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Special Issue "COST CM1307: Targeted Chemotherapy towards Diseases Caused by Endoparasites—Proceedings in Medicinal and Natural Product Chemistry"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 30 June 2018

Special Issue Editor

Guest Editor
Prof. Dr. Thomas J. Schmidt

Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Corrensstrasse 48, D-48149 Münster, Germany
Website | E-Mail
Interests: natural products; anti-parasitic activity; anti-cancer activity; structure elucidation; spectroscopy; computer-aided structure-activity relationship studies

Special Issue Information

Dear Colleagues,

More than a billion people world-wide suffer from diseases caused by endoparasites. Many of them are currently classified by the WHO as Neglected Tropical Diseases (NTDs). These diseases represent a major cause of morbidity, disability and mortality in tropical regions of the world. They are termed “neglected” due to lack of financial investment into research and development of new drugs and almost non-existent public awareness in high-income countries. Being associated with poor socioeconomic and hygienic circumstances, they could also be termed diseases of neglected populations. NTDs comprise, besides some infections with bacterial (e.g., Leprosy, Trachoma) and viral (Dengue fever) pathogens, other infections that are caused by endoparasites such as Helminths (e.g., Schistosomiasis, Filariasis), as well as Protozoa (African sleeping sickness, Chagas’ disease, Leishmaniasis). In environments where NTDs prevail, Malaria, the most widespread disease caused by a “protozoan” endoparasite—although not currently treated as such by the WHO—can also be considered as a neglected disease. Notwithstanding recent partial successes in the struggle to eliminate or even eradicate some of these diseases, which have been achieved by the WHO’s consequent strategies of disease monitoring, vector control, preventive chemotherapy and others, the development of new, safe and affordable drugs remains an urgent need. Existing pharmacotherapies, especially in the case of “protozoan” parasitoses, suffer from various shortcomings, namely, a high degree of toxicity and side effects, lack of availability and/or problematic application under the life conditions of affected populations, as well as emergence of resistant pathogens, so that the search for new chemical entities showing activity against the pathogens under study is a very important field of research. Needless to say that these diseases, for a long time restricted mostly to poor, underdeveloped parts of the world, are now—in these times of climate change and unhindered migration—spreading to all parts of the planet and thus may shortly become a truly global problem.

It is a great pleasure and an important political sign that the European Union has decided to dedicate one of its actions for European Cooperation in Science and Technology, COST action CM1307, to “Targeted chemotherapy towards diseases caused by endoparasites” and allows researchers from all relevant fields to participate in this quest of global importance!

The present Special Issue, meant as a joint publication platform for Medicinal and Natural Product Chemists and researchers from related fields as members of the COST Action CM1307 Working Groups 2 and 3, dedicated to Medicinal Chemistry and Natural products, respectively, focuses on chemical entities that show a promising potential to act against the pathogens responsible for the diseases under study. All aspects related to the discovery and further development of synthetic and natural products against such endoparasitoses will be covered by the issue. It is therefore a pleasure to invite high quality studies, as well as timely review papers, on in vitro and in vivo biological activity, isolation and structure elucidation of natural and synthetic molecules, hit-to-lead development, lead optimization, investigations of the pharmacodynamics and -kinetics, as well as structure–activity relationships against diseases caused by endoparasites.

As the editor, I cordially invite all participating scientists to publish their work related to the COST Action CM1307 in this Special Issue. It is of particular importance, especially in a field such as neglected diseases, to disseminate such work supported by the European public in a manner that the results become accessible to any interested reader world-wide, i.e., in a reputed open-access journal such as Molecules. I am therefore convinced that this Special Issue will become a success for those who publish and those who may benefit from the scientific results of this initiative.

Prof. Dr. Thomas J. Schmidt
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • endoparasites
  • drug research
  • drug design
  • medicinal chemistry
  • natural products
  • antiparasitic chemotherapy
  • structure–activity relationships
  • bioactivity testing/screening
  • mechanism of action
  • chagas disease
  • human African trypanosomiasis (Sleeping sickness)
  • leishmaniasis
  • malaria
  • dracunculiasis (guinea-worm disease)
  • echinococcosis
  • foodborne trematodiases
  • lymphatic filariasis
  • onchocerciasis (river blindness)
  • schistosomiasis
  • soil transmitted helminthiases
  • taeniasis/cysticercosis
  • veterinary parasitoses

Published Papers (5 papers)

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Research

Open AccessArticle Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity
Molecules 2017, 22(3), 426; doi:10.3390/molecules22030426
Received: 7 February 2017 / Revised: 1 March 2017 / Accepted: 3 March 2017 / Published: 8 March 2017
PDF Full-text (2968 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (13) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic
[...] Read more.
Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (13) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1–TbPTR1 and Leishmania major–LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants. Full article
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Open AccessArticle Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties
Molecules 2017, 22(1), 161; doi:10.3390/molecules22010161
Received: 4 December 2016 / Revised: 8 January 2017 / Accepted: 12 January 2017 / Published: 19 January 2017
Cited by 1 | PDF Full-text (10947 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N-arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting
[...] Read more.
With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and N-arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal -N(Me)2 or -N(Et)2 in different positions (ortho, meta and para) on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable N-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para-position of the substituent remains the most favourable position on the benzyl chain and the carbamate -NHBoc was found active both in vitro (42 nM versus 29 nM for plasmodione) and in vivo in Plasmodium berghei-infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization. Full article
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Open AccessArticle In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids
Molecules 2016, 21(7), 853; doi:10.3390/molecules21070853
Received: 1 May 2016 / Revised: 4 June 2016 / Accepted: 10 June 2016 / Published: 29 June 2016
Cited by 3 | PDF Full-text (1332 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance
[...] Read more.
Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery. Full article
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Open AccessArticle Arginase Flavonoid Anti-Leishmanial in Silico Inhibitors Flagged against Anti-Targets
Molecules 2016, 21(5), 589; doi:10.3390/molecules21050589
Received: 22 March 2016 / Revised: 26 April 2016 / Accepted: 27 April 2016 / Published: 5 May 2016
Cited by 4 | PDF Full-text (2290 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Arginase, a drug target for the treatment of leishmaniasis, is involved in the biosynthesis of polyamines. Flavonoids are interesting natural compounds found in many foods and some of them may inhibit this enzyme. The MetIDB database containing 5667 compounds was screened using an
[...] Read more.
Arginase, a drug target for the treatment of leishmaniasis, is involved in the biosynthesis of polyamines. Flavonoids are interesting natural compounds found in many foods and some of them may inhibit this enzyme. The MetIDB database containing 5667 compounds was screened using an EIIP/AQVN filter and 3D QSAR to find the most promising candidate compounds. In addition, these top hits were screened in silico versus human arginase and an anti-target battery consisting of cytochromes P450 2a6, 2c9, 3a4, sulfotransferase, and the pregnane-X-receptor in order to flag their possible interactions with these proteins involved in the metabolism of substances. The resulting compounds may have promise to be further developed for the treatment of leishmaniasis. Full article
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Open AccessArticle Binding Mode and Selectivity of Steroids towards Glucose-6-phosphate Dehydrogenase from the Pathogen Trypanosoma cruzi
Molecules 2016, 21(3), 368; doi:10.3390/molecules21030368
Received: 5 February 2016 / Revised: 8 March 2016 / Accepted: 11 March 2016 / Published: 17 March 2016
Cited by 3 | PDF Full-text (6182 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Glucose-6-phosphate dehydrogenase (G6PDH) plays a housekeeping role in cell metabolism by generating reducing power (NADPH) and fueling the production of nucleotide precursors (ribose-5-phosphate). Based on its indispensability for pathogenic parasites from the genus Trypanosoma, G6PDH is considered a drug target candidate. Several
[...] Read more.
Glucose-6-phosphate dehydrogenase (G6PDH) plays a housekeeping role in cell metabolism by generating reducing power (NADPH) and fueling the production of nucleotide precursors (ribose-5-phosphate). Based on its indispensability for pathogenic parasites from the genus Trypanosoma, G6PDH is considered a drug target candidate. Several steroid-like scaffolds were previously reported to target the activity of G6PDH. Epiandrosterone (EA) is an uncompetitive inhibitor of trypanosomal G6PDH for which its binding site to the enzyme remains unknown. Molecular simulation studies with the structure of Trypanosoma cruzi G6PDH revealed that EA binds in a pocket close to the G6P binding-site and protrudes into the active site blocking the interaction between substrates and hence catalysis. Site directed mutagenesis revealed the important steroid-stabilizing effect of residues (L80, K83 and K84) located on helix α-1 of T. cruzi G6PDH. The higher affinity and potency of 16α-Br EA by T. cruzi G6PDH is explained by the formation of a halogen bond with the hydrogen from the terminal amide of the NADP+-nicotinamide. At variance with the human enzyme, the inclusion of a 21-hydroxypregnane-20-one moiety to a 3β-substituted steroid is detrimental for T. cruzi G6PDH inhibition. The species-specificity of certain steroid derivatives towards the parasite G6PDH and the corresponding biochemically validated binding models disclosed in this work may prove valuable for the development of selective inhibitors against the pathogen’s enzyme. Full article
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