Novel Amino-pyrazole Ureas with Potent In Vitro and In Vivo Antileishmanial Activity

Abstract

Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series.

Antiparasitic Efficacy of Artemisia ludoviciana Nutt. (Asteraceae) Essential Oil for Acanthamoeba castellanii, Leishmania infantum and Trichomonas vaginalis

“…34 The toxic side effects of anti-leishmanial medications used for treatment and the development of resistance of the parasite to these medications have led to studies related to definition and formulation of new molecules to date. 37 Different studies have been completed; [12][13][14][15][16][17][18] from a study showing the anti-leishmanial activity of ethanol extracts from Allium sativa (garlic) and Azadirachta indica (Neem), locally used for treatment of Cutaneous leishmaniasis in the Sudan, had no significant difference when compared to pentostam, 16 to studies emphasizing that the anti-leishmanial efficacy on promatigotes and amastigotes of Leishmania tropica was higher compared to two antibiotics in the macrolid group of azithromycin and clarithromycin. 38 The AL-EO presented in this study can be considered for use as an antileishmanial.…”

“…[12][13][14][15][16] Due to the lack of an effective prophylactic against the disease, the toxic effects of currently-used medications and the increasing resistance to these medications, the necessity for discovery and development of new therapeutic agents has been reported. 11,17,18 Trichomoniosis is a common infection everywhere in the world and the infection rates are reported to show great variations from country to country and society to society. Researchers have stated that the different results obtained by different people in different regions may be due to factors such as the use of different techniques for diagnosis, and deficient and mistaken assessments.…”

Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

“…The in vitro anti‐ Leishmania assay of 9a–d was performed as previously described by using Leishmania infantum MHOM/MA (BE)/67 intracellular amastigotes collected from the spleen of an infected donor hamster and used to infect primary peritoneal mouse macrophages . Miltefosine was included as reference drug.…”

“…Cytotoxicity assays were performed both on MRC5 SV2 and PMM cells according to procedures previously reported . Tamoxifen was included as the reference drug.…”

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

“…[26] F I G U R E 1 Structures of CPB2.8ΔCTE inhibitors | 599 SCALA et AL. Tamoxifen was employed as the reference drug.…”