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Molecular hybridization approach is a powerful medicinal chemistry tool for designing ligands and prototypes able to act in at least two different molecular targets, promoting a beneficial effect to the treatment of multifactorial diseases. In this context, this review describes some examples where the use of this molecular modification approach lead to the design of novel chemotherapy prototypes able to act simultaneously in more than one target enzyme useful to control diseases promoted by bacterial, viral, protozal or fungal pathogens.