Synthesis and Antimicrobial Evaluation of Diverse 3,4-Dihydroquinazolines

Lake Superior State University, Sault Sainte Marie MI

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Abstract

Antibiotic resistance is one of the most pressing global health issues, with emerging resistance leading to infections that are increasingly difficult to treat. Lending to the problem is the fact that very few new antimicrobial agents are currently in development. Quinolone antibiotics comprise one major class of agents currently being used to confront bacterial infections in clinical settings, and their success has led to their use worldwide. Resistance to quinolone antibiotics has been countered through modification of the molecular scaffolds of existing quinoline drugs and the release of new antibacterial drugs. Recently, the structurally related quinazolinones and quinazolines have been recognized for their antimicrobial properties, particularly against methicillin resistant Staphylococcus aureus (MRSA). The 3,4-dihydroquinazoline scaffold, or the partially reduced quinazoline scaffold, has not been investigated for similar antimicrobial properties, even in light of the higher diversity permitted about the core scaffold. However, it stands to reason that modification of the proven scaffolds with antibacterial properties, namely the quinolones and quinazolines, may lead to promising clinical candidates. We propose to investigate a novel multicomponent synthesis of 3,4- dihydroquinazolines, with a particular focus on aspects of molecular diversity and stereoselectivity. We also propose to evaluate the antimicrobial properties of compounds prepared in these studies via rapid screening through the use of simple disc diffusion assays followed by determination of antibacterial MIC values for those compounds that show promise in disc diffusion assays. Finally, we propose to investigate structure activity relationships, wherein diverse compounds will be synthesized to include features that have been found to lend to antimicrobial potency in earlier portions of our study.