Sch-39185

A new macrolactam, fluvirucin B0 (1), and two known macrolactams, Sch 38516/fluvirucin B1 (2) and Sch 39185/fluvirucin B3 (3), have been isolated from an acetone extract of a strain of Nonomuraea turkmeniaca. These compounds were isolated by bioassay-guided fractionation as part of our search for new anthelmintics. The structures of these compounds were elucidated by comparison of their NMR and MS data to those of previously reported fluvirucins, and confirmed by 2D-NMR. 1approximately 3 exhibited in vitro activity (EC90 <1.0 approximately 1.7 microg/ml) against Haemonchus contortus larvae, but were ineffective in reducing worm counts in vivo against Heligmosomoides polygyrus in mice at 50 mg/kg dosed intramuscularly.

A route to fluvirucinins B(2-5) (the common aglycon of fluvirucins B(2)-B(5), Sch 38518, and Sch 39185) is reported for the first time. A ring-closing metathesis (RCM) generated the C6-C7 double bond, which by catalytic hydrogenation (in toluene) gave the desired epimer with a 9:1 diastereoselection. Azide 8a and carboxylic acid 5 came from ethyl-branched fragments C9-C13 (CHO at C9) and C1-C5 via an asymmetric allylation of the former and a cross metathesis (CM) followed by a ketone methylenation (with 20 mol % of DMF as a sacrificial additive) of the latter.

Three novel antifungal antibiotics, Sch 38518, Sch 39185 and Sch 38516 were isolated from the fermentation broths of two actinomycetes identified by chemical, morphological and physiological analysis as a new species of Actinomadura. The compounds were isolated from broth by solvent extraction and purified by silica gel chromatography. Physico-chemical properties, mass spectral analysis, IR and UV suggested the compounds were similar. Sch 38518 and Sch 39185 have a molecular formula of C25H48N2O5. 1H NMR, 13C NMR and hydrolysis indicated the aglycones were identical, however the compounds differed in containing isomeric sugar moieties. Sch 38518 contains mycosamine while Sch 39185 contains 3,6-dideoxy-3-amino-L-talopyranose. Sch 38516 has a molecular formula of C24H46N2O5 and is a lower homolog of Sch 39185. The three compounds, Sch 38518 (1), Sch 39185 (2), and Sch 38516 (3) exhibit similar activity against Candida spp. with geometric mean MICs of 1.81, 2.00 and 0.91 micrograms/ml, respectively.