Isoxazole-3-hydroxamic acid

Researchers at Combio and Arpida have reported a series of isoxazole-3-hydroxamic acids as PDF inhibitors [109], Molecular modelling studies predict that the aryl substituent of isoxazole (37) binds into the SF pocket and that the oxygen atom of the isoxazole is involved in a H-bonding interaction with Ile-44 in E. coli PDF, similar to the PF carbonyl of actinonin. None of the inhibitors reported has sub-micromolar inhibitory activity against E. coli or S. aureus PDF. Not surprisingly, these moderately active inhibitors also lack antibacterial activity. 

Isoxazole-3-hydroxamic Acid Derivatives as Potential PDF Inhibitors. . . 193... 

Scheme 29 Synthesis of isoxazole-3-hydroxamic acid derivatives...

Krogsgaard-Larsen and co-workers have protected the P-keto functionality as a ketal as a modification to the traditional conditions so attack of hydroxylamine is directed towards the ester. They prepared hydroxamic acid 10 from ester 9 then cyclized with sulfuric acid to isoxazole 11, in route to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a selective GABAa receptor agonist studied clinically for insomnia. 

The first synthesis of a 3,5-diarylisoxazole from aryl hydroxamic acid chlorides and sodium phenyl acetylides was that effected by Weygand and Bauer in 1927. Beginning in 1946, when Quilico and Speroni showed that acid chlorides of hydroxamic acids on treatment with alkalies readily yielded nitrile oxides,numerous isoxazole and especially A -isoxazoline derivatives have been prepared. 

Some hydroxamic acids of the isoxazole series also display a marked antituberculosis activity. The penicillin derivatives, acylated with isoxazole carboxylic acids possess an antibacterial activity similar to that of penicillin, against resistant species.Among other isoxazole derivatives possessing activity one should especially mention the sulfonamides of this series, and 4-hydroxyiminoisoxazol-5-... 

Benzonitrile oxide (C in Figure 15.44) is an isolable 1,3-dipole. It can be generated from benzaldoxime and anNaOH/Cl2 solution. Under these reaction conditions the oxime/nitroso anion (A B) is initially formed and chlorine disproportionates into Cl—O and chloride. An SN reaction of the negatively charged C atom of the anion A B at the Cl atom of Cl— O or of Cl—O—H affords the oc-chlorinated nitroso compound E, which tautomerizes to the hydroxamic acid chloride D. From that species, the nitrile oxide C is generated via a base mediated 1,3-elimination. Isoxazoles are formed in the reactions of C with alkynes (Figure 15.44), while isoxazolines would be formed in its reactions with alkenes. 

Beginning in 1946 when it was shown that treatment of acid chlorides of hydroxamic acids with alkali hydroxide gave nitrile oxides (46G148), numerous isoxazole derivatives have been prepared. This method lead to isoxazolo[4,5-d]isoxazoles (equation 31) (59G571). 

The reaction between ethyl aceto acetate and hydroxylamine yields the hydroxamic acid which is cyclised to a hydroxy isoxazole... 

Nitrile oxides 7 react as 1,3-dipoles with alkynes in a [3+2] cycloaddition to give isoxazoles (Quilico synthesis). The nitrile oxides are generated in situ. They are obtained, for instance, by dehy-drohalogenation of hydroxamic acid chlorides (cr-chloraldoximes) with triethylamine ... 

The carboxylic function of active compounds has been changed to direct derivatives such as hydroxamic acids R— CO—NH—OH, acyl-cyanamides R—CO—NH—CN and acyl-sulfonamides R—CO—NH—SO2—R to planar acidic heterocycles such as tetrazoles, hydroxy-isoxazoles, etc., or even to non-planar sulfur- or phosphorus-derived acidic functions (Table 13.8). 

The phosphazene bases BTPP and Bu-P2 mediate the rearrangement of unactivated A -alkyl-(9-benzoyl hydroxamic acid derivatives to give 2-benzoyl amides. The rate of reaction was found to be dependent upon the steric nature of the A -alkyl substituent [39a]. Treatment of malonyl derived (9-acyUiydroxamic acid derivatives with the phosphazene superbase Bu-P2 gives 2,3-dihydro-4-isoxazole carboxylic ester derivatives. The rate and yield of the reaction depend upon the (9-acyl substituent [36b] (Scheme 5.21). 

Clark, A.J., Al-Faiyz, Y.S.S., Patel, D. and Broadhurst, M.J. (2001) Rearrangement of unactivated A-alkyl-O-benzoyl hydroxamic acid derivatives with phosphazene bases. Tetrahedron Letters, 42, 2007-2009 Clark, A.J., Patel, D. and Broadhurst, M.J. (2003) Base-mediated reaction of A-alkyl-O-acyl hydroxamic acids synthesis of 3-oxo-2,3-dihydro-4-isoxazole carboxylic ester derivatives. Tetrahedron Letters, 44, 7763-7765. 

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