Novel aroyl guanidine anti-trypanosomal compounds that exert opposing effects on parasite energy metabolism.

Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease with current treatments marred by severe side effects or delivery issues. To identify novel classes of compounds for the treatment of HAT, high throughput screening (HTS) had previously been conducted on bloodstream forms of T. b.

Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis.

Giardia duodenalis is the causative agent of the neglected diarrhoeal disease giardiasis. While often self-limiting, giardiasis is ubiquitous and impacts hundreds of millions of people annually. It is also a common gastro-intestinal disease of domestic pets, wildlife, and livestock animals.

Impact of Laboratory-Adapted Intracellular Strains on the Activity Profiles of Compounds with Anti- Activity.

Chagas disease is caused by infection with the protozoan parasite, . The disease causes ~12,000 deaths annually and is one of the world's 20 neglected tropical diseases, as defined by the World Health Organisation. The drug discovery pipeline for Chagas disease currently has few new clinical candidates, with high attrition rates an ongoing issue.

Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection.

Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the and profiles of a new bicyclic nitroimidazole subclass, namely, nitroimidazopyrazinones, against mycobacteria and .

Temporal and Wash-Out Studies Identify Medicines for Malaria Venture Pathogen Box Compounds with Fast-Acting Activity against Both and .

Chagas disease caused by the protozoan is endemic to 21 countries in the Americas, effects approximately 6 million people and on average results in 12,000 deaths annually. Human African Trypanosomiasis (HAT) is caused by the sub-species, endemic to 36 countries within sub-Saharan Africa. Treatment regimens for these parasitic diseases are complicated and not effective against all disease stages; thus, there is a need to find improved treatments.

Investigation of thiazolyl-benzothiophenamides as potential agents for African sleeping sickness.

African sleeping sickness is a potentially fatal neglected disease affecting sub-Saharan Africa. High-throughput screening identified the thiazolyl-benzothiophenamide to be active against the causative parasite, . This work establishes structure-activity relationships of , guiding the design of second generation derivatives.

Hit-to-lead optimization of novel benzimidazole phenylacetamides as broad spectrum trypanosomacides.

and are the parasitic causative agents of Chagas disease and human African trypanosomiasis (HAT), respectively. The drugs currently used to treat these diseases are not efficacious against all stages and/or parasite sub-species, often displaying side effects. Herein, we report the SAR exploration of a novel hit, 2-(4-chlorophenyl)--(1-propyl-1-benzimidazol-2-yl)acetamide previously identified from high throughput screens against , and An informative set of analogues was synthesized incorporating key modifications of the scaffold resulting in improved potency whilst the majority of compounds retained low cytotoxicity against H9c2 and HEK293 cell lines.

Antitubercular and Antiparasitic 2-Nitroimidazopyrazinones with Improved Potency and Solubility.

Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains.

Re-evaluating pretomanid analogues for Chagas disease: Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy.

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe.

Investigation of pyrimidine nucleoside analogues as chemical probes to assess compound effects on the proliferation of Trypanosoma cruzi intracellular parasites.

Trypanosoma cruzi parasites utilise de novo pyrimidine biosynthesis to produce DNA and survive within mammalian host cells. This pathway can be hijacked to assess the replication of intracellular parasites with the exogenous addition of a DNA specific probe. To identify suitable probe compounds for this application, a collection of pyrimidine nucleoside analogues was assessed for incorporation into T.

Total Synthesis of the Antimalarial Ascidian Natural Product Albopunctatone.

The first approaches to the 10'-anthronyl-2-anthraquinone skeleton have been devised, allowing two syntheses of the marine natural product albopunctatone. Both routes involve regioselective addition of a nucleophilic masked anthraquinone to a protected chrysazin derivative; the best affords albopunctatone in five steps and 35% overall yield. Albopunctatone exhibits potent inhibitory activity against and negligible toxicity to a range of other microbial pathogens and mammalian cells.

The cubane paradigm in bioactive molecule discovery: further scope, limitations and the cyclooctatetraene complement.

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne).

Design, Synthesis, and Biological Evaluation of 2-Nitroimidazopyrazin-one/-es with Antitubercular and Antiparasitic Activity.

Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis, and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that antitubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here, we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazooxazines.

3-pyridyl inhibitors with novel activity against Trypanosoma cruzi reveal in vitro profiles can aid prediction of putative cytochrome P450 inhibition.

Using high throughput, high-content imaging, a proprietary library was screened against intracellular Trypanosoma cruzi amastigotes to identify compounds with novel activity against the parasite. Five inhibitors were discovered, which did not clear all of the parasites from 3T3 host cells following 48 hours exposure, and were identified as putative T. cruzi cytochrome P450 (TcCYP51) inhibitors.

Screening a Natural Product-Based Library against Kinetoplastid Parasites.

Kinetoplastid parasites cause vector-borne parasitic diseases including leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease. These Neglected Tropical Diseases (NTDs) impact on some of the world's lowest socioeconomic communities. Current treatments for these diseases cause severe toxicity and have limited efficacy, highlighting the need to identify new treatments.

Screening the Medicines for Malaria Venture Pathogen Box across Multiple Pathogens Reclassifies Starting Points for Open-Source Drug Discovery.

Open-access drug discovery provides a substantial resource for diseases primarily affecting the poor and disadvantaged. The open-access Pathogen Box collection is comprised of compounds with demonstrated biological activity against specific pathogenic organisms. The supply of this resource by the Medicines for Malaria Venture has the potential to provide new chemical starting points for a number of tropical and neglected diseases, through repurposing of these compounds for use in drug discovery campaigns for these additional pathogens.

Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway.

Background: In the fight against malaria, the discovery of chemical compounds with a novel mode of action and/or chemistry distinct from currently used drugs is vital to counteract the parasite's known ability to develop drug resistance. Another desirable aspect is efficacy against gametocytes, the sexual developmental stage of the parasite which enables the transmission through Anopheles vectors. Using a chemical rescue approach, we previously identified compounds targeting Plasmodium falciparum coenzyme A (CoA) synthesis or utilization, a promising target that has not yet been exploited in anti-malarial drug development.

Development and application of a sensitive, phenotypic, high-throughput image-based assay to identify compound activity against Trypanosoma cruzi amastigotes.

We have developed a high content 384-well, image-based assay to estimate the effect of compound treatment on Trypanosoma cruzi amastigotes in 3T3 fibroblasts. In the same well, the effect of compound activity on host cells can also be determined, as an initial indicator of cytotoxicity. This assay has been used to identify active compounds from an in-house library of compounds with either known biological activity or that are FDA approved, and separately, from the Medicines for Malaria Venture Malaria Box collection.

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors.

From a whole-organism high throughput screen of approximately 87000 compounds against Trypanosoma brucei brucei, we recently identified eight new unique compounds for the treatment of human African trypanosomiasis. In an effort to understand the structure-activity relationships around these compounds, we report for the first time our results on a new class of trypanocides, the pyrazine carboxamides. Attracted by the low molecular weight (270 g·mol(-1)) of our starting hit (9) and its potency (0.

Pyridyl benzamides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei.

A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships.

Trypanocidal activity of marine natural products.

Marine natural products are a diverse, unique collection of compounds with immense therapeutic potential. This has resulted in these molecules being evaluated for a number of different disease indications including the neglected protozoan diseases, human African trypanosomiasis and Chagas disease, for which very few drugs are currently available. This article will review the marine natural products for which activity against the kinetoplastid parasites; Trypanosoma brucei brucei, T.

Approaches to protozoan drug discovery: phenotypic screening.

Determining the activity of a compound and the potential impact on a diseased state is frequently undertaken using phenotypic or target-based approaches. Phenotypic screens have the advantage of the whole organism being exposed to the compound and thus all the targets and biological pathways associated with it. Cell penetration and access to targets in their "natural" environment are taken into account.

3-(Oxazolo[4,5-b]pyridin-2-yl)anilides as a novel class of potent inhibitors for the kinetoplastid Trypanosoma brucei, the causative agent for human African trypanosomiasis.

A whole organism high-throughput screen of approximately 87,000 compounds against Trypanosoma brucei brucei led to the recent discovery of several novel compound classes with low micromolar activity against this organism and without appreciable cytotoxicity to mammalian cells. Herein we report a structure-activity relationship (SAR) investigation around one of these hit classes, the 3-(oxazolo[4,5-b]pyridin-2-yl)anilides. Sharp SAR is revealed, with our most active compound (5) exhibiting an IC₅₀ of 91 nM against the human pathogenic strain T.

Identification of compounds with anti-proliferative activity against Trypanosoma brucei brucei strain 427 by a whole cell viability based HTS campaign.

Human African Trypanosomiasis (HAT) is caused by two trypanosome sub-species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Drugs available for the treatment of HAT have significant issues related to difficult administration regimes and limited efficacy across species and disease stages. Hence, there is considerable need to find new alternative and less toxic drugs.

Iotrochamides A and B, antitrypanosomal compounds from the Australian marine sponge Iotrochota sp.

Bioassay-guided isolation of the CH(2)Cl(2)/MeOH extract from the Australian sponge Iotrochota sp. resulted in the purification of two new N-cinnamoyl-amino acids, iotrochamides A (1) and B (2). The chemical structures of 1 and 2 were determined by 1D/2D NMR and MS data analyses.