Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases

Abstract

Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis belong to a group of infectious diseases known as neglected tropical diseases and are induced by infection with protozoan parasites named trypanosomatids. Drugs in current use have several limitations, and therefore new candidate drugs are required. The majority of current therapeutic trypanosomatid targets are enzymes or cell‐surface receptors. Among these, eukaryotic protein kinases are a major group of protein targets whose modulation may be beneficial for the treatment of neglected tropical protozoan diseases. This review summarizes the finding of new hit compounds for neglected tropical protozoan diseases, by repurposing known human kinase inhibitors on trypanosomatids. Kinase inhibitors are grouped by human kinase family and discussed according to the screening (target‐based or phenotypic) reported for these compounds on trypanosomatids. This collection aims to provide insight into repurposed human kinase inhibitors and their importance in the development of new chemical entities with potential beneficial effects on the diseases caused by trypanosomatids.

Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2‐Benzyl‐5‐nitroindazole‐Derived Amines

“…Recent effortst oward the repurposing of human kinases inhibitors in this field should also be highlighted. [7] Within the area of new potentiala ntichagasic drugs,w er ecently described the synthesis and activity of many 5-nitroindazole derivatives. In direct relationship to the current work, we highlighted interesting results found for several1 ,2-disubstituted indazolin-3-ones.…”

“…Additionally, some highly active imidazo‐ and triazolopyrimidines, acting through inhibition of the proteasome of several pathogenic trypanosomatid protozoa ( Trypanosoma , Leishmania ), have been described. Recent efforts toward the repurposing of human kinases inhibitors in this field should also be highlighted …”

“…Pentamidine, amphotericin B, miltefosine, and paromomycin are generally considered second‐line antileishmanial drugs . The above‐mentioned imidazo‐ and triazolopyrimidine‐derived proteasome inhibitors and repurposed human kinases inhibitors appear very promising in this field as well. However, it is also necessary to obtain new antileishmanial agents of lower cost, greater effectiveness, and with lower adverse side effects.…”

“Click” on PLGA‐PEG and hyaluronic acid: Gaining access to anti‐leishmanial pentamidine bioconjugates

“…[10][11][12][13][14] In our article, we propose a novel polymer-drug conjugate based on PP copolymer as carrier for Pentamidine (Pent), an antiparasitic drug used against Leishmania infections. 15 Chemically, Pent is a bifunctional aromatic diamidine with two terminal amidine groups that are the sole reactive moieties of the drug, useful to obtain both monolinked polymer-Pent derivatives and polymer-Pent crosslinked frameworks via amide bond formation. Herein, we describe an efficient and easy approach to link the pendant end-groups of Pent with PP copolymer and hyaluronic acid (HA), using the click chemistry strategy.…”

Ensemble‐based ADME–Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

“…If the Sb-based drugs turn out to be ineffective, pentamidine, amphotericin, paromomycin, and miltefosine are recommended as second-line drugs of choice, but unfortunately, they are also toxic and require long-term treatments. [2][3][4] Although leishmaniasis presents high rates of morbidity and mortality only in endemic areas of tropics and subtropics, it is considered a global health concern due to the fact that several risk factors contribute to the spread and proliferation of the causative Leishmania species and its vector (i.e., phlebotomine sandfly). [5] In view of that, and in the absence of an effective vaccine, there is a continuous interest in the identification of new drug targets and the development of new drug candidates for the treatment of this disease.…”