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Special Issue "20th Anniversary of Molecules—Recent Advances in Medicinal Chemistry"

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

Deadline for manuscript submissions: closed (15 December 2015)

Special Issue Editors

Guest Editor
Dr. Jean Jacques Vanden Eynde

Formerly head of the Department of Organic Chemistry (FS), University of Mons-UMONS, 7000 Mons, Belgium
Website | E-Mail
Interests: heterocycles; microwave-induced synthesis; medicinal chemistry; green chemistry
Advisory Board Member
Dr. Michael Berger

Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria
Website | E-Mail
Interests: neurotransmitter receptors
Advisory Board Member
Prof. Dr. Osvaldo Andrade Santos-Filho

Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, IPPN, Av. Carlos Chagas Filho, 373, Bloco H - Ilha do Fundão, Rio de Janeiro, RJ - 21941-902, Brazil
Website | E-Mail
Interests: molecular modeling; computer-aided drug design; bioinformatics; chemoinformatics
Advisory Board Member
Prof. Dr. Sylvain Rault

Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie UPRES EA 4258–FR CNRS 3038 INC3M, Bd Becquerel, Caen Cedex, France
Website | E-Mail
Interests: Medicinal Chemistry
Advisory Board Member
Prof. Dr. Melanie T. Cushion

Department of Internal Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 560, Cincinnati, OH 45267-056, USA
Website | E-Mail

Special Issue Information

Dear Colleagues,

Twenty years! Can you believe it? In 2015 we are celebrating the 20th anniversary of our journal Molecules. The growth of Molecules has only been possible because authors, reviewers, editors, and all people working in some way for the journal have joined their efforts for years. Thank you for your confidence and your enthusiasm.

Molecules (ISSN 1420-3049) was initiated by Dr. Shu-Kun Lin in Switzerland in 1996 with the additional original idea of encouraging the repository and exchange of chemical samples. The early days were not easy, but in Volume 2, you could already read 232 pages covering an editorial, 26 interesting research papers, and 42 short notes belonging to the MolBank section (http://www.mdpi.com/journal/molecules/sections/molbank). What a successful road since that time! Indeed, volume 18 (2013) was completed with 15,803 pages and we can reasonably foresee that volume 19 (2014) will surpass 20,000 pages.

To mark that important milestone, a special issue entitled “Recent Advances in Medicinal Chemistry” is being launched. On behalf of the members of the Advisory Board created for the occasion, I kindly invite all groups involved in the field to contribute by submitting an up-to-date review, with the aim of providing to our readers a comprehensive survey of the many topics covered by the discipline.

Dr. Jean Jacques Vanden Eynde
Guest Editor

Dr. Michael Berger
Dr. Osvaldo Andrade Santos-Filho
Dr. Sylvain Rault
Dr. Melanie T. Cushion
Advisory Board Members

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a 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.

Published Papers (8 papers)

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Review

Open AccessReview Flavin-Dependent Thymidylate Synthase as a New Antibiotic Target
Molecules 2016, 21(5), 654; doi:10.3390/molecules21050654
Received: 6 April 2016 / Revised: 9 May 2016 / Accepted: 13 May 2016 / Published: 20 May 2016
Cited by 3 | PDF Full-text (2246 KB) | HTML Full-text | XML Full-text
Abstract
In humans de novo synthesis of 2′-deoxythymidine-5′-monophosphate (dTMP), an essential building block of DNA, utilizes an enzymatic pathway requiring thymidylate synthase (TSase) and dihydrofolate reductase (DHFR). The enzyme flavin-dependent thymidylate synthase (FDTS) represents an alternative enzymatic pathway to synthesize dTMP, which is not
[...] Read more.
In humans de novo synthesis of 2′-deoxythymidine-5′-monophosphate (dTMP), an essential building block of DNA, utilizes an enzymatic pathway requiring thymidylate synthase (TSase) and dihydrofolate reductase (DHFR). The enzyme flavin-dependent thymidylate synthase (FDTS) represents an alternative enzymatic pathway to synthesize dTMP, which is not present in human cells. A number of pathogenic bacteria, however, depend on this enzyme in lieu of or in conjunction with the analogous human pathway. Thus, inhibitors of this enzyme may serve as antibiotics. Here, we review the similarities and differences of FDTS vs. TSase including aspects of their structure and chemical mechanism. In addition, we review current progress in the search for inhibitors of flavin dependent thymidylate synthase as potential novel therapeutics. Full article
Figures

