Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation

publisher: Elsevier articletitle: Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2015.08.014 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.publisher: Elsevier articletitle: Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2015.08.014 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.publisher: Elsevier articletitle: Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2015.08.014 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.publisher: Elsevier articletitle: Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2015.08.014 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved

Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma

Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for their in vitro activity against M. mycetomatis hyphae, rendering four further hit compounds. To assess the in vivo potency of these hit compounds, a Galleria mellonella larvae model infected with M. mycetomatis was used. Several of the compounds identified in vitro demonstrated promising efficacy in vivo in terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of an Open Source Mycetoma (MycetOS) approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases

Active natural product scaffolds against trypanosomatid parasites : a review

This work was supported through funding from the EPSRC and the School of Chemistry (University of St Andrews).Neglected tropical diseases caused by trypanosomatid parasites are a continuing and escalating problem, which devastate the less economically developed cultures in countries in which they are endemic by impairing both human and animal health. Current drugs for these diseases are regarded as out-of-date and expensive, with unacceptable side-effects and mounting parasite resistance, meaning there is an urgent need for new therapeutics. Natural products have long been a source of potent, structurally diverse bioactive molecules. Herein are reviewed natural products with reported trypanocidal activity, which have been clustered based on core structural similarities, to aid the future discovery of new trypanocidal core motifs with potential routes to synthetically accessible natural product cores suggested.PostprintPeer reviewe

Identification of phenolic constituents of cytisus multiflorus

The phenolic composition of the ethanolic extract obtained from the flowers of the medicinal plant Cytisus multiflorus has been elucidated by high performance liquid chromatography, electrospray mass spectrometry and nuclear magnetic resonance analysis. The extract was mainly composed of flavones, including the common chrysin, orientin, luteolin-5-O-glucoside, luteolin-7-O-glucoside, apigenin and apigenin-7-O-glucoside, which appeared as minor components. The major flavone in the extract was chrysin-7-O-B-D-glucopyranoside, and it also contained moderate amounts of a dihydroxyflavone isomer of chrysin, as well as of 2''-O-pentosyl-6-C-hexosyl-luteolin, 2''-O-pentosyl-8-C-hexosyl-luteolin and 6''- O-(3-hydroxy-3-methylglutaroyl)-2''-O-pentosyl-C-hexosyl-apigenin, which are not commonly found in the Fabaceae family. Other novel phenolic compounds found in the ethanolic extract of C. multiflorus comprised the flavones 2''-O-pentosyl-6-C-hexosyl-apigenin, 2''-O-pentosyl-8-C-hexosyl-apigenin and 6''-O-(3-hydroxy-3-methylglutaroyl)-200-O-pentosyl-C-hexosyl-luteolin. The assessment of the biological activities of the main compounds of this extract are now keen, in order to determine their relevance in the beneficial properties of the plant

Novel 3-nitrotriazole-based amides and carbinols as bifunctional anti-Chagasic agents.

3-Nitro-1H-1,2,4-triazole-based amides with a linear, rigid core and 3-nitrotriazole-based fluconazole analogs were synthesized as dual functioning antitrypanosomal agents. Such compounds are excellent substrates for type I nitroreductase (NTR) located in the mitochondrion of trypanosomatids and, at the same time, act as inhibitors of the sterol 14α-demethylase (T. cruzi CYP51) enzyme. Because combination treatments against parasites are often superior to monotherapy, we believe that this emerging class of bifunctional compounds may introduce a new generation of antitrypanosomal drugs. In the present work, the synthesis and in vitro and in vivo evaluation of such compounds is discussed.This work was supported in part by internal funds of the Radiation Medicine Department at NorthShore University HealthSystem. Experiments on T. cruzi CYP51 were funded by NIH (GM067871, to G.I.L.). In vitro screenings against parasites were funded by DNDi. For that project, DNDi received funding from the following donors: Department for Internationl Development (DFID), U.K.; Bill & Melinda Gates Foundation (BMGF), USA; Reconstruction Credit Institution-Federal Ministry of Education and Research (KfW-BMBF), Germany; and Directorate-General for International Cooperation (DGIS), The Netherlands. B.A.-V. acknowledges financial support by FONDECYT Postdoctorado 3130364

Aristolochic Acid I Induced Autophagy Extenuates Cell Apoptosis via ERK 1/2 Pathway in Renal Tubular Epithelial Cells

Autophagy is a lysosomal degradation pathway that is essential for cell survival and tissue homeostasis. However, limited information is available about autophagy in aristolochic acid (AA) nephropathy. In this study, we investigated the role of autophagy and related signaling pathway during progression of AAI-induced injury to renal tubular epithelial cells (NRK52E cells). The results showed that autophagy in NRK52E cells was detected as early as 3–6 hrs after low dose of AAI (10 µM) exposure as indicated by an up-regulated expression of LC3-II and Beclin 1 proteins. The appearance of AAI-induced punctated staining of autophagosome-associated LC3-II upon GFP-LC3 transfection in NRK52E cells provided further evidence for autophagy. However, cell apoptosis was not detected until 12 hrs after AAI treatment. Blockade of autophagy with Wortmannin or 3-Methyladenine (two inhibitors of phosphoinositede 3-kinases) or small-interfering RNA knockdown of Beclin 1 or Atg7 sensitized the tubular cells to apoptosis. Treatment of NRK52E cells with AAI caused a time-dependent increase in extracellular signal-regulated kinase 1 and 2 (ERK1/2) activity, but not c-Jun N-terminal kinase (JNK) and p38. Pharmacological inhibition of ERK1/2 phosphorylation with U0126 resulted in a decreased AAI-induced autophagy that was accompanied by an increased apoptosis. Taken together, our study demonstrated for the first time that autophagy occurred earlier than apoptosis during AAI-induced tubular epithelial cell injury. Autophagy induced by AAI via ERK1/2 pathway might attenuate apoptosis, which may provide a protective mechanism for cell survival under AAI-induced pathological condition

Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma

Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, the

Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

BACKGROUND: Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. METHODS: Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed. RESULTS: Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. CONCLUSIONS: Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems