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In an effort to optimize the antibacterial activity of kanamycin class aminoglycoside antibiotics, we have accomplished the synthesis and antibacterial assay of new kanamycin B analogues. A rationale-based glycodiversification strategy was employed. The activity of the lead is comparable to that of commercially available kanamycin. These new members, however, were found to be inactive against aminoglycoside resistant bacteria. Molecular modeling was used to provide the explanation. Thus, a new strategy for structural modifications of kanamycin class aminoglycosides is suggested.

A novel method for achieving the desired regioselective reduction of the N-1 azido group on a tetraazidoneamine has been developed that leads to the synthesis of both kanamycin and neomycin class antibiotics bearing N-1 modification. Both classes of aminoglycosides are active against aminoglycoside-resistant bacteria carrying APH(3‘)-I and AAC(6‘)/APH(2‘ ‘).

Ammodendrine (1) was found to occur as a mixture of enantiomers in two different collections of plants identified as Lupinus formosus. The ammodendrine fraction was reacted in a peptide coupling reaction with 9-fluorenylmethoxycarbonyl-l-alanine (Fmoc-l-Ala-OH) to give diastereomers, which were separated by preparative HPLC. The pure d- and l-ammodendrine enantiomers were then obtained by Edman degradation. Optical rotation measurements revealed that the d- and  l-enantiomers had optical rotations of [α]²⁴D +5.4° and −5.7°, respectively. d- and l-N-methylammodendrine enantiomers were synthesized from the corresponding ammodendrine enantiomers, and their optical rotations established as [α]²³D +62.4° and −59.0°, respectively. A mouse bioassay was used to determine the difference in toxicity between these two pairs of naturally occurring enantiomers. The LD50 of (+)-d-ammodendrine in mice was determined to be 94.1 ± 7 mg/kg and that of (−)-l-ammodendrine as 115.0 ± 7 mg/kg. The LD50 of (+)-d-N-methylammodendrine in mice was estimated to be 56.3 mg/kg, while that of (−)-l-N-methylammodendrine was determined to be 63.4 ± 5 mg/kg. These results establish the rotation values for pure ammodendrine and N-methylammodendrine and indicate that there is little difference in acute murine toxicity between the respective enantiomers.

The expedient synthesis of a library of kanamycin B analogues is reported. The revealed SAR will guide future designs in developing kanamycin-type aminoglycoside antibiotics against drug-resistant bacteria.

Continuing from the syntheses and the antibacterial studies of a library of pyranmycins, we further probed the proximity around ring III of pyranmycin by introducing an “extended arm” that has hydroxyethyl or aminoethyl groups at the O-2‘ ‘, O-3‘ ‘, or O-4‘ ‘ positions. The results from the antibacterial studies reveal the optimal structural motif is the attachment of an extended arm with a terminal hydroxyl group at the O-3‘ ‘ position.

The synthesis of a novel class of aminoglycosides, pyranmycins, is reported along with the structure activity relationship (SAR) of their antibacterial activity against Escherichia coli. Two pyranmycins show prominent activity (9 μM). Pyranmycins also manifest superior stability in acidic media. The SAR information will lead to the future designs of pyranmycin against drug resistant bacteria.

The synthesis of a novel class of aminoglycoside, pyranmycin, and a convenient method for the preparation of 6-amino-l-idopyranosides were reported. One of the members in the reported pyranmycin families, TC010, has prominent activity against Escherichia coli, Staphylococcus aureus, and Bacillus megaterium. We also discovered that the ⁴C1 chair conformation on ring III of pyranmycin is essential for the antibacterial activity.

A library of seven trehalosamine analogues with various natural and non-natural binding motifs was synthesized through an expedient divergent synthetic approach. The final products were prepared in sufficient quantities and purities for different types of assay against various pathogens. Several stereo- and regioselective reactions on the trehalose scaffold were developed for rapid synthesis of all of the designed compounds.