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Antistaphylococcal activity of new salicylamide analogues
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Antimicrobial resistance is still a serious global threat. Staphylococcus aureus is a common cause of severe infections in health facilities and the community. People with methicillin-resistant S. aureus (MRSA) are estimated to be 64% more likely to die than people with a non-resistant form of the infection [1]. For that reason, the research and development of new active compounds is really needed.

Salicylamides are anti-infectious agents with a wide range of pharmacological effects, such as antiviral, antibacterial, antifungal and anthelminthic [2]. Thus, derivatives of this group are very promising compounds.

A series of newly synthesized complex salicylamide derivatives was tested for their antimicrobial effect against methicillin-resistant Staphylococcus aureus (MRSA). Staphylococcus aureus ATCC 29213 as a control and three isolates of MRSA were used. The activity was assessed by the evaluation of minimum inhibitory concentration. Using the microdilution method with subcultivation of aliquots, the minimum bactericidal concentration was determined too. Ciprofloxacin and ampicillin were used as standard antibacterial drugs. Four most promising compounds from the series were chosen and are demonstrated in this contribution.

This study was supported by the institutional support from Ministry of Education, Youth and Sports of the Czech Republic (LO1305).

References:

  1. Antimicrobial resistance. World Health Organization Available at: https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance (Oct. 12, 2019).
  2. Pospíšilová, Š.; Michnová, H.; Kauerová, T.; Pauk, K.; Kollár, P.; Vinšová, J.; Imramovský, K.; Čížek, A.; Jampílek, J. In vitro activity of salicylamide derivatives against vancomycin-resistant enterococci. Med. Chem. Lett. 2018, 28, 2184-2188.
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Screening of antibacterial activity of fucoxanthin
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session Posters

Fucoxanthin is an orange-coloured pigment present in brown algae (Phaeophyceae) and diatoms (Bacillariophyceae). This non-provitamin A carotenoid shows various biological activities, including antioxidant, anti-inflammatory, anti-obesity, anti-diabetic, and anticancer properties. Its antimicrobial effect is not sufficiently confirmed. Therefore, the purpose of the present work was to determine the activity of fucoxanthin against clinical strains of 20 species of bacteria.
In the study, there were tested six Gram-positive bacteria (Enterococcus faecalis, Staphylococcus aureus, S. epidermidis, Streptococcus agalactiae, S. pneumoniae, S. pyogenes), and seven Gram-negative ones (Acinetobacter lwoffii, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens). Additionally, we investigated seven strict anaerobic pathogens (Actinomyces israelii, Atopobium parvulum, Mitsuokella multacida, Peptococcus niger, Porphyromonas gingivalis, Propionibacterium acnes, Veilonella parvula). The microbial growth inhibitory potential of fucoxanthin was determined according to recommendations of the Clinical and Laboratory Standards Institute (CLSI) and as described in our previous publication [1,2] using the agar disc-diffusion and the micro-dilution methods.
The obtained results indicated the biological activity of fucoxanthin against all tested strains of aerobic bacteria. The mean diameter of zone of inhibition (ZOI) ranged from 7.2 (P. mirabilis) to 12.2 mm (S. agalactiae), while the minimal inhibitory concentration (MIC) varied between 62.5 (S. agalactiae) and 500 μg/mL (P. mirabilis, P. aeruginosa, S. marcescens). Statistically significant stronger effect was observed in the case of Gram-positive (mean of ZOIs = 10.5 mm) than Gram-negative bacteria (8.3 mm). On the other hand, fucoxanthin was not active against strict anaerobic bacteria with the ZOIs of 6.0 mm and the MICs above 1000 μg/mL [3].
In conclusion, our study confirmed the antimicrobial activity of fucoxanthin. It seems that this substance can be a good antibacterial agent on some Gram-positive pathogens such as S. agalactiae, S. epidermidis, S. aureus, and weaker against Gram-negative bacteria.

[1] Karpiński T.M., Adamczak A. Antibacterial activity of ethanolic extracts of some moss species. Herba Pol. 2017; 63: 11-17.
[2] Karpiński T.M. Efficacy of octenidine against Pseudomonas aeruginosa strains. Eur J Biol Res. 2019; 9: 135-140.
[3] Karpiński T.M., Adamczak A. Fucoxanthin - an antibacterial carotenoid. Antioxidants 2019; 8(8): 239.

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Anticancer activity of the seaweed compound fucoxanthin in breast cancer cell lines cultured as 2D and 3D models
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session Posters

Breast cancer (BC) accounts for the most cancer-related deaths amongst women worldwide, implying an urgent need of finding new drugs more effective than those currently in use [1, 2]. Fucoxanthin (Fx) is a marine carotenoid derived from brown seaweed that has been showing antitumor effects on different cancer cell lines, mainly in 2D models [3]. However, 3D culture models have a better predictive capacity of in vivo cellular responses against cytotoxic compounds [4]. This study aimed to evaluate the potential anticancer effects of Fx versus Doxorubicin (Dox) (a conventional anticancer drug) in a panel of three BC cell lines, representative of different molecular subtypes (MCF-7, SKBR3 and MDA-MB-231), and in a non-tumoral BC cell line (MCF-12A), cultured under 2D and 3D conditions. Effects on cell viability, death, proliferation and DNA damage were targeted. Results from the 2D cultures showed that Dox and Fx caused cytotoxicity on all the cell lines. Cytotoxic activity of Dox involved mechanisms of cell death induction (in MCF-12A cells) and genotoxicity (in MDA-MB-231 cells), contrarily to Fx, where neither cell death nor genotoxic mechanisms were detected. Under 3D conditions, cells were less responsive to Dox and Fx, compared to 2D cultures. Antiproliferative effects were solely registered in SKBR3 cells exposed to Dox and Fx, and in MCF-12A cells exposed to Dox. The in vitro data revealed that the Fx may be a potential anticancer agent against BC cells, with differential effects according to the cell subtype. The data warrants further studies on the underlying anticancer mechanisms.

Acknowledgments: We thank the fundamental financial support of the ICBAS of the UPorto, namely via its Laboratory of Histology and Embryology and Master Program in Environmental Contamination and Toxicology. This research was also partially supported by the Strategic Funding UID/Multi/04423/2019 through national funds provided by FCT and ERDF, in the framework of the program PT2020.

[1] DeSantis, C.E., F. Bray, J. Ferlay, J. Lortet-Tieulent, B.O. Anderson, and A. Jemal, International Variation in Female Breast Cancer Incidence and Mortality Rates. Cancer Epidemiol Biomarkers Prev, 2015. 24(10): p. 1495-506.

[2] Pádua, D., E. Rocha, D. Gargiulo, and A.A. Ramos, Bioactive compounds from brown seaweeds: Phloroglucