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Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective

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

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 62283

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Special Issue Editors

Dr. Marta Barniol-Xicota

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Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven - University of Leuven. Herestraat 49, box 802, 3000 Leuven, Belgium
Interests: RNA viruses; proteases; membrane proteins; lipid-protein interactions
Special Issues, Collections and Topics in MDPI journals

Dr. Marta Ruiz Santa Quiteria Saavedra

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Organic Molecular Materials, Department of Organic Chemistry, Universidad Complutense de Madrid, Avda/ Complutense s/n, 28040 Madrid, Spain
Interests: medicinal chemistry; protein–protein interactions; leishmaniasis; peptide synthesis; drug discovery; fullerenes; HIV

Prof. Dr. Diego Muñoz-Torrero

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Laboratory of Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Avenue Joan XXIII, 27-31, E-08028 Barcelona, Spain
Interests: multitarget anti-Alzheimer agents; hybrid compounds; cholinesterase inhibitors; amyloid anti-aggregating compounds; BACE-1 inhibitors; antiprotozoan compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

With the main aim of sharing the latest medicinal chemistry research results, giving voice to young researchers, the young division of the Spanish Medicinal Chemistry Society (SEQT) initiated, four years ago, a series of conferences, where post-doc, pre-doc, Master’s degree, and Bachelor’s degree students were given the opportunity to present and discuss their research results in a top-level scientific environment. Since the first edition in 2014, the SEQT young division symposium (SJI-SEQT) has been gaining attention, as well as participation, to become, in the upcoming fifth edition, a hallmark for young medicinal chemistry researchers in Spain, but also all over the globe. The V Conference of the SEQT young division (SJI-SEQT-2018) will be held in Madrid on June 22, 2018, at the Spanish National Research Council (CSIC) headquarters, with registration being open, not only for junior, but also senior, researchers. All in all, SJI-SEQT-2018 will bring together senior, renowned scientists and young, highly motivated researchers in a one-day dynamic event that fosters networking, new collaborations, and excellent science (more details can be found at http://www.seqt.org/es/eventos/symposium-jovenes/).

As a further step to increase the involvement of young medicinal chemists in the communication of their research results, we have set up this Special Issue of Molecules, where we want to collect original research articles, short communications and reviews on any topic related to medicinal chemistry, in which young researchers play a prominent role (first author and/or corresponding author, shared or not with a senior author). This Special Issue is open to contributions beyond the SJI-SEQT-2018. All submissions to this Special Issue will benefit from a 20% discount over the publication fee.

For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on the website.

Dr. Marta Barniol-Xicota
Dr. Marta Ruiz Santa Quiteria Saavedra
Prof. Dr. Diego Muñoz-Torrero
Guest Editors

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 submissions that pass pre-check are 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 semimonthly 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 2700 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

drug design/delivery
organic synthesis
peptide chemistry
chemical biology
computational chemistry
pharmacology and ADME
molecular biology
biochemistry
new therapeutic targets
structure, function, and interactions of proteins
protein-protein interactions
natural products
structural analysis
nucleic acids chemistry
new bioactive scaffolds
nanomaterials and biomaterials
crystallography

Published Papers (9 papers)

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Research

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14 pages, 4533 KiB

Open AccessArticle

Microparticles of Lamivudine—Poly-ε-Caprolactone Conjugate for Drug Delivery via Internalization by Macrophages

by Tomasz Urbaniak, Daniela Machová, Olga Janoušková and Witold Musiał

Molecules 2019, 24(4), 723; https://doi.org/10.3390/molecules24040723 - 17 Feb 2019

Cited by 7 | Viewed by 3442

Abstract

The past decade may be considered as revolutionary in the research field focused on the physiological function of macrophages. Unknown subtypes of these cells involved in pathological mechanisms were described recently, and they are considered as potential drug delivery targets. The innate ability to internalize foreign bodies exhibited by macrophages can be employed as a therapeutic strategy. The efficiency of this uptake depends on the size, shape and surface physiochemical properties of the phagocyted objects. Here, we propose a method of preparation and preliminary evaluation of drug-polymer conjugate-based microspheres for macrophage targeted drug delivery. The aim of the study was to identify crucial uptake-enhancing parameters for solid, surface modified particles. A model drug molecule—lamivudine—was conjugated with poly-ε-caprolactone via ring opening polymerization. The conjugate was utilized in a solvent evaporation method technique to form solid particles. Interactions between particles and a model rat alveolar cell line were evaluated by flow cytometry. The polymerization product was characterized by a molecular weight of 3.8 kDa. The surface of the obtained solid drug-loaded cores of a hydrodynamic diameter equal to 2.4 µm was modified with biocompatible polyelectrolytes via a layer-by-layer assembly method. Differences in the internalization efficiency of four particle batches by the model RAW 264.7 cell line suggest that particle diameter and surface hydrophobicity are the most influential parameters in terms of phagocytic uptake. Full article

