title: Design, Synthesis and Qualitative Structure Activity Relationship Evaluations of Quinoline-Based Bisarylimidazoles as Antibacterial Motifs.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicinal Chemistry, Collage of Pharmacy and Sharjah Institute for Medical Research, University of Sharjah, P.O. Box 27272, Sharjah, UAE. taltal@sharjah.ac.ae.
authors.forename: Raed A
authors.initials: RA
authors.lastname: Al-Qawasmeh
authors.forename: Basil B
authors.initials: BB
authors.lastname: Huthail
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Sinnokrot
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Semreen
authors.forename: Raed A
authors.initials: RA
authors.lastname: Odeh
authors.forename: Musa H
authors.initials: MH
authors.lastname: Abu-Zarga
authors.forename: Hamadeh
authors.initials: H
authors.lastname: Tarazi
authors.forename: Imad A
authors.initials: IA
authors.lastname: Yousef
authors.forename: Taleb H
authors.initials: TH
authors.lastname: Al-Tel
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D016106:Methicillin Resistance; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D011804:Quinolines