Background: The emergence of drug-resistant bacteria in clinical practice has propelled a concerted effort to
find new classes of antibiotics that will circumvent current modes of resistance. We previously described a set of imidazopyridine
antibacterial leads that contain a core composed of benzimidazole and a central phthalic acid linker. These
compounds showed potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. In
this respect, we conducted a systematic exploration of new disubstituted imidazole functionalities on quinoline 4-position
as the central linker, to determine the factors that direct the potent antibacterial activity. We found that some of the newly
synthesized compounds possessed more potent activity compared to currently available medications. The newly synthesized
compounds were screened against several clinical isolates and Staphylococcus aureus, including the methicillinresistant
(MRSA) and the methicillin-sensitive (MSAA).
Methods: The goal of this work is to undertake rigorous testing of new hybrid scaffolds of quinoline flanked by diaryl
imidazoles and their structure-activity against a range of bacterial strains. Described herein is the account of the modification
of the central linker region, the imidazole functionality, and substituents at the 4-position of the quinoline, and their
effect on the antibacterial potency of the resulting derivatives. Our efforts here have been driven by previous reports on
the applications of Pfitzinger cyclization protocol. This complexity-generating reaction transforms a relatively simple substrate,
into a more complex products with the potential for diversification via functionalization of the resultant acid.
Results: We identified compounds that possess potent and broad-spectrum antibacterial activities against clinical isolates
and drug resistant strains. Structure-Activity relationships of these compounds were further explored to determine the crucial
structural features needed to enhance their antibacterial activity. In this respect, it was found that, hydrophobic and
electron-withdrawing moieties, such as halogens, were required on each end of the isoquinoline-based bisaryl imidazole
hybrid motifs to produce broad-spectrum activity against the tested strains. Thus, molecules containing halophenyl or
pyridyl arms were found more potent than molecules containing thiophene and/or electron-releasing groups on the phenyl
arms, which showed much less antibacterial activity against the tested strains.
Conclusion: In summary, 4-(4,5-diphenyl-1H-imidazol-2-yl)-2-phenylquinoline systems can be assembled efficiently
through the Pfitzinger ring expansion- condensation strategy. This approach appears to hold considerable synthetic utility.
The particular value of such a synthetic route resides on the conciseness and efficiency through which imidazo-quinoline
construction can be synthesized from structurally simple and accessible acetophenone precursors.