(This article belongs to the Special Issue Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective)

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27 pages, 7710 KiB

Open AccessArticle

5-Arylideneimidazolones with Amine at Position 3 as Potential Antibiotic Adjuvants against Multidrug Resistant Bacteria

by Aneta Kaczor, Karolina Witek, Sabina Podlewska, Joanna Czekajewska, Annamaria Lubelska, Ewa Żesławska, Wojciech Nitek, Gniewomir Latacz, Sandrine Alibert, Jean-Marie Pagès, Elżbieta Karczewska, Katarzyna Kieć-Kononowicz and Jadwiga Handzlik

Molecules 2019, 24(3), 438; https://doi.org/10.3390/molecules24030438 - 26 Jan 2019

Cited by 11 | Viewed by 4199

Abstract

Searching for new chemosensitizers of bacterial multidrug resistance (MDR), chemical modifications of (Z)-5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one (6) were performed. New compounds (7–17), with fused aromatic rings at position 5, were designed and synthesized. Crystallographic X-ray analysis proved that the final compounds (7–17) were substituted with tertiary amine-propyl moiety at position 3 and primary amine group at 2 due to intramolecular Dimroth rearrangement. New compounds were evaluated on their antibiotic adjuvant properties in either Gram-positive or Gram-negative bacteria. Efflux pump inhibitor (EPI) properties towards the AcrAB-TolC pump in Enterobacter aerogenes (EA289) were investigated in the real-time efflux (RTE) assay. Docking and molecular dynamics were applied to estimate an interaction of compounds 6–17 with penicillin binding protein (PBP2a). In vitro ADME-Tox properties were evaluated for compound 9. Most of the tested compounds reduced significantly (4-32-fold) oxacillin MIC in highly resistant MRSA HEMSA 5 strain. The anthracene-morpholine derivative (16) was the most potent (32-fold reduction). The tested compounds displayed significant EPI properties during RTE assay (37–97%). The naphthyl-methylpiperazine derivative 9 showed the most potent “dual action” of both oxacillin adjuvant (MRSA) and EPI (E. aerogenes). Molecular modeling results suggested the allosteric mechanism of action of the imidazolones, which improved binding of oxacillin in the PBP2a active site in MRSA. Full article

(This article belongs to the Special Issue Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective)

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15 pages, 3649 KiB

Open AccessArticle

A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies

by Anca-Maria Borcea, Gabriel Marc, Ioana Ionuț, Dan C. Vodnar, Laurian Vlase, Felicia Gligor, Andreea Pricopie, Adrian Pîrnău, Brîndușa Tiperciuc and Ovidiu Oniga

Molecules 2019, 24(1), 184; https://doi.org/10.3390/molecules24010184 - 06 Jan 2019

Cited by 7 | Viewed by 3580

Abstract

In the context of an increased incidence of invasive fungal diseases, there is an imperative need of new antifungal drugs with improved activity and safety profiles. A novel series of acylhydrazones bearing a 1,4-phenylene-bisthiazole scaffold was designed based on an analysis of structures known to possess anti-Candida activity obtained from a literature review. Nine final compounds were synthesized and evaluated in vitro for their inhibitory activity against various strains of Candida spp. The anti-Candida activity assay revealed that some of the new compounds are as active as fluconazole against most of the tested strains. A molecular docking study was conducted in order to evaluate the binding poses towards lanosterol 14α-demethylase. An in silico ADMET analysis showed that the compounds possess drug-like properties and represent a biologically active framework that should be further optimized as potential hits. Full article

(This article belongs to the Special Issue Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective)

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17 pages, 1902 KiB

Open AccessArticle

Pentafluorosulfanyl-containing Triclocarban Analogs with Potent Antimicrobial Activity

by Eugènia Pujol, Núria Blanco-Cabra, Esther Julián, Rosana Leiva, Eduard Torrents and Santiago Vázquez

Molecules 2018, 23(11), 2853; https://doi.org/10.3390/molecules23112853 - 02 Nov 2018

Cited by 24 | Viewed by 7694

Abstract

Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel N,N′-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds. Full article

(This article belongs to the Special Issue Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective)

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14 pages, 3492 KiB

Open AccessArticle

TrypanocidalActivity of Natural Sesquiterpenoids Involves Mitochondrial Dysfunction, ROS Production and Autophagic Phenotype in Trypanosoma cruzi

by Ana Cristina Souza Bombaça, Daniela Von Dossow, Juliana Magalhães Chaves Barbosa, Cristian Paz, Viviana Burgos and Rubem Figueiredo Sadok Menna-Barreto

Molecules 2018, 23(11), 2800; https://doi.org/10.3390/molecules23112800 - 28 Oct 2018

Cited by 21 | Viewed by 3672

Abstract

Chagas disease is a neglected tropical disease that is caused by the protozoan Trypanosoma cruzi and represents a serious health problem, especially in Latin America. The clinical treatment of Chagas disease is based on two nitroderivatives that present severe side effects and important limitations. In folk medicine, natural products, including sesquiterpenoids, have been employed for the treatment of different parasitic diseases. In this study, the trypanocidal activity of compounds isolated from the Chilean plants Drimys winteri, Podanthus mitiqui and Maytenus boaria on three T. cruzi evolutive forms (epimastigote, trypomastigote and amastigote) was evaluated. Total extracts and seven isolated sesquiterpenoids were assayed on trypomastigotes and epimastigotes. Polygodial (Pgd) from D. winteri, total extract from P. mitiqui (PmTE) and the germacrane erioflorin (Efr) from P. mitiqui were the most bioactive substances. Pgd, Efr and PmTE also presented strong effects on intracellular amastigotes and low host toxicity. Many ultrastructural effects of these substances, including reservosome disruption, cytosolic vacuolization, autophagic phenotype and mitochondrial swelling (in the case of Pgd), were observed. Flow cytometric analysis demonstrated a reduction in mitochondrial membrane potential in treated epimastigotes and an increase in ROS production and high plasma membrane permeability after treatment with Pgd. The promising trypanocidal activity of these natural sesquiterpenoids may be a good starting point for the development of alternative treatmentsforChagas disease. Full article

(This article belongs to the Special Issue Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective)

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26 pages, 6210 KiB

Open AccessArticle

Computer-Aided Studies for Novel Arylhydantoin 1,3,5-Triazine Derivatives as 5-HT₆ Serotonin Receptor Ligands with Antidepressive-Like, Anxiolytic and Antiobesity Action In Vivo

by Rafał Kurczab, Wesam Ali, Dorota Łażewska, Magdalena Kotańska, Magdalena Jastrzębska-Więsek, Grzegorz Satała, Małgorzata Więcek, Annamaria Lubelska, Gniewomir Latacz, Anna Partyka, Małgorzata Starek, Monika Dąbrowska, Anna Wesołowska, Claus Jacob, Katarzyna Kieć-Kononowicz and Jadwiga Handzlik

Molecules 2018, 23(10), 2529; https://doi.org/10.3390/molecules23102529 - 03 Oct 2018

Cited by 19 | Viewed by 3865

Abstract

This study focuses on the design, synthesis, biological evaluation, and computer-aided structure-activity relationship (SAR) analysis for a novel group of aromatic triazine-methylpiperazines, with an hydantoin spacer between 1,3,5-traizine and the aromatic fragment. New compounds were synthesized and their affinities for serotonin 5-HT₆, 5-HT_1A, 5-HT_2A, 5-HT₇, and dopamine D₂ receptors were evaluated. The induced-fit docking (IFD) procedure was performed to explore the 5-HT₆ receptor conformation space employing two lead structures. It resulted in a consistent binding mode with the activity data. For the most active compounds found in each modification line, anti-obesity and anti-depressive-like activity in vivo, as well as “druglikeness” in vitro, were examined. Two 2-naphthyl compounds (18 and 26) were identified as the most active 5-HT₆R agents within each lead modification line, respectively. The 5-(2-naphthyl)hydantoin derivative 26, the most active one in the series (5-HT₆R: K_i = 87 nM), displayed also significant selectivity towards competitive G-protein coupled receptors (6–197-fold). Docking studies indicated that the hydantoin ring is stabilized by hydrogen bonding, but due to its different orientation, the hydrogen bonds form with S5.44 and N6.55 or Q6.58 for 18 and 26, respectively. Compound 26 exerted anxiolytic-like and antidepressant-like activities. Importantly, it demonstrated anti-obesity properties in animals fed palatable feed, and did not show toxic effects in vitro. Full article

(This article belongs to the Special Issue Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective)

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23 pages, 3969 KiB

Open AccessArticle

New N-(oxazolylmethyl)-thiazolidinedione Active against Candida albicans Biofilm: Potential Als Proteins Inhibitors

by Gabriel Marc, Cătălin Araniciu, Smaranda Dafina Oniga, Laurian Vlase, Adrian Pîrnău, Mihaela Duma, Luminița Măruțescu, Mariana Carmen Chifiriuc and Ovidiu Oniga

