Design, Synthesis, and Efficacy Testing of Nitroethylene- and 7-Nitrobenzoxadiazol-Based Flavodoxin Inhibitors against Helicobacter pylori Drug-Resistant Clinical Strains and in Helicobacter pylori-Infected Mice.

Helicobacter pylori (Hp) infection is the main cause of peptic ulcer and gastric cancer. Hp eradication rates have fallen due to increasing bacterial resistance to currently used broad-spectrum antimicrobials. We have designed, synthesized, and tested redox variants of nitroethylene- and 7-nitrobenzoxadiazole-based inhibitors of the essential Hp protein flavodoxin. Derivatives of the 7-nitrobenzoxadiazole lead, carrying reduced forms of the nitro group and/or oxidized forms of a sulfur atom, display high therapeutic indexes against several reference Hp strains. These inhibitors are effective against metronidazole-, clarithromycin-, and rifampicin-resistant Hp clinical isolates. Their toxicity for mice after oral administration is low, and, when administered individually at single daily doses for 8 days in a mice model of Hp infection, they decrease significantly Hp gastric colonization rates and are able to eradicate the infection in up to 60% of the mice. These flavodoxin inhibitors constitute a novel family of Hp-specific antimicrobials that may help fight the constant increase of Hp antimicrobial-resistant strains.

Chiral iminoesters derived from D-glyceraldehyde in [3 + 2] cycloaddition reactions. Asymmetric synthesis of a key intermediate in the synthesis of neuramidinase inhibitors.

Silver-catalyzed endo-selective and copper-catalyzed exo-selective asymmetric [3 + 2] cycloadditions of acrylates to chiral iminoesters derived from D-glyceraldehyde have been investigated. The reaction diastereoselectively provides highly functionalized pyrrolidines. This approach was used to develop the first asymmetric synthesis of a key intermediate in the synthesis of pyrrolidine influenza neuramidinase inhibitors.

Improved flavodoxin inhibitors with potential therapeutic effects against Helicobacter pylori infection.

Helicobacter pylori (Hp) infection affects one-half of the human population and produces a variety of diseases from peptic ulcer to cancer. Current eradication therapies achieve modest success rates (around 70%), resistance to the antibiotics of choice is on the rise, and vaccination has not proved to be successful yet. Using an essential Hp protein, flavodoxin, as target, we identified three low-molecular-weight flavodoxin inhibitors with bactericidal anti-Hp properties. To improve their therapeutic indexes, we have now identified and tested 123 related compounds. We have first tested similar compounds available. Then we have designed, synthesized, and tested novel variants for affinity to flavodoxin, MIC for Hp, cytotoxicity, and bactericidal effect. Some are novel bactericidal inhibitors with therapeutic indexes of 9, 38 and 12, significantly higher than those of their corresponding leads. Developing novel Hp-specific antibiotics will help fighting Hp resistance and may have the advantage of not generally perturbing the bacterial flora.

Helix propensities of conformationally restricted amino acids. Non-natural substitutes for helix breaking proline and helix forming alanine.

Alpha helices are useful scaffolds to build biologically active peptides. The intrinsic stability of an alpha-helix is a key feature that can be successfully designed, and it is governed by the constituting amino acid residues. Their individual contributions to helix stability are given, according to Lifson-Roig theory, by their w parameters, which are known for all proteinogenic amino acids, but not for non-natural ones. On the other hand, non-natural, conformationally-restricted amino acids can be used to impart biochemical stability to peptides intended for in vivo administration. Efficient design of peptides based on these amino acids requires the previous determination of their w parameters. We begin here this task by determining the w parameters of two restricted analogs of alanine: (alpha-methyl)alanine and 1-aminocyclopropanecarboxylic acid. According to their w values (alpha-methyl)alanine is almost as good a helix forming residue as alanine, while 1-aminocyclopropanecarboxylic acid is, similarly to proline, a helix breaker.