Synthesis and biological properties of nitrobenzoxadiazole derivatives as potential nitrogen(ii) oxide donors: SOX induction, toxicity, genotoxicity, and DNA protective activity in experiments using Escherichia coli-based lux biosensors

Abstract

Dihetaryls containing superelectrophilic and π-excessive heterocycles were synthesized by the nucleophilic aromatic substitution and cycloaddition. The structures of the compounds and the mechanism of 1,3-N-oxide tautomerism were studied by NMR spectroscopy, X-ray diffraction, and quantum chemical methods. The ability of these compounds to initiate SOX induction, which is probably due to the in vivo generation of nitrogen(ii) oxide, was quantified using genetically engineered E. coli-based lux biosensors. 7-(1-Methylpyrrol-3-yl)-4,6-dinitrobenzofuroxan is the most active inducer, which is an order of magnitude more effective than nitroglycerin used as the reference compound. The absence of toxicity was established using the E. coli MG 1655 biosensor (pXen7-lux). The DNA protective effect of this leading compound was confirmed using the E. coli MG 1655 biosensor (pRecA-lux).