Scaffold and Parasite Hopping: Discovery of New Protozoal Proliferation Inhibitors

Abstract

Utilizing a target repurposing and parasite-hopping approach, we tested a previously reported library of compounds that were active against Trypanosoma brucei, plus 31 new compounds, against a variety of protozoan parasites including Trypanosoma cruzi, Leishmania major, Leishmania donovani, and Plasmodium falciparum. This led to the discovery of several compounds with submicromolar activities and improved physicochemical properties that are early leads toward the development of chemotherapeutic agents against kinetoplastid diseases and malaria.

Identification of Leucinostatins from Ophiocordyceps sp. as Antiparasitic Agents Against Trypanosoma cruzi

“…Primary screening of fungal extract samples. A subset of 5,631 samples from the University of Oklahoma fungal natural products library were tested at 2 µg/mL against T. cruzi strain CA-I/72 in a phenotypic high-content imaging assay we had previously developed and implemented in other drug discovery initiatives [16][17][18][19] . Dimethyl sulfoxide (DMSO) vehicle-treated infected mouse myocytes were included as positive infection controls, while infected mouse myocytes treated with 50 µM benznidazole were included as the negative infection control.…”

Collaborative virtual screening to elaborate an imidazo[1,2-a]pyridine hit series for visceral leishmaniasis

“…RSC Medicinal Chemistry Research Article and selectivity indices (9,12), presence of both basic (10,15) and non-basic (13,16) heteroatoms appear detrimental to anti-parasitic activity. Conversely, presence of additional polar heteroatoms or halogens in the case of aniline-type substitution in the 3-position seemed to enhance potency and in certain cases selectivity over host cell cytotoxicity (5,21), although, as previously mentioned, this selectivity seemed to partly depend on the nature of additional substitution at positions 6 and 7 on the imidazo[1,2-a] pyridine core (22)(23)(24)(25)(29)(30). A combination of alkyl and aryl substituents on the 3-position amine appeared to result in an interesting combination of both potency and selectivity over background cytotoxicity (20).…”

“…25 Despite this promising situation, the reality of clinicallevel attrition in drug discovery R&D dictates that if the global health community are to ensure delivery of new, improved treatments to VL patients, further new chemical entities (NCEs) capable of tackling Leishmania infections still need to be identified and developed. 26,27 Alongside the traditional target and phenotypic approaches mentioned above, recent reports have highlighted a number of efforts to identify novel anti-leishmanial NCEs via repurposing of existing drugs and clinical stage compounds, 28 combined scaffold and parasite hopping, 29 the screening of natural products, 30 as well as investigation into host-mediated treatments for Leishmania infections. 31 We report herein on early discovery efforts around an antileishmanial chemotype derived from the output of a kinetoplastid high throughput screening (HTS) campaign.…”

Antiparasitic Derivatives of the Furoquinoline Alkaloids Kokusaginine And Flindersiamine

“…and trypanosomes, and some synthetic C4 substituted quinolines have shown increased activity against T. cruzi compared to their precursors. For instance, some 7‐chloro‐4‐amino(oxy)quinolones, [28] 4‐aryl‐quinolines, [29] and 4,7‐aryl‐quinolines, [30] have been reported as potential antichagasic compounds. These previous results, together with a steady and sustainable supply of the parent furoquinoline alkaloids, gave support to the exploration of the semisynthetic possibilities of these compounds, in order to improve their known biological activities and at the same time to find new biological targets.…”