Amphotericin B is the most potent antimycotic known to date. However due to its large collateral toxicity, its use, although long standing, had been limited. Many attempts have been made to produce derivatives with reduced collateral damage. The molecular mechanism of polyene has also been closely studied for this purpose and understanding it would contribute to the development of safe derivatives. Our study examined polyene action, including chemical synthesis, electrophysiology, pharmacology, toxicology and molecular dynamics. The results were used to support a novel Amphotericin B derivative with increased selectivity: L-histidine methyl ester of Amphotericin B. We found that this derivative has the same form of action as Amphotericin B, i.e. pore formation in the cell membrane. Its reduced dimerization in solution, when compared to Amphotericin B, is at least partially responsible for its increased selectivity. Here we also present the results of preclinical tests, which show that the derivative is just as potent as Amphotericin B and has increased safety.

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A21 (2) is a new polyene macrolide Amphotericin B amide antibiotic derived from amphotericin B AmB (1), which has been tested extensively on preclinical trials showing the same antimycotic effectiveness and increased margin of safety over AmB (1). We present the multigram scale synthesis, isolation, purity assessment by HPLC, and key aspects of its characterization by NMR studies of A21 (2).

The opportunistic human pathogen Pseudomonas aeruginosa exhibits great resistance to antibiotics; so, new therapeutic agents are urgently needed. Since polyamines levels are incremented in infected tissues, we explored whether the formation of a toxic aldehyde in polyamines degradation can be exploited in combating infection. We cloned the gene encoding the only aminoaldehyde dehydrogenase involved in P. aeruginosa polyamines‐degradation routes, PaPauC, overexpressed this enzyme, and found that it oxidizes 3‐aminopropionaldehyde (APAL) and 3‐glutamyl‐3‐aminopropionaldehyde (GluAPAL) − produced in spermine (Spm), spermidine (Spd), and diaminopropane (Dap) degradation, as well as 4‐aminobutyraldehyde (ABAL) and 4‐glutamyl‐4‐aminobutyraldehyde (GluABAL) − formed in putrescine (Put) degradation. As the catalytic efficiency of PaPauC with APAL was 30‐times lower than with GluAPAL, and GluAPAL is predominantly formed, APAL will be poorly oxidized ‘in vivo’. We found polyamines‐induced increases in the PaPauC activity of cell crude‐extracts and in the expression of the PapauC gene that were diminished by glucose. Spm, Spd, or Dap, but not Put, were toxic to P. aeruginosa even in the presence of other carbon and nitrogen sources, particularly to a strain with the PapauC gene disrupted. APAL, but not GluAPAL, was highly toxic even to wild‐type cells, suggesting that its accumulation, particularly in the absence of, or low, PaPauC activity is responsible for the toxicity of Spm, Spd, and Dap. Our results shed light on the toxicity mechanism of these three polyamines and strongly support the critical role of PaPauC in this toxicity. Thus, PaPauC emerges as a novel potential drug target whose inhibition might help in combating infection by this important pathogen.

This article describes a study on the Michael addition reaction of cyclohexanone to nitroolefins catalyzed by the chiral secondary amine (1S,4S)-2-tosyl-2,5-diazabicyclo[2.2.1]heptane. Reactions were carried out under solvent-free conditions to make them more environmentally friendly. Initially, the observed diastereoand enantioselectivities were moderate to good, but were significantly improved by lowering the reaction temperature. Furthermore, a variety of chiral acids were also tested as co-catalysts in both of their enantiomeric forms, which revealed that (R)-mandelic acid affords excellent results in terms of yield and stereoselectivity. Monitoring the reaction by MS-TOF allowed for the detection of key reaction intermediates, and a reasonable reaction mechanism in which both catalysts are involved is proposed.