Synthesis and Antimicrobial Activity of Nitroalkenyl Arenes

Gina      Nicoletti; Hugh      J. Cornell; Helmut      M. Hugel; Kylie      S. White; Thu      Nguyen; Liliana      Zalizniak; Dayanthi      Nugegoda

doi:10.2174/2211352511311020012

Abstract

We report here on the synthesis of substituted nitroalkenyl arenes and their evaluation for microbiological activity and for development as anti-infective drugs. Twenty compounds, based on the nitropropenyl benzene structure (1), were synthesized, chemically characterized and investigated for their minimum inhibitory concentration (MIC) to bacteria and fungi and for toxicity to zebrafish eggs and embryos for comparative evaluation of potential mammalian toxicity. The compounds were broadly antimicrobial, with greater activity overall against Gram-positive bacteria and fungi and less against enteric Gram-negative rods. The antimicrobial activity spectrum of the compounds varied greatly. Two compounds, 14 (5-[(E)-2-nitroprop-1-enyl]-1,3-benzodioxole) and 9 ((4-[(E)-2-nitroprop-1-enyl]-1-fluorobenzene), were the most broadly antimicrobial. The chemical groups most closely associated with microbial toxicity were the β-nitropropenyl side chain, fluoro, methylenedioxy and thiazole substitutions on the benzene ring. Thirteen compounds inhibited hatching of zebrafish eggs at concentrations ≤6 µg/mL. Egg toxicity did not correlate with inhibition of microbial growth or with rodent toxicity where data were available. Four compounds were investigated for effect on zebrafish embryonic development. The major effect observed was reduction of heart rate at 24 h with minimal or no morphological abnormalities at the highest doses. It is hypothesised that this series of compounds act as tyrosine mimetics, inhibiting protein tyrosine phosphatases (PTP) and interfering with cell signaling in microorganisms. The data confirms the diversity in function and distribution of bacterial PTPs and the potential for the design of further nitroalkenyl arenes active against specific pathogens.

Keywords: Antibacterial, antifungal, nitropropenyl arenes, structure-activity relationships, tyrosine phosphatase, zebrafish.