Editorial [Hot Topic: The Medicinal Chemistry of Hybrid-Based Drugs Targeting Multiple Sites of Action (Guest Editors: Jose Marco-Contelles, & Elena Soriano)]

Although the single-target approach still remains the current drug discovery strategy in medicinal chemistry for the development of new bioactive molecules, there is increasing recognition that this is the main reason of a lack of a successful therapy for the treatment of multifactorial, complex diseases such as cancer or Alzheimer. Thus, an alternative approach, routinely named the “Multi-target Directed Ligand” (MTDL), based on the use of “multifunctional” or “pluripotential” drugs, is attracting the interest of the researchers in academia, and in the pharmaceutical companies. The idea now would be designing single molecules able to bind or interact with several of the diverse enzymatic systems or receptors implicated in the pathology of the disease. The advantages (and limitations also) of these drugs have been highlighted, and can be summarized in the simplification of dosing regimens, improve the patient comfort, avoiding the challenge of administering various single-drugs showing diverse bioavailability, pharmacokinetic and metabolic profiles. In this special issue of Current Topics in Medicinal Chemistry, a series of leading authors in their areas of research, present their ideas on the theme “hybrid-based drugs”, that we hope catch the attention of the interested reader, and gain new enthusiastic practioners Certainly, neurodegenerative disorders, such as Alzheimer's disease (AD), have concentrated most of the review articles shown here, submitted by Rampa, Gutschow, Bolognesi, Binda, and de los Rios. Rampa describes the progresses in medicinal chemistry over the last few years on the design of molecules incorporating in a single scaffold two pharmacophores from known chemical entities with well established biological activities for AD. Based on this strategy, acetylcholinesterase inhibitors have been extensively coupled with appropriate selected biological active molecules to give homo- and heterodimers endowed with increased potency. In addition, particular attention has been devoted to show the number of AChE inhibitors able to contact the peripheral anionic site of AChE, and consequently, able to prevent the AChE-mediated aggregation of the β-amyloid peptide into the senile plaques, which is a key event in the neurotoxic cascade of AD.