Open AccessReview Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development
Molecules 2016, 21(5), 615; doi:10.3390/molecules21050615
Received: 9 February 2016 / Revised: 19 April 2016 / Accepted: 4 May 2016 / Published: 11 May 2016
Cited by 2 | PDF Full-text (6867 KB) | HTML Full-text | XML Full-text
Abstract
Dimethylarginine dimethylaminohydrolase (DDAH) is a highly conserved hydrolytic enzyme found in numerous species, including bacteria, rodents, and humans. In humans, the DDAH-1 isoform is known to metabolize endogenous asymmetric dimethylarginine (ADMA) and monomethyl arginine (l-NMMA), with ADMA proposed to be a
[...] Read more.
Dimethylarginine dimethylaminohydrolase (DDAH) is a highly conserved hydrolytic enzyme found in numerous species, including bacteria, rodents, and humans. In humans, the DDAH-1 isoform is known to metabolize endogenous asymmetric dimethylarginine (ADMA) and monomethyl arginine (l-NMMA), with ADMA proposed to be a putative marker of cardiovascular disease. Current literature reports identify the DDAH family of enzymes as a potential therapeutic target in the regulation of nitric oxide (NO) production, mediated via its biochemical interaction with the nitric oxide synthase (NOS) family of enzymes. Increased DDAH expression and NO production have been linked to multiple pathological conditions, specifically, cancer, neurodegenerative disorders, and septic shock. As such, the discovery, chemical synthesis, and development of DDAH inhibitors as potential drug candidates represent a growing field of interest. This review article summarizes the current knowledge on DDAH inhibition and the derived pharmacokinetic parameters of the main DDAH inhibitors reported in the literature. Furthermore, current methods of development and chemical synthetic pathways are discussed. Full article
Open AccessReview Elicitation, an Effective Strategy for the Biotechnological Production of Bioactive High-Added Value Compounds in Plant Cell Factories
Molecules 2016, 21(2), 182; doi:10.3390/molecules21020182
Received: 14 December 2015 / Revised: 26 January 2016 / Accepted: 28 January 2016 / Published: 3 February 2016
Cited by 28 | PDF Full-text (608 KB) | HTML Full-text | XML Full-text
Abstract
Plant in vitro cultures represent an attractive and cost-effective alternative to classical approaches to plant secondary metabolite (PSM) production (the “Plant Cell Factory” concept). Among other advantages, they constitute the only sustainable and eco-friendly system to obtain complex chemical structures biosynthesized by rare
[...] Read more.
Plant in vitro cultures represent an attractive and cost-effective alternative to classical approaches to plant secondary metabolite (PSM) production (the “Plant Cell Factory” concept). Among other advantages, they constitute the only sustainable and eco-friendly system to obtain complex chemical structures biosynthesized by rare or endangered plant species that resist domestication. For successful results, the biotechnological production of PSM requires an optimized system, for which elicitation has proved one of the most effective strategies. In plant cell cultures, an elicitor can be defined as a compound introduced in small concentrations to a living system to promote the biosynthesis of the target metabolite. Traditionally, elicitors have been classified in two types, abiotic or biotic, according to their chemical nature and exogenous or endogenous origin, and notably include yeast extract, methyl jasmonate, salicylic acid, vanadyl sulphate and chitosan. In this review, we summarize the enhancing effects of elicitors on the production of high-added value plant compounds such as taxanes, ginsenosides, aryltetralin lignans and other types of polyphenols, focusing particularly on the use of a new generation of elicitors such as coronatine and cyclodextrins. Full article
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Open AccessReview Is Stevia rebaudiana Bertoni a Non Cariogenic Sweetener? A Review
Molecules 2016, 21(1), 38; doi:10.3390/molecules21010038
Received: 6 November 2015 / Revised: 14 December 2015 / Accepted: 21 December 2015 / Published: 26 December 2015
Cited by 4 | PDF Full-text (750 KB) | HTML Full-text | XML Full-text
Abstract
Stevia rebaudiana Bertoni is a small perennial shrub of the Asteraceae (Compositae) family that is native to South America, particularly Brazil and Paraguay, where it is known as “stevia” or “honey leaf” for its powerful sweetness. Several studies have suggested that in addition
[...] Read more.
Stevia rebaudiana Bertoni is a small perennial shrub of the Asteraceae (Compositae) family that is native to South America, particularly Brazil and Paraguay, where it is known as “stevia” or “honey leaf” for its powerful sweetness. Several studies have suggested that in addition to their sweetness, steviosides and their related compounds, including rebaudioside A and isosteviol, may offer additional therapeutic benefits. These benefits include anti-hyperglycaemic, anti-hypertensive, anti-inflammatory, anti-tumor, anti-diarrheal, diuretic, and immunomodulatory actions. Additionally, critical analysis of the literature supports the anti-bacterial role of steviosides on oral bacteria flora. The aim of this review is to show the emerging results regarding the anti-cariogenic properties of S. rebaudiana Bertoni. Data shown in the present paper provide evidence that stevioside extracts from S. rebaudiana are not cariogenic. Future research should be focused on in vivo studies to evaluate the effects on dental caries of regular consumption of S. rebaudiana extract-based products. Full article
Open AccessReview Soy Isoflavones and Breast Cancer Cell Lines: Molecular Mechanisms and Future Perspectives
Molecules 2016, 21(1), 13; doi:10.3390/molecules21010013
Received: 29 October 2015 / Revised: 13 December 2015 / Accepted: 14 December 2015 / Published: 22 December 2015
Cited by 8 | PDF Full-text (1371 KB) | HTML Full-text | XML Full-text
Abstract
The potential benefit of soy isoflavones in breast cancer chemoprevention, as suggested by epidemiological studies, has aroused the interest of numerous scientists for over twenty years. Although intensive work has been done in this field, the preclinical results continue to be controversial and
[...] Read more.
The potential benefit of soy isoflavones in breast cancer chemoprevention, as suggested by epidemiological studies, has aroused the interest of numerous scientists for over twenty years. Although intensive work has been done in this field, the preclinical results continue to be controversial and the molecular mechanisms are far from being fully understood. The antiproliferative effect of soy isoflavones has been commonly linked to the estrogen receptor interaction, but there is growing evidence that other pathways are influenced as well. Among these, the regulation of apoptosis, cell proliferation and survival, inhibition of angiogenesis and metastasis or antioxidant properties have been recently explored using various isoflavone doses and various breast cancer cells. In this review, we offer a comprehensive perspective on the molecular mechanisms of isoflavones observed in in vitro studies, emphasizing each time the dose-effect relationship and estrogen receptor status of the cells. Furthermore, we present future research directions in this field which could provide a better understanding of the inner molecular mechanisms of soy isoflavones in breast cancer. Full article
Open AccessReview Unfolded Protein Response and Macroautophagy in Alzheimer’s, Parkinson’s and Prion Diseases
Molecules 2015, 20(12), 22718-22756; doi:10.3390/molecules201219865
Received: 30 October 2015 / Revised: 30 November 2015 / Accepted: 9 December 2015 / Published: 18 December 2015
Cited by 8 | PDF Full-text (2421 KB) | HTML Full-text | XML Full-text
Abstract
Proteostasis are integrated biological pathways within cells that control synthesis, folding, trafficking and degradation of proteins. The absence of cell division makes brain proteostasis susceptible to age-related changes and neurodegeneration. Two key processes involved in sustaining normal brain proteostasis are the unfolded protein
[...] Read more.
Proteostasis are integrated biological pathways within cells that control synthesis, folding, trafficking and degradation of proteins. The absence of cell division makes brain proteostasis susceptible to age-related changes and neurodegeneration. Two key processes involved in sustaining normal brain proteostasis are the unfolded protein response and autophagy. Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases (PrDs) have different clinical manifestations of neurodegeneration, however, all share an accumulation of misfolded pathological proteins associated with perturbations in unfolded protein response and macroautophagy. While both the unfolded protein response and macroautophagy play an important role in the prevention and attenuation of AD and PD progression, only macroautophagy seems to play an important role in the development of PrDs. Macroautophagy and unfolded protein response can be modulated by pharmacological interventions. However, further research is necessary to better understand the regulatory pathways of both processes in health and neurodegeneration to be able to develop new therapeutic interventions. Full article
Open AccessReview Progress in Studies on Rutaecarpine. II.—Synthesis and Structure-Biological Activity Relationships
Molecules 2015, 20(6), 10800-10821; doi:10.3390/molecules200610800
Received: 14 May 2015 / Revised: 27 May 2015 / Accepted: 1 June 2015 / Published: 11 June 2015
Cited by 7 | PDF Full-text (1006 KB) | HTML Full-text | XML Full-text
Abstract
Rutaecarpine is a pentacyclic indolopyridoquinazolinone alkaloid found in Evodia rutaecarpa and other related herbs. It has a variety of intriguing biological properties, which continue to attract the academic and industrial interest. Studies on rutaecarpine have included isolation from new natural sources, development of
[...] Read more.
Rutaecarpine is a pentacyclic indolopyridoquinazolinone alkaloid found in Evodia rutaecarpa and other related herbs. It has a variety of intriguing biological properties, which continue to attract the academic and industrial interest. Studies on rutaecarpine have included isolation from new natural sources, development of new synthetic methods for its total synthesis, the discovery of new biological activities, metabolism, toxicology, and establishment of analytical methods for determining rutaecarpine content. The present review focuses on the synthesis, biological activities, and structure-activity relationships of rutaecarpine derivatives, with respect to their antiplatelet, vasodilatory, cytotoxic, and anticholinesterase activities. Full article
Open AccessReview Potential Role of Olive Oil Phenolic Compounds in the Prevention of Neurodegenerative Diseases
Molecules 2015, 20(3), 4655-4680; doi:10.3390/molecules20034655
Received: 23 January 2015 / Revised: 3 March 2015 / Accepted: 5 March 2015 / Published: 13 March 2015
Cited by 34 | PDF Full-text (562 KB) | HTML Full-text | XML Full-text
Abstract
Adherence to the Mediterranean Diet (MD) has been associated with a reduced incidence of neurodegenerative diseases and better cognitive performance. Virgin olive oil, the main source of lipids in the MD, is rich in minor phenolic components, particularly hydroxytyrosol (HT). HT potent antioxidant
[...] Read more.
Adherence to the Mediterranean Diet (MD) has been associated with a reduced incidence of neurodegenerative diseases and better cognitive performance. Virgin olive oil, the main source of lipids in the MD, is rich in minor phenolic components, particularly hydroxytyrosol (HT). HT potent antioxidant and anti-inflammatory actions have attracted researchers’ attention and may contribute to neuroprotective effects credited to MD. In this review HT bioavailability and pharmacokinetics are presented prior to discussing health beneficial effects. In vitro and in vivo neuroprotective effects together with its multiple mechanisms of action are reviewed. Other microconstituents of olive oil are also considered due to their potential neuroprotective effects (oleocanthal, triterpenic acids). Finally, we discuss the potential role of HT as a therapeutic tool in the prevention of neurodegenerative diseases. Full article

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review article
Title: Mechanisms of flavonoids anti-inflammatory capacity: progress in the last decade
Authors: Andreia P. Oliveira, Paula B. Andrade and Patrícia Valentão
Affiliations: REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, R. Jorge Viterbo Ferreira, n.º 228, 4050-313 Porto, Portugal
Abstract: Inflammation is a complex protective reaction caused by endogenous and exogenous factors. Increasing evidence suggests that activated macrophages play an important role in inflammation by the production of pro-inflammatory cytokines, tumor necrosis factor α (TNF-α), and other inflammatory mediators like nitric oxide (•NO) and prostaglandin E2 (PGE2). The overproduction of inflammatory mediators is involved in many diseases and the regulation of their production in tissues might be important for the treatment of inflammation. Flavonoids, polyphenolic plant secondary metabolites ubiquitously present in fruits and vegetables, possess interesting anti-inflammatory actions. The results of several epidemiological studies suggest that an increase in flavonoids intake is beneficial for inflammation. In fact, these metabolites inhibit transcription factors, such as nuclear factor-kappa B (NF-κB), nuclear factor-erythroid 2-related factor 2 (Nrf2), and activating protein-1 (AP-1).They are also known to inhibit the production of pro-inflammatory cytokines like interleukin 1β (IL-1β), IL-6 and TNF-α, as well as for their capacity to reduce •NO levels by scavenging or by inhibition of inducible nitric oxide synthase (iNOS) activity and/or expression. Furthermore, some flavonoids are able to inhibit key enzymes of the inflammatory cascade, such as phospholipase A2 (PLA2), lipoxygenase (LOX) and cyclooxygenase (COX). This review considers the advances in the knowledge of the anti-inflammatory potential of dietary flavonoids found in the last decade, by focusing their action mechanism and structure-activity relationships.

