Kanamycin analogs

A number of kanamycin analogs, including 3 -deoxy-2 -e/ i-kanamycin A [90], 5-deoxy-, 5,4 -dideoxy-, 5-deoxy-5-epi-chloro-, and 5,4 -dideoxy-5,4 -di-epi-chlo-rokanamycin A [91], as well as 3 -deoxykanamycin B (tobramycin) [92], were prepared and tested against several sensitive and resistant organisms. Antibacterial activity data profile revealed that deoxygenation of kanamycin at the 5-position results in the loss of activity and that the 4 -epichlorination of kanamycin A results in lack of activity. 

Considerably fewer CI-NH2 alkyl derivatives have been synthesized and tested for activity, but it seems that considerable structural diversity can be tolerated. For example, both AHBA-like alkane and Cl-NHg dihy-dro propyl kanamycin analogs showed near equal elBcacy despite being structurally dissimilar (66,67). 

Figure 5. Structures of Kanamycin Analogs with Extended Arm...

From the MIC values, all the synthesized aminoglycoside with the attachment of AHB group at N-1 regain the activity against both resistant strains of bacteria (Table V). One of the synthesized kanamycin analog, JLN027, Is even more active than the clinically used amikacin against APH(3 )-I. 

Unit tig/mL The corresponding kanamycin analogs without AHB group at N>l... 

FIGURE 11.10 Library of kanamycin analogs. (From Li, J. et al., Application of glycodiversification expedient synthesis and antibacterial evaluation of a library of kanamycin B analogs, Org. Lett., 6, 1381, 2004.)... 

Five kanamycin analogs were separated from kanamycin on a silica column (A = 254nm). A 35-min 95/5—>-65/35 chloroform/ethyl acetate gradient gave good peak shapes and resolution [795]. 

Preparation of several fluorinated analogs of kanamycin A (673) were reported. 6"-Deoxy-6"-fluorokanamycin A (674) was prepared through... 

Nishimura, Y., Adachi, H., Kyo, M., Murakami, S., Hattori, S., and Ajito, K. (2005) A proof of the specificity of kanamycin-ribosomal RNA interaction with designed synthetic analogs and the antibacterial activity. Bioorg. Med. Chem. Lett. 15, 2159-2162. 

Scheme 4.19. Synthesis of 3, 4 -dideoxy kanamycin B analog and pyranmycin.

The trend of antibacterial activity of these kanamycin derivatives with N-1 AHB (amikacin analogs) is similar to amikacin regardless of the presence of 3 -deoxygenation (Table 4.10). The design of amikacin is, however, less effective against AAC(6 ). One interesting finding is the difference between 3, ... 

Scheme 4.22. Synthesis of pyranmycin and kanamycin B analogs with AHB group at N-1.

Recently, Hanessian has reported methods for direct modification of tobramycin. Tobramycin (or nebramycin) differs from kanamycin B only in its 3 -deoxygenation, which makes tobramycin immune from the modification catalyzed by APH(3 ). A library of tobramycin analogs bearing various functionalities at 0-5 was prepared (Scheme 4.23). In general, these tobramycin analogs were less active than tobramycin (Table 4.15). However, compounds 157 and 159 showed activity against P. aeruginosa (ATCC 27853) (MIC = 12.5 fig/mL). 

Kawaguchi et al. [9] selectively modihed aminoglycosides to prepare amikacin 2, a valuable and potent analog of kanamycin A, with activity against many strains of... 

An attempt to make 3, 4 -dideoxy analogs of kanamycin A and B by mutational biosynthesis in the presence of gentamicin-producing Micromonospora organisms... 

Several other kanamycin A analogs, including 4"-e/7i-kanamycin A together with 4",5"-unsaturated, and 3",4"-cyclic urethane by products [104], 4"-deoxy-4",5"-didehydro, and 4"-deoxy-5"-e/7i-kanamycin A [105], as well as a number of 4"-epi-analogs (OH, F, N3) of amikacin [106] have also been prepared, all of which are much less active than the parent antibiotics. 

The same group has also synthesized a number of 4"-epi-kanamycin A analogs, including 4",6"-dideoxy-4",6"-difluoro-, 4",6"-dideoxy-4"-fluoro-, 6"-deoxy-6"-fluoro-,... 

A series of halogenated analogs of kanamycins, including 3, 4, 6 -trideoxy-6 -fluorokanamycin C (218), 3, 4 -dideoxy-6 -C-fluoromethyl kanamycin B [114], 6"-chloro-6"-deoxyamikacin (202) and some of its derivatives [115], as well as 3 -deoxy-3 -fiuorokanamycin A (219) and its 3, 4 -dideoxy-3 -fluoro analog 220 [45] were also prepared by the same research group. Antibacterial activity results showed weak activity for 6 -fluoro, moderate activity for 6 -fluoromethyl, and good activity (better than the parent antibiotics) for 3 -fluoro derivatives. 

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