Oh

Compound 239

(d) N-Acylkanamycins. Umezawa and coworkers [124] further modified several analogs of 5,3',4'-trideoxykanamycin B (240), including chloro, deoxy, andV-methyl compounds (241-245 ), to 1-V-[(S)-4-amino-2-hydroxybutyryl] derivatives (246251) (compounds 240-251). Antibacterial activity results were the best activity for compound 250 and were improved for 6"-chlorinated compounds against gram-positive bacteria, with a concomitant increase in toxicity, compared to the related 6"-hydroxy derivatives, and marked increase in the activity by 1-V-acylation [124].

The same group has also reported the synthesis of 1-V-(2-aminoethoxycar-bonyl) and 1-V-(3-aminopropoxycarbonyl) kanamycin A, the latter being less active than amikacin (2). However, the former showed activity similar to that of amikacin, implying that the (S)-4-aminohydroxybutyryl residue of amikacin can be replaced

by a simple residue such as aminoethoxycarbonyl and retain its activity [125]. Reactions reported include enzymatic O-phosphorylation of kanamycin A and N-acet-ylation of tobramycin [126], regiospecific synthesis of 1-N-[(5)-4-amino-2-hydroxy-butyryl]-2"-deoxykanamycin B from neamine [127], and preparation of 1-N-(2-aminoethanesulfonyl) derivatives of kanamycin A and B, ribostamycin, and dibekacin [128]. In contrast to earlier observations for 2"-deoxyaminoglycosides, the 1-N-acylamido-2"-deoxy derivative of kanamycin B showed loss of activity relative to amikacin [127]. All the aminoethanesulfonyl derivatives showed strong activity against both gram-positive and gram-negative bacteria, suggesting that the (5)-4-amino-2-hydroxybutanoyl group can be replaced by a simple group such as amino-ethanesulfonyl moiety and still be an effective antibiotic [128]. In another report, kanamycin A was biologically converted to amikacin by a mutant strain of the bu-tirosin-producing organism Bacillus circulans [129].

6'-N-Formimidoylamikacin (253), 6'-N-acetimidoylamikacin (254), and 6'-N-formimidoyldibekacin (256) have been synthesized from the appropriately protected amikacin and dibekacin derivatives 252 and 255, respectively (compounds 252-256 ). Compared to the parent antibiotics, all these compounds showed improved activity against resistant strains producing AAC(6') enzyme; but in general, the 6'-N-ami-dination slightly decreased the antibacterial activity of kanamycins [21].

Another report described the synthesis of N-guanyl derivatives (at positions 6', 2', 3') of kanamycin A and gentamicins C1, C1a, and C2 [130]. Likewise, a series of 3"-N-trifluoroacetyl derivatives of kanamycin A, possessing C5-C22 acyl groups, or related alkoxy, amino, and thiocarbonyl substituents at the C1 amino group have been synthesized and tested for their activity against herpes simplex virus type I (HSV-I) and influenza virus. The optimum antiviral activity was found for the C14-C16 acyl derivatives [131,132]. The same group also has prepared N-palmitoylkan-amycin A derivatives modified at the 1-, 3-, 6'-, or 3"-amino groups having a 3"-

r-NH2

1) EtOCH=NH.HCI

iMnDuu I. wn c

NHBoc u OH

MeC(=NH)OMe.HCI

0 0

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