New Developments in the Quinolone Class of Antibacterial Drugs

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The increasing drug resistance and the insufficiency of the newly developing antibiotics constitute a serious and growing health threat in the world. Especially Gram (-) bacteria acquire genetic material encoding antibiotic resistance by multiple mechanisms. Development of novel antibacterial agents with little tendency to bacterial resistance is, therefore, an important and challenging topic in the medicinal chemistry, and synthetic organic chemistry is an indispensable part of the design and synthesis of efficient antibacterial drug candidates. Among the broad-spectrum antibiotics, fluoroquinolones constitute the most attractive drugs in the anti-infective chemotherapy field. These antibiotics target the bacterial type II topoisomerase enzymes (DNA gyrase and topoisomerase IV) which are essential enzymes involved in bacterial cell growth and division. Since their advent, they were widely applied to treat infections. Unfortunately, most of them suffered from the resistance problem by mutations in the bacterial targets due to their wide use. Recently, the synthetic organic and medicinal chemists focused their research on the design of new fluoroquinolones with improved features by molecular hybridization technique. One of the most promising approaches aiming to combat resistant pathogens is the design and synthesis of new hybrid molecules in which different pharmacophore groups with different modes of action are joined together using a flexible linker. This strategy supplies a way to improve traditional drug combination therapies simplifying optimization of the pharmacokinetics/pharmacodynamic (PK/PD) profile, efficacy at both targets is usually synergistic.