Synthesis and antibacterial activities of 1-N [(S)-.OMEGA.-amino-2-hydroxyalkyl] kanamycin a derivatives.

Abstract

Four 1-N-aminohydroxy-alkyl derivatives of kanamycin A were prepared and their in vitro activities against aminoglycoside-sensitive and aminoglycoside-resistant organisms were compared with amikacin.1-N-[(S)-4-Amino-2-hydroxybutyl] kanamycin A (Fig. 1, compound 2, code no. UK-18,892) was equipotent to amikacin in all these tests and in mouse protection studies.A, has been reported1) to be highly active against both kanamycin-sensitive and kanamycin-resistant bacteria.In contrast, several other 1-N-acyl derivatives of kanamycin A have been shown to possess low antibacterial activity.21 We undertook a program of 1-N-alkyl modifications of kanamycin A to investigate structure-activity relationships in this area, and this paper describes the synthesis and antibacterial properties of some of the compounds produced. Materials and MethodsKanamycin A-1-N-Alkylated Derivatives 1-N-(S)-w-Amino-2-hydroxyalkyl derivatives of kanamycin A were prepared by diborane reduction of the corresponding 1-N-acyl derivatives, using the trifluoroacetate salts to improve solubility. The 1-N-acyl derivative (150 mg) was converted to its trifluoroacetate salt by dissolving in anhydrous trifluoroacetic acid followed by evaporation under reduced pressure. The resulting salt was dissolved in dry tetrahydrofuran (5 ml) and treated portionwise with a 1 M solution of diborane in tetrahydrofuran (20 ml), under a nitrogen atmosphere. After 6 hours at 50°C the reaction mixture was cooled and excess diborane was destroyed by the addition of a small amount of water. After evaporation under reduced pressure, the residue was taken up in water (10 ml), adjusted to pH 12 with 0.1 N sodium hydroxide solution and then to pH 5 using 2 N hydrochloric acid. The resulting solution was chromatographed on a column of Amberlite CG-50 ion-exchange resin (50 ml), in the ammonium ion form, eluting with dilute ammonia solution (linear increase, 0.1 to 1 M). Fractions containing the product were combined and evaporated under reduced pressure to yield the product as an amorphous solid (Table 1). The requisite 1-N-acyl compounds were synthesized by the method of NAITO et al.2,The structures of the products prepared in the present study have been confirmed by 13C-n.m.r. and/or mass spectral data. Microanalyses of the products reported are in agreement with the expected formulae calculated as the carbonate salts.Micro-organisms The bacteria designated 'aminoglycoside-sensitive' were pathogenic strains well adapted to growth under laboratory conditions. The aminoglycoside-resistant organisms were bacteria with proven inactivating mechanisms and were obtained from Prof. J. DAVIES, University of Wisconsin.M.I.C. Determinations Minimum inhibitory concentrations (M.I.C.) of the compounds were determined by a standard dilution method in Diagnostic Sensitivity Test Agar (DSTA-Oxoid). Serial dilutions (in 2-fold steps) of the compounds were prepared in the agar plates over the required concentration range and, after the

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Therapeutic Agents Acting on RNA Targets

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Synthesis and antibacterial activity of 1-N-[(S)-ω-amino-2-hydroxyalkyl] derivatives of dibekacin, 5-deoxydibekacin, 3′-deoxykanamycin A and gentamicin B

“…Richardson et al 7 synthesized 1-N-aminoalkyl derivatives of kanamycin A by borane reduction of the corresponding 1-N-aminoalkanoyl derivatives and characterized their antibacterial activities. Among them, 1-N-[(S)-4-amino-2-hydroxybutyl]kanamycin A (butikacin), which is an AMK analog, showed excellent antibacterial activity similar to that of AMK and with a lower ototoxicity than that of AMK.…”