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.
Keywords: Aminoglycoside, Drug resistance, Flavonoid, β-Lactam, Macrocyclic,
Molecular hybridization, Oxazolidinone, Pyrazole, Pyrazine, Pyrimidine,
Quinolone, Triazole.
