Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1.

Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of Leishmania donovani and L.

Validation of Trypanosoma cruzi inactivation techniques for laboratory use.

Trypanosoma cruzi (T. cruzi) is the causative agent of Chagas' disease, a parasitic infection responsible for significant morbidity and mortality in Latin America. The current treatments have many serious drawbacks and new drugs are urgently required.

The critical role of mode of action studies in kinetoplastid drug discovery.

Understanding the target and mode of action of compounds identified by phenotypic screening can greatly facilitate the process of drug discovery and development. Here, we outline the tools currently available for target identification against the neglected tropical diseases, human African trypanosomiasis, visceral leishmaniasis and Chagas' disease. We provide examples how these tools can be used to identify and triage undesirable mechanisms, to identify potential toxic liabilities in patients and to manage a balanced portfolio of target-based campaigns.

Monocyclic Nitro-heteroaryl Nitrones with Dual Mechanism of Activation: Synthesis and Antileishmanial Activity.

5-Nitro-furan nitrones () and 5-nitro-thiophene nitrones () were synthesized in one step. Compounds - had the most potent leishmanicidal activity against intracellular amastigote forms of and (from 0.019 to 2.

Surmounting structural barriers to tackle endemic infectious diseases.

A unique experiment in bringing academic and industrial scientists together to tackle endemic infectious diseases has proved a success. The Tres Cantos Open Lab Foundation, guided and advised by independent experts, funds extended stays of academics at the campus of a pharmaceutical company, where they access the firm's resources in partnership with company scientists. Progress in tackling tuberculosis, protozoal infections, and enteric bacterial diseases has sustained the decade-long evolution of the model, whose distinctive features complement other public-private partnerships with similar goals.

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series.

8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi.

An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs.

New 8-Nitroquinolinone Derivative Displaying Submicromolar Activities against Both and .

An antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated against , , and , in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative was revealed, presenting EC values of 12 and 500 nM on trypomastigotes and amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC ≤ 13 μM).

Discovery of an Allosteric Binding Site in Kinetoplastid Methionyl-tRNA Synthetase.

Methionyl-tRNA synthetase (MetRS) is a chemically validated drug target in kinetoplastid parasites and . To date, all kinetoplastid MetRS inhibitors described bind in a similar way to an expanded methionine pocket and an adjacent, auxiliary pocket. In the current study, we have identified a structurally novel class of inhibitors containing a 4,6-diamino-substituted pyrazolopyrimidine core (the MetRS02 series).

The Q Site of Cytochrome is a Promiscuous Drug Target in and .

Available treatments for Chagas' disease and visceral leishmaniasis are inadequate, and there is a pressing need for new therapeutics. Drug discovery efforts for both diseases principally rely upon phenotypic screening. However, the optimization of phenotypically active compounds is hindered by a lack of information regarding their molecular target(s).

Fexinidazole for the treatment of human African trypanosomiasis.

On November 15, 2018, Fexinidazole Winthrop received a positive opinion from the European Medicines Agency (EMA) (under Article 58) for treatment of first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis caused by Trypanosoma gambiense (gHAT) in adults and children 6 years and older and weighing 20 or more kg. This is the first oral regimen for gHAT that is effective in treating both disease stages. Although fexinidazole has potential to simplify current therapies, it does not entirely eliminate the need for disease staging by lumbar puncture because patients with severe stage 2 disease (CSF WBC [cerebrospinal fluid white blood cells] greater than 100 cells/µL) should only be treated with fexinidazole if no other suitable treatment is available.

Substituted Aminoacetamides as Novel Leads for Malaria Treatment.

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities.

Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.

Visceral leishmaniasis (VL), caused by the protozoan parasites and , is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease.

Nongenotoxic 3-Nitroimidazo[1,2-]pyridines Are NTR1 Substrates That Display Potent Antileishmanial Activity.

Twenty nine original 3-nitroimidazo[1,2-]pyridine derivatives, bearing a phenylthio (or benzylthio) moiety at position 8 of the scaffold, were synthesized. evaluation highlighted compound as an antiparasitic hit molecule displaying low cytotoxicity for the human HepG2 cell line (CC > 100 μM) alongside good antileishmanial activities (IC = 1-2.1 μM) against , , and ; and good antitrypanosomal activities (IC = 1.

Pharmacological Validation of N-Myristoyltransferase as a Drug Target in Leishmania donovani.

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and L. infantum, is responsible for ∼30 000 deaths annually. Available treatments are inadequate, and there is a pressing need for new therapeutics.

Development of Chemical Proteomics for the Folateome and Analysis of the Kinetoplastid Folateome.

The folate pathway has been extensively studied in a number of organisms, with its essentiality exploited by a number of drugs. However, there has been little success in developing drugs that target folate metabolism in the kinetoplastids. Despite compounds being identified which show significant inhibition of the parasite enzymes, this activity does not translate well into cellular and animal models of disease.

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions.

An antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.

Author Correction: Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.

The structures of nifurtimox in Table 1 were incorrect and have been updated in the pdf and online. The authors apologize for any confusion caused.

8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases.

Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T.

A role for trypanosomatid aldo-keto reductases in methylglyoxal, prostaglandin and isoprostane metabolism.

Trypanosomatid parasites are the infectious agents causing Chagas disease, visceral and cutaneous leishmaniasis and human African trypanosomiasis. Recent work of others has implicated an aldo-keto reductase (AKR) in the susceptibility and resistance of to benznidazole, a drug used to treat Chagas disease. Here, we show that AKR and homologues in the related parasites and do not reductively activate monocyclic (benznidazole, nifurtimox and fexinidazole) or bicyclic nitro-drugs such as PA-824.