Metabolic products of microorganisms. 243. Pyridazomycin, a new antifungal antibiotic produced by Streptomyces violaceoniger.

Abstract

Pyridazomycin (1), a new antifungal antibiotic produced by Streptomyces violaceoniger sp. griseofuscus (strain Tii 2557), was detected in a selective screening against Mucor hiemalis (Tii 179/180). The amino acid side chain of 1 can be seen as L-ornithine, whose r-nitrogen atom is part of a pyridazine ring building a quaternary ammonium system. The structure of 1 was established by spectroscopic analysis of the parent compoundand degradation products. The occurrence of a pyridazine ring in microbial secondary metabolites is unique.In the course of our screening for antifungal antibiotics especially active against Mucor hiemalis (Tii 179/180) we isolated pyridazomycin as a strongly basic compound from the culture filtrate of Streptomyces violaceoniger sp. griseofuscus (strain Tii 2557). In this report we describe the fermentation, isolation, physico-chemical characterization, structural elucidation and some biological properties of pyridazomycin2).Fermentation and Isolation The producing organism was a new soil isolate collected near Tula, Mexico, and identified as Streptomyces violaceoniger sp. griseofuscus (strain Tii 2557). Production of pyridazomycin was conducted in 100-ml Erlenmeyer flasks. The cultures were harvested at 72 hours, when pyridazomycin production was maximal. The culture filtrate was adjusted to pH 3.0~3.5 and applied to Dowex 50W-X4.The active fractions were eluted with 4%aqueous ammoniasolution and adsorbed on charcoal. After elution with methanol the crude extract was further purified by chromatography on silica gel (butanol -acetic acid -water, 2 : 1 : 1) and Sephadex G-10 (water) followed by cation exchange on an Amberlite IRC-50 column with 0.5 msodium chloride solution as eluent. Repeated chromatography on Sephadex G-10 yielded pure pyridazomycin.Characterization and Structure ElucidationPyridazomycin is a white, hygroscopic amorphous powder (dec above 119°C), insoluble in t Seerefl.

Formation of the Pyridazine Natural Product Azamerone by Biosynthetic Rearrangement of an Aryl Diazoketone

“…Biosynthetic investigations of the azoxy containing antibiotic valanimycin ( 1 ) [2] and the antifungal antibiotic pyridazomycin ( 2 ) [3a] (Figure 1) have shown that both of these natural products are derived from the condensation of amino acids. Pyridazomycin [3b] was the only natural product containing a pyridazine ring until the phthalazinone meroterpenoid azamerone ( 3 ) was isolated from the marine sediment-derived bacterium Streptomyces sp.…”

“…Pyridazomycin [3b] was the only natural product containing a pyridazine ring until the phthalazinone meroterpenoid azamerone ( 3 ) was isolated from the marine sediment-derived bacterium Streptomyces sp. CNQ-766.…”

Six‐Membered Heterocycles: 1,2‐, 1,3‐, and 1,4‐Diazines and Related Systems

“…Antrimycins [11] (11, from Streptomyces xanthocidiens) are tuberculostatic peptides that also contain nonribosomal amino acids. The quaternary salt pyridazinomycin [12] (12, from Streptomyces violaceoniger) is an antifungal antibiotic whose amino acid side chain can be viewed as L-ornithine with its terminal nitrogen atom as part of the pyridazine ring. As synthetic compounds, pyridazines constitute an important pharmacophoric moiety present in many drugs acting on various pharmacological targets.…”

Microwave‐enhanced Efficient Synthesis of Some Polyfunctional Pyridazines

“…The discovery of pyridazomycin , a new antifungal antibiotic from Streptomyces violaceoniger , and Zarzissine , a new cytotoxic guanidine alkaloid isolated from Mediterranean sponge Anchinoe paupertas , both containing this heteroatom scaffold, is expected to stimulate even broader interest in 1,2‐diazanine chemistry.…”

“…Except few, most of the aforementioned approaches to the synthesis of diversified pyridazines have several disadvantages, for example, harsh reaction conditions, a number of steps, inconvenient operations, limited availability of substances, use of toxic chemicals, lack of atom economy, and poor yields. Inspired by the wide spectrum applications of pyridazine nuclei and our continuous interest in developing an efficient ecofriendly procedure , we herein report, for the first time, a convenient microwave‐assisted synthesis of polyfunctional pyridazines in ionic liquids, viz.…”