Minireview The Old Made New: Natural Compounds against Erectile Dysfunction Valeria Pavan 1 , Carla Mucignat-Caretta 2 , Marco Redaelli 2 , Giovanni Ribaudo 1 , and Giuseppe Zagotto 1 1 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy 2 Department of Molecular Medicine, University of Padova, Padova, Italy The interest toward sex-related diseases keeps growing through the years. In this review, we focus our attention on erectile dysfunction (ED), a condition that caught much attention especially after the introduction on the market of phosphodiesterase 5 inhibitors such as the well-known sildenafil. Here, we briefly describe both the etiology of ED and the available treatments, examining then extensively some natural derivatives that, coming from traditional medicine, could represent promising starting points for the development of alternative remedies. In fact, herbal remedies from several parts of the world have been traditionally known for long, and were recently reconsidered and are now being studied to demonstrate their eventual potential in the treatment of ED. Among the various examples reported in the literature and reviewed here, plants and extracts containing polyphenols—especially a class of compounds called kraussianones—appear to be particularly effective and promising against ED. Keywords: Erectile dysfunction / PDE5 / Polyphenols / Sildenafil / Traditional medicine Received: February 24, 2015; Revised: March 27, 2015; Accepted: April 15, 2015 DOI 10.1002/ardp.201500075 Introduction Although erectile dysfunction (ED) represents a common, well-defined condition with a prevalence reaching 50% of men in the 40–70 age range [1], the field is still wide open for investigation of the molecular mechanisms underlying and, consequently, potential therapies. A general representative definition of ED was given by Goldstein: “a consistent inability to get or keep an erection that is satisfactory for sexual performance” [2]. It is commonly accepted that ED can be connected to an abnormal penile circulation; it has been demonstrated, through the years, how lifestyle risk factors and their modification can influence the outcome of this condition, even if in most cases medication is anyway needed to achieve an acceptable to satisfactory result [3]. In this connection, phosphodiesterase type 5 inhibitors (PDE5-I), according to their proven and trusted efficacy and overall safety, are widely used as both on-demand and chronic treatments and represent the first-line choice for most ED cases [4]. On the other hand, limitations such as a poor response in some diabetes and nerve-injury affected patients [5] and refracto- riness [6] are still pushing the search for novel targets and/or novel chemical species potentially active against ED. In addition to this, the worldwide success of the synthetic drug sildenafil (see structure 1 in Fig. 1), together with the common interest captivated by this disease, is promoting the search or the re-investigation of compounds, especially within mole- cules of a natural origin, that could play a role in this field [7]. In this connection, the present review focuses on the properties of some natural compounds reported to show an activity, at different levels, against ED, with special consider- ation for the possible molecular mechanisms involved, even if different from PDE5 inhibition. The present literature provides a number of research papers and reviews dealing with different aspects of ED, some of which are related to remedies of a natural origin. Therefore, we focused our research according to some reasonable, quality-based, crite- ria. In the first instance, we performed a preliminary examination on well-acknowledged online databases [8–10] to lay the ground for a more concentrated literature search. The latest state-of-the-art developments were taken into Correspondence: Prof. Giuseppe Zagotto, Department of Phar- maceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova (PD), Italy. E-mail: giuseppe.zagotto@unipd.it Fax: þ39-049-8275366 Arch. Pharm. Chem. Life Sci. 2015, 348, 607–614 Archiv der Pharmazie ARCH RCH P HARM HARM ß 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com 607