Angel H Romero ^* FRANCISCO DELGADO

• Universidad de la República, Montevideo, Uruguay

Leishmaniasis is one of the most important neglected tropical diseases with more than 2 million new cases annually. It is endemic in several regions worldwide, representing a public health problem for more than 88 countries, in particular, in the tropical and subtropical regions of developing countries. At the moment, there are neither approved vaccines nor effective drugs for the treatment of the human leishmaniasis under none of their three typical clinical manifestations and, importantly, the drugs of clinical use have several side-effects, require complex administration regimens, present high cost and are ineffective in many populations due to pathogen resistance. Moreover, beyond the pharmacological exigencies, there are other challenges concerning the parasite nature such as its great genetic plasticity and adaptability, which is able to activate a battery of genes to develop resistance in a short time. All these aspects obligate the identification and development of new chemical systems highly effective and safe, which must not only be focused on medicinal chemistry and pharmacological aspects but also consider key aspects relative to the parasite survival. In this sense, the quinoline and, in particular, the 4-aminoquinoline, represents a privileged scaffold for the design of potential leishmanicidal candidates due not only to its versatility to generate compounds highly active and selective but also to its correlation with well-defined biological targets. These facts make it possible to generate safe leishmanicidal agents targeted on key aspects of the parasite survival. Then, the current review summarizes the most current examples of leishmanicidal agents based on 4-aminoquinolines focusing the analysis on two essential aspects: (i) structure-property relationship to identify the key pharmacophores, (ii) mode of action focused on key targets in parasite survival (e.g. depolarization of potential mitochondrial, accumulation into macrophage lysosome and immunostimulation of host cell). With that information, we seek to give useful guidelines for interested researchers in order to rationally face the drug discovery and development of selective and potent leishmanicidal agents based on 4aminoquinolines.