Synthesis of 2″-oxidized derivatives of 5-deoxy-5-epi-5-fluoro-dibekacin and -arbekacin, and study on structure-chemical shift relationships of urethane(or amide)-type NH protons in synthetic intermediates

Aminoglycosides: Activity and Resistance

“…position 5 of the 2-deoxystreptamine [protection against ANT(2Љ), APH(3Ј), AAC(3), and partly against AAC(2Ј) [(91)]. Yet, this approach has clear limitations since the introduction of a fluorine in positions 2Ј, 3Ј, and 4Ј (95,100,101,105) or in positions 2Љ and 6Љ (44) protects only against the enzymes acting on the modified positions. Chlorine has also been introduced into positions 3Ј and 6Љ of kanamycin A (105) as well as in position 6Љ of amikacin.…”

Fluorinated aminoglycosides

“…101 N-[(2'''S,4'''S) and (2'''S,4'''R)-5-amino-4-fluoro-2-hydroxypentanoyl] derivatives of dibekacin 102 The homologous (2S,4S) and (2R,4R)-5-amino-4-fluoro-2-hydroxypentanoic acids (prepared from malic acid) were coupled to 1-N of the aminoglycoside dibekacin (3) to obtain compounds 259 and 260 (Figure 17). Compounds 259 and 260 had the same potency as arbekacin (93). The acute toxicities in mice determined for 259 (~130 mg/kg) and 260 (~125 mg/kg) were approximately 1.7-fold weaker than that of arbekacin (93) (~75 mg/kg).…”

“…The antibacterial potencies of compounds 130a, 130b and 131 were generally lower than those of dibekacin (3) and arbekacin (93). Compound 131 was at least two-fold more active than 130a and 130b.…”

“…With the exception of 208, which showed some potency, the 210 and the 2''-acylamino-2''-deoxy derivatives (not shown) exhibited lower potencies or a complete absence of antibacterial activity, indicating that N-acylation at C-2'' is detrimental to the bacteriotoxic nature of these molecules. The antibacterial activity potencies of 216-219 were considerably diminished compared with that of arbekacin (93); this effect was attributed to the absence of the equatorial OH-2" of the AG when in the oxo form.…”

“…The LD50 for 262 (~120 mg/kg), which possesses a 5-carbon chain, is similar to that of 259 (~130 mg/kg), indicating that the chain length and not the presence of the fluorine atom at C -4''' controls the toxicity. With respect to antibacterial activity, 263 was less potent than arbekacin (93), while 261 and 260 are almost equipotent to the aforementioned AG, 102 indicating that a butanoic derivative presents the best balance between high antibacterial potency and low acute toxicity. to 271, and subsequent reduction of the azides and olefins by catalytic hydrogenation afforded 273 and 274.…”