)
3. [776] D. Takano et al., Tetrahedron Lett., 42, 3017–3020 (2001)
4. [785] K. Shiomi et al., Bioscience and Industry, 59, 37–38 (2001)
5. [787] D. Takano et al., Org Lett., 3, 2289–2291 (2001)