J Med Chem 1991 Apr;34(4):1468-75

New derivatives of kanamycin B obtained by modifications and substitutions in
position 6". 1. Synthesis and microbiological evaluation.

Van Schepdael A, Delcourt J, Mulier M, Busson R, Verbist L, Vanderhaeghe HJ,
Mingeot-Leclercq MP, Tulkens PM, Claes PJ

Laboratorium voor Farmaceutische Chemie, Rega Instituut, Katholieke Universiteit
Leuven, Belgium.

The clinical use of the potent, wide-spectrum aminoglycoside antibiotics is
limited by oto- and nephrotoxicities. The latter is related to the binding of
these polycationic drugs to negatively charged phospholipids and to the
subsequent inhibition of lysosomal phospholipases. In order to explore the
influence of a modification of the hydrophobic/hydrophilic balance at a specific
site of an aminoglycoside, kanamycin B has been chemically modified in position
6" by substitution of the hydroxyl group with a halogen atom (or a pseudohalogen
group), or an amino, an amido, a thioalkyl, or an alkoxy group, each series
containing increasingly bulkier chains. Examination of the antibacterial
activity of the synthesized compounds revealed a negative correlation between
the size of the 6"-substituent and the antibacterial activity against kanamycin
B sensitive Gram-positive and -negative organisms. Only derivatives with small
substituents in position 6", namely chloro, bromo, azido, amino,
methylcarbamido, acetamido, methylthio, methylsulfinyl, O-methyl, O-ethyl, and
O-isopropyl, showed acceptable activity (geometric mean of minimum inhibitory
concentrations for Gram-negative strains less than or equal to 2.5 mg/L; value
for kanamycin B, 0.5 mg/L). In vitro toxicological evaluation of all derivatives
and computer-aided conformational analysis of selected compounds inserted in a
phosphatidylinositol monolayer are presented in the following paper in this
issue.

PMID: 2016724, UI: 91202506