Therefore, various powerful approaches were recently applied in many interesting antileishmanial drug development programs. Nevertheless, currently available antileishmanial therapies are significantly limited (low efficacy, toxicity, adverse side effects, drug-resistance, length of treatment, and cost), so there is an urgent need to discover new compounds with antileishmanial activity, which are ideally inexpensive and orally administrable with few side effects and a novel mechanism of action. As there is an endemic in more than 90 countries worldwide, this complex and major health problem has different clinical forms depending on the parasite species involved, with the visceral form being the most worrying since it is fatal when left untreated. Some of them, such as Mediterranean visceral leishmaniasis, are zoonotic diseases transmitted from vertebrate to vertebrate by a hematophagous insect, the sand fly. Leishmaniases are a group of vector-borne diseases caused by infection with the protozoan parasites Leishmania spp. We also propose an ideal cascade of assays for the identification of new drug candidates for clinical development using leishmaniasis as an example. In this article we discuss the perspectives of phenotypic HTS for trypanosomatid drug discovery with emphasis on the role of image-based, high-content methods. In trypanosomatids, due to the scarcity of validated molecular targets and biological complexity of these parasites, phenotypic screening has become an essential tool for the discovery of new bioactive compounds.
Therefore, high-throughput screening (HTS) of compounds still is a much-needed exercise in drug discovery to fuel other rational approaches. Paradoxically however, the mainstay of these computational methods is data-driven, meaning they need activity data for new compounds to be generated and available in databases. In the last decades a so-called rational drug design paradigm, heavily dependent on computational approaches, has promised to deliver new drugs in a more cost-effective way. The drug discovery process is often analogous to finding a needle in the haystack. Novel drugs are highly needed since there are no vaccines and available treatment has several limitations, such as resistance, low efficacy, and high toxicity. Diseases caused by trypanosomatid parasites affect millions of people mainly living in developing countries.