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3D Printing in Medicinal Chemistry: Applications, Prospective and Consideration
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session Posters

Three Dimensional Printing (3D Printing) has been defined by ISO as “fabrication of objects through the deposition of a material using a print head, nozzle, or another printer technology”. 3D Printing has been trending in various disciplines from Science to Industry and Art. Being a tool of high precision and flexibility 3D Printing has been both recognized and challenged in the field of Medicinal Chemistry (MC).

The purpose of this poster is to provide an overview of the current and prospective applications and of the debatable aspects of the intersection between 3D Printing and MC.

This is a literature study. We have searched biomedical (Pubmed, Google Scholar) and tech – oriented (InTech) databases with key words (3D Printing, Medicinal Chemistry, considerations). We included studies authored in English or Greek and excluded studies declaring considerable conflict of interest.

The concept 3D Printing has appeared back in 1984. It took about ten years to print the first 3D Printed placebo tablet through the DOS method. In the next two decades 3D Printing related research has focused on tissue engineering. Nonetheless after 2010 various novelties have been developed enabling manufacturers to produce non-placebo drugs in a wealth of forms including tablets (orodispersable, floating, multicompartment etc), insulin and implants. 3D Printing can be categorized under three major variants; Powder solidification, Liquid solidification and Extrusion based systems.

It has been widely accepted that 3D Printing has the potential to revolutionize MC in terms of research and fabrication. Clinical trials can be considerably speeded up grace to the modifying properties of 3D Printing in pair with organ-in-a-chip technologies. Moreover pharmaceutical industry may be greatly altered given that 3D Printing will gradually enable single laboratories, pharmacists and potentially any trained individual to produce medication. The legibility of 3D Printing mediated clinical trials and the accessibility of 3D Printers are potential sources of controversy from a legal point of view.

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3D Printing for medicinal chemistry in space: Crafting our way to Mars

Three Dimensional Printing (3DP) - defined by ISO as “fabrication of objects through the deposition of a material using a print head, nozzle, or another printer technology” - is an emerging component of Medicinal Chemistry (MC). Space provides a challenging environment where 3DP and MC can offer great services while expanding their borders, with regard to pharmaceutical design and tissue engineering.

The purpose of this presentation is twofold. We first present an overview of existing and emerging applications of the 3DP - MC intersection in Space and we then discuss some debatable aspects from a legal point of view.

This is a literature study. We searched biomedical (Pubmed, Google Scholar) and tech – oriented (InTech) databases with key words (3D Printing, Medicinal Chemistry, Space). Moreover we searched the official websites and depositories of national or international Space Agencies.

3DP equipment has recently been installed in the International Space Station marking a revolution in Space Research. 3DP in Space has been a synonym to Additive Manufacturing (AM). Astronauts will soon be able to print medication, instead of receiving it from Earth, or even grow tissues such as skin grafts in case of injuries. Clinical trials or pharmaceutical design experiments may be also carried out in microgravity environment. Last but not least, 3DP mediated MC research in Space investigate the recycling of previously used materials or even debris in pharmaceutical design and bioengineering.

In the future 3DP is expected to play a crucial role in Space Exploration. Long term missions or even colonization of the Moon or Mars will not be possible unless the astronauts are able to produce medication, experimental kits and biomaterials among others on their own. The repercussions of such a 3DP - MC coalition are also expected to have an impact on Earth. Remote healthcare facilities, single laboratories and pharmacists and potentially any trained individual will be able to produce medication and biomaterials. Such a potential hides a considerable amount of controversy. Liability and safety issues, patent obtaining procedures and transferability of Space 3DP - MC research findings to Earth consist of emerging concepts in the field of Space Jurisdiction.

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The influence of quercetin on the interaction of haloperidol with human serum albumin
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session Posters

Protein-binding interactions are displacement reactions which have been implicated as the causative mechanisms in many drug-drug interactions. Thus, the aim of presented study was to analyse human serum albumin-binding displacement interaction between two ligands, haloperidol (HPD) and widely distributed plant flavonoid quercetin. Fluorescence analysis was used in order to investigate the effect of substances on intrinsic fluorescence of human serum albumin (HSA) and to define binding and quenching properties of ligand-albumin complexes in binary and ternary systems, respectively. Both ligands showed the ability to bind to HSA, although to a different extent. The displacement effect of one ligand from HSA by the other one has been described on the basis of the quenching curves and binding constants comparison for the binary and ternary systems.

