RESUMEN
Novel fungicides are urgently needed. It was recently reported that the attachment of an octyl group at the O-4â³ position of kanamycin B converts this antibacterial aminoglycoside into a novel antifungal agent. To elucidate the structure-activity relationship (SAR) for this phenomenon, a lead compound FG03 with a hydroxyl group replacing the 3â³-NH2 group of kanamycin B was synthesized. FG03's antifungal activity and synthetic scheme inspired the synthesis of a library of kanamycin B analogues alkylated at various hydroxyl groups. SAR studies of the library revealed that for antifungal activity the O-4â³ position is the optimal site for attaching a linear alkyl chain and that the 3â³-NH2 and 6â³-OH groups of the kanamycin B parent molecule are not essential for antifungal activity. The discovery of lead compound, FG03, is an example of reviving clinically obsolete drugs like kanamycin by simple chemical modification and an alternative strategy for discovering novel antimicrobials.
Asunto(s)
Antibacterianos/síntesis química , Antifúngicos/síntesis química , Kanamicina/química , Tensoactivos/síntesis química , Antibacterianos/química , Antifúngicos/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Descubrimiento de Drogas , Datos de Secuencia Molecular , Relación Estructura-Actividad , Tensoactivos/químicaRESUMEN
We report the parallel synthesis of a series of novel 4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-ium chloride salts, which are analogs to cationic anthraquinones. Three synthetic protocols were examined leading to a convenient and facile library synthesis of the cationic anthraquinone analogs that contain double alkyl chains of various lengths (C(2)-C(12)) at N-1 and N-3 positions. The antibacterial activities of these compounds were evaluated against Gram-positive bacterium Staphylococcus aureus and Gram-negative bacterium Escherichia coli. The antibacterial activities of these compounds were expected to be associated with the structural features of naphthoquinone, cation and lypophilic alkyl chain and, interestingly, they showed much higher levels of antibacterial activities against G+ than G- bacteria. In addition, when the total number of carbon atoms of the alkyl groups at both N-1 and N-3 positions lies between 9 and 18, the bactericidal activity against S. aureus increased with increasing alkyl chain length at both N-atoms with MIC ≤ 1 µg/mL.