Type of Paper: Review
Title: Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (Ddah): Discovery, Synthesis, and Development
Authors: Rhys B. Murphy †, Sara Tommasi †, Benjamin C. Lewis and Arduino A. Mangoni *
Affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia
† These authors Contributed equally to this manuscript
Author to whom correspondence should be addressed; E-Mail: arduino.mangoni@flinders.edu.au; Tel.: +61 8 8204 7495; Fax: +61 8 8204 5114
Abstract: Dimethylarginine dimethylaminohydrolase (DDAH) is a highly conserved hydrolytic enzyme found in numerous species including, bacteria, rodents, and humans. In humans, the DDAH-1 isoform is known to metabolize endogenous asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA), with ADMA proposed to be a putative marker of cardiovascular disease. Current literature reports identify the DDAH family of enzymes as a potential therapeutic target in the regulation of vascular homeostasis, mediated via its biochemical interaction with the nitric oxide synthase (NOS) family of enzymes. Increased DDAH expression and nitric oxide production have been linked to multiple pathological conditions, specifically, cancer, neurodegenerative disorders, and septic shock. As such, the discovery, chemical synthesis, and development of DDAH small molecule inhibitors as potential drug candidates represent a growing field of interest. This review article summarizes the current knowledge on DDAH inhibition and compares the derived pharmacokinetic parameters of the main DDAH inhibitors reported in the literature. Furthermore, current methods of development and chemical synthetic pathways will be discussed.

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