Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity.

Despite the fact that the introduction of a fluorine atom at the C-6 position has resulted in the evolution of fluoroquinolones, fluoroquinolone-induced cardiac toxicity has drawn considerable attention. In this context, desfluoroquinolone-based hybrids with involvement of C-7 aminopyrimidine functional group were designed and synthesized. The biological results showed majority of these hybrids still demonstrated potent anti-MRSA activity with MIC values between 0.38 and 1.5 µg/mL, despite the lack of the typical C-6 fluorine atom. Particularly, the most active B14 exhibited activities at submicromolar concentrations against a panel of MRSA strains including vancomycin-intermediate strains, levofloxacin-resistant isolates, and linezolid-resistant isolates, etc. As expected, it also displayed highly selective toxicity toward bacterial cells and low hERG inhibition. Further resistance development study indicated MRSA is unlikely to acquire resistance against B14. The docking study revealed that two hydrogen bonds were formed between the C-7 substituent and the surrounding DNA bases, which might contribute to overcome resistance by reducing the dependence on the magnesium-water bridge interactions with topoisomerase IV. These results indicate a promising strategy for developing new antibiotic quinolones to combat multidrug resistance and cardiotoxicity.

Amine-Mediated Transimination and Aromatization-Triggered Domino Reaction in the Synthesis of Polyfunctionalized 4-Aminoquinolines.

Dearomatization provides numerous possibilities for the development of new transformative modes of aromatic compounds. A conceptually novel metal-free multicomponent domino reaction of the dearomatized products of 2-alkynylanilines is developed. The reaction involves the secondary amine-mediated transimination with α-amino nitriles and subsequent aromatization-triggered cascade rearrangement, nucleophilic cyclization, and retro-Strecker reaction. This process provided a new practical method for the rapid synthesis of polyfunctionalized 4-aminoquinolines from readily available starting materials.