The molecular structure of Nafuredin

Click on the image above to interact with the 3D model of the Nafuredin structure


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)


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)