Fluorescent spectroscopic data showed that the fluorescence quenching of HSA results from the formation of the HPD -HSA-quercetin complex. Spectroscopic analyses at different temperatures indicate that the mechanism of extinguishing the human serum albumin and the quercetin dynamic process. Process constants (Ka and Ksv) and connective sites (n), of interaction between HPD and HAS at 303 K were Ka= 4.07 × 103 mol/l, Ksv = 3.5 × 103 and n=1.02. In the presence of a quercetin, Ka = 3.75 x 102 mol/l, Ksv = 9.65 x 102 mol/l and n=0.89.

A decrease in the constants indicates that the binding of quercetin to HSA leads to a lower binding of haloperidol to human serum albumin, which can result in an increase in the free fraction of the drug in the plasma and the occurrence of adverse effects.

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The membrane/aqueous partitioning as an essential tool for pharmacokinetic profiling to support drug design
Published: 01 November 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session Posters

Advances in automated synthesis and combinatorial chemistry have led to the preparation of a vast number of potential candidates, often making the inefficacy to reach the pharmaceutical target as the rate-limiting step in drug design. To elicit its pharmacological and therapeutic effects, a compound has to be able to pass through several physiological barriers. Membrane permeability is fundamental and determines the pharmacokinetic profile of drugs (Absorption, Distribution, Metabolism and Excretion – ADME). In this regard, a thorough understanding of the structure and characteristics of physiological barriers and of the mechanisms of drug transport is necessary. Numerous significant correlations between lipophilicity and drug membrane permeation have been stablished. Additionally, anisotropic membrane-like systems, such as liposomes/water partitioning systems, are increasingly described as an alternative to octanol/water for the estimation of pharmacokinetic behaviour. In fact, lipophilicity measured in isotropic organic octanol/water system only expresses the balance of hydrophobic and polar interactions. However, lipophilicity is the net result of all intermolecular forces, and when measured in the liposome/water systems, it also considers the ionic bounds, providing a better correlation with the intermolecular forces operating in molecular pharmacology and biochemistry. Thus, different biomimetic models were prepared, and partitioning behaviour of several compounds were evaluated by derivative spectroscopy to obtain information about their affinity to several biological membranes/barriers and respective implications in in vivo pharmacokinetic behaviour.

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Synthesis of N-acetyl and N-formyl pyrazoline derivatives from vanillin and their antigenotoxic activity
Published: 01 November 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Vanillin is one of the most important natural products, used as a starting material in the new drug design procedures. Starting from vanillin, we can prepare different chalcones, which are known for their pronounced pharmacological and biological activities. For this reason some chalcone analogues have been synthesized from the corresponding vanillin derivatives. Further reaction with hydrazine in formic acid or acetic acid yielded 20 new pyrazoline compounds with N-formyl and N-acetyl groups, respectively. All new compounds were well characterized by IR, 1H and 13C NMR spectroscopy and physical data. In vitro DNA protective potential of selected compounds on hydroxyl and peroxyl radical-induced DNA damage was investigated. The results showed that the new synthesized compounds had expressed potential to prevent DNA damage.

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Development of the model of in silico design of AMPs active against Staphylococcus aureus 25923
Published: 01 November 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Emerging bacterial resistance to the existing antibiotics makes the development of new types of antibiotics an increasingly important challenge. Antimicrobial peptides (AMPs) can be considered as novel and efficient type of antibiotics that are hard to acquire resistance against. We have developed an algorithm to design peptides that are active against certain species. The prediction is based on clusterization of peptides with known biological activities by physicochemical properties. The Database of Antimicrobial Activity and Structure of Peptides (DBAASP, https://dbaasp.org) now includes Special Prediction (SP) tool, which allows to apply this algorithm to any amino acid sequence to predict whether this peptide is active against particular microbes. To verify the efficiency of the algorithm, we designed several variants of active peptides and tested them in vitro against two strains Escherichia coli ATCC 25922 and Staphylococcus aureus 25923. Prediction precision for the designed peptides against Escherichia coli ATCC was 95% and against Staphylococcus aureus was 68%. To improve prediction precision against Staphylococcus aureus we applied the linear regression analysis based on binary classification. This approach allows us to improve the prediction precision of the peptides designed for Staphylococcus aureus 25923 up to 92%.