Molecules 2018, 23(10), 2522; https://doi.org/10.3390/molecules23102522 - 02 Oct 2018

Cited by 20 | Viewed by 23250

Abstract

C. albicans is the most frequently occurring fungal pathogen, and is becoming an increasing public health problem, especially in the context of increased microbial resistance. This opportunistic pathogen is characterized by a versatility explained mainly by its ability to form complex biofilm structures that lead to enhanced virulence and antibiotic resistance. In this context, a review of the known C. albicans biofilm formation inhibitors were performed and a new N-(oxazolylmethyl)-thiazolidinedione scaffold was constructed. 16 new compounds were synthesized and characterized in order to confirm their proposed structures. A general antimicrobial screening against Gram-positive and Gram-negative bacteria, as well as fungi, was performed and revealed that the compounds do not have direct antimicrobial activity. The anti-biofilm activity evaluation confirmed the compounds act as selective inhibitors of C. albicans biofilm formation. In an effort to substantiate this biologic profile, we used in silico investigations which suggest that the compounds could act by binding, and thus obstructing the functions of, the C. albicans Als surface proteins, especially Als1, Als3, Als5 and Als6. Considering the well documented role of Als1 and Als3 in biofilm formation, our new class of compounds that target these proteins could represent a new approach in C. albicans infection prevention and management. Full article

(This article belongs to the Special Issue Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective)

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14 pages, 1893 KiB

Open AccessArticle

A Novel Class of Tyrosyl-DNA Phosphodiesterase 1 Inhibitors That Contains the Octahydro-2H-chromen-4-ol Scaffold

by Nikolai S. Li-Zhulanov, Alexandra L. Zakharenko, Arina A. Chepanova, Jinal Patel, Ayesha Zafar, Konstantin P. Volcho, Nariman F. Salakhutdinov, Jóhannes Reynisson, Ivanhoe K. H. Leung and Olga I. Lavrik

Molecules 2018, 23(10), 2468; https://doi.org/10.3390/molecules23102468 - 26 Sep 2018

Cited by 27 | Viewed by 4207

Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that mends topoisomerase 1-mediated DNA damage. Tdp1 is a current inhibition target for the development of improved anticancer treatments, as its inhibition may enhance the therapeutic effect of topoisomerase 1 poisons. Here, we report a study on the development of a novel class of Tdp1 inhibitors that is based on the octahydro-2H-chromene scaffold. Inhibition and binding assays revealed that these compounds are potent inhibitors of Tdp1, with IC₅₀ and K_D values in the low micromolar concentration range. Molecular modelling predicted plausible conformations of the active ligands, blocking access to the enzymatic machinery of Tdp1. Our results thus help establish a structural-activity relationship for octahydro-2H-chromene-based Tdp1 inhibitors, which will be useful for future Tdp1 inhibitor development work. Full article

(This article belongs to the Special Issue Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective)

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Review

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24 pages, 653 KiB

Open AccessReview

Selenium, Selenoproteins, and Female Reproduction: A Review

by Izhar Hyder Qazi, Christiana Angel, Haoxuan Yang, Bo Pan, Evangelos Zoidis, Chang-Jun Zeng, Hongbing Han and Guang-Bin Zhou

Molecules 2018, 23(12), 3053; https://doi.org/10.3390/molecules23123053 - 22 Nov 2018

Cited by 79 | Viewed by 7064

Abstract

Selenium (Se) is an essential micronutrient that has several important functions in animal and human health. The biological functions of Se are carried out by selenoproteins (encoded by twenty-five genes in human and twenty-four in mice), which are reportedly present in all three domains of life. As a component of selenoproteins, Se has structural and enzymatic functions; in the latter context it is best recognized for its catalytic and antioxidant activities. In this review, we highlight the biological functions of Se and selenoproteins followed by an elaborated review of the relationship between Se and female reproductive function. Data pertaining to Se status and female fertility and reproduction are sparse, with most such studies focusing on the role of Se in pregnancy. Only recently has some light been shed on its potential role in ovarian physiology. The exact underlying molecular and biochemical mechanisms through which Se or selenoproteins modulate female reproduction are largely unknown; their role in human pregnancy and related complications is not yet sufficiently understood. Properly powered, randomized, controlled trials (intervention vs. control) in populations of relatively low Se status will be essential to clarify their role. In the meantime, studies elucidating the potential effect of Se supplementation and selenoproteins (i.e., GPX1, SELENOP, and SELENOS) in ovarian function and overall female reproductive efficiency would be of great value. Full article

(This article belongs to the Special Issue Present and Future of Medicinal Chemistry Research: A Young Researchers’ Perspective)

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