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In vitro toxicity of α-amanitin in human kidney cells and evaluation of protective effect of polymyxin B
Published: 01 November 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Amanita phalloides is an extremely toxic and frequently lethal mushroom, especially due to its high levels of powerful toxins such as α-amanitin, a well-established RNA polymerase II inhibitor. α-Amanitin intoxications have been associated with acute kidney injury and renal failure, besides its well-known hepatotoxic effects. Currently, no effective antidote against α-amanitin toxicity exists. Recent in vivo studies have shown that polymyxin B (PolB) decreases α-amanitin toxicity and that the associated renal damage is largely decreased by that antibiotic. Thus, this work aimed to characterize α-amanitin cytotoxicity in HK-2 cells and evaluate PolB’s putative antidotal effectiveness in this in vitro system.

HK-2 cells were exposed to α-amanitin (0.01-10 µM) for 24- or 48h. Additionally, 1 and 2h incubations with α-amanitin (1-10 µM) followed by a 48-h α-amanitin-free period were also performed to assess the effect of early entrance of the toxin to the cells. Cytotoxicity was evaluated by the 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction and neutral red (NR) uptake assays. To assess PolB putative protective effects, two paradigms were used: (i) 30 min pre-incubation with PolB followed by 48h incubation with α-amanitin (0.5 and 1 µM) or (ii) PolB co-incubation with α-amanitin (5 and10 µM) for 2h followed by a 48h drug/toxin-free period.

α-Amanitin toxicity was observed at 24h at concentrations above 1 µM in the MTT reduction assay. At 48h, α-amanitin 0.5 µM also caused significant cytotoxicity showing that the toxicity observed after the toxin was time- and concentration-dependent. Nonetheless, α-amanitin caused lower toxicity after shorter incubation periods (1 or 2h), possibly indicating a slow α-amanitin uptake by HK-2 cells. In fact, a 5 times higher concentration was needed to obtain a similar effect to the one obtained under a 48h continuous incubation period. In addition, PolB did not confer protection any against α-amanitin cytotoxicity in either the long exposure or the low exposure α-amanitin approaches tested.

To sum up, α-amanitin led to cytotoxicity effects on kidney cells at clinical relevant concentrations. The effectiveness of a previously described antidote, PolB, was not verified in vitro, which highlights the importance of further investigation on this antidotal strategy and its mechanisms.

This work was supported by FEDER funds through the Operational Programme for Competitiveness Factors – COMPETE and by national funds by the FCT within the project PTDC-DTP-FTO-4973-2014 – POCI-01-0145-FEDER 016545. VMC acknowledges Fundação da Ciência e Tecnologia (FCT) for her grant (SFRH/BPD/110001/2015), that was funded by national funds through FCT – Fundação para a Ciência e a Tecnologia, I.P., under the Norma Transitória – DL57/2016/CP1334/CT0006.

  • Open access
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Synthesis, biological evaluation, and docking study of indole aryl sulfonamides as aromatase inhibitors
Published: 01 November 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Breast cancer is the most common type of cancer in women, and two-thirds of post-menopausal breast cancer are estrogen-dependent.[1] The estrogen production is regulated by CYP19A1 (aromatase) responsible for the conversion of androgens (C19) to estrogens (C18) by demethylation and aromatization of the steroidal A-ring.[2] Two types of endocrine therapies are available: selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). AIs suppress the aromatase activity interacting with the substrate-binding site of the aromatase, and, based on their structure, were usually classified in steroidal (exemestane) and non-steroidal (letrozole and anastrozole). The third generation of AIs is the most selective and with less secondary effects compared to the previous generations.[3]

In order to identify new aromatase enzyme inhibitors,[4] a library of thirty aryl sulfonamide derivatives containing an indole nucleus, have been synthesized. All compounds were tested using an enzymatic assay to identify compounds with a good inhibitor activity of CYP19A1, compared to letrozole. The IC50 of best ones, cell-viability and cytotoxicity on MCF7 human breast cancer cells were further evaluated.

Finally, the docking study showed that the best active compounds efficiently bound in the active site of the aromatase; high values of HBD and low levels of HBA are the principal requirement evidenced by the QSAR model.

  1. J. Chan, K. Petrossian, S. Chen, J. Steroid. Biochem. Mol. Biol. 161 (2016) 73–83.
  2. G. Waks, E.P. Winer, JAMA 321 (2019) 288-300.
  3. A. Sychev, G.M. Ashraf, A.A. Svistunov, et al., Drug Des. Devel. Ther. 12 (2018) 1147–1156.
  4. Di Matteo, A. Ammazzalorso, F. Andreoli, I. Caffa, B. De Filippis, M. Fantacuzzi, L. Giampietro, C. Maccallini, A. Nencioni, M.D. Parenti, D. Soncini, A. Del Rio, R. Amoroso, Bioorg. Med. Chem. Letters 26 (2016) 3192–3194.
  • Open access
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New heterocyclic polyphenols with skin anti-aging potential
Published: 01 November 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Xanthones or dibenzo-gamma-pyrones are heterocyclic polyphenolic compounds that can be found in microorganisms, fungi, lichens, and some higher plants. Structure-activity relationship studies emerged from a library of natural and synthetic polyoxygenated have suggested that xanthones with vicinal diol groups have promising antioxidant activity. Antioxidants have long been used in the cosmetic industry to prevent or minimize skin aging which is mediated by oxidative stress, making the search for new antioxidant agents highly desirable in this field.

Considering the structure-activity relationship studies, it was hypothesized that trioxygenated xanthones could be promising antioxidants with potential as skin anti-aging ingredients. Hence, the synthesis of trioxygenated xanthones was attempted by the Smiles rearrangement pathway and also via acyl radical cyclization. The Smiles rearrangement pathway failed to yield the ester intermediate that was essential in this approach and was therefore abandoned. In the acyl radical cyclization method it was possible to obtain the 1,4-dihydroxy-3-methoxy-9H-xanthen-9-one.

The antioxidant activity of this new xanthone as well as of four other polyoxygenated xanthones was evaluated by the DPPH assay, and two new derivatives showed IC50 values in the same range as the ascorbic acid. Almost all of the compounds were excellent tyrosinase inhibitors, more active than control inhibitor kojic acid. Concerning the other skin-degrading enzymes, the compounds tested were weak to moderate collagenase inhibitors, and showed no activity against elastase. The stability in presence of metal ions (FeCl3 and CuCl2) and dependence of the pH of their aqueous solutions was also studied, as well as their solubility in water and glycerol. Finally, the phototoxicity of the most promising xanthone was evaluated in a human keratinocyte cell line and no phototoxicity was observed in the concentration range tested, which is an important requirement for topical ingredients.

Acknowledgements:

This work was developed under the Strategic Funding UID/Multi/04423/2019 and Project No. POCI-01-0145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds, QREN,FEDER, COMPETE, by funding the cE3c centre (Ref. UID/BIA/00329/2019) and Azores DRCT for funding ABG. This work was also supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019.

  • Open access
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In silico studies towards new BACE1 inhibitors
Published: 01 November 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Beta-site APP-cleaving enzyme (BACE)1 is a type-1 membrane-anchored aspartyl protease playing an essential role in the release of Aβ peptides and Alzheimer’s Disease (AD) progression. Hence, the development of potent BACE1 inhibitors represents a logical approach for AD therapy development and it have been widely explored by the pharmaceutical industry worldwide.1

Herein, we report the design of a virtual library of 300 compounds for in silico BACE1 inhibition assessment. These compounds were designed based on the hybridization of several hydrophobic fragments with aliphatic and aromatic amines, motifs identified in the literature by their ability to establish essential interactions with the amino acids present in the catalytic pocket of BACE1.

Affinity for BACE1 was measure through the binding energy estimation of the ligand-protein complex. Additionally, the compounds designed were assessed through the Lipinsky’s rule of 5 and additional attributes crucial for central nervous system (CNS) drugs were also considered.2

The most promising compounds will be synthesized through suitable and green N-alkylation techniques and their biological activity will be assessed in in vitro studies.

Acknowledgements: We thank the UID/Multi/04423/2019 through national funds provided by FCT-Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the program PT2020. This research was developed under Project No. POCI-01-0145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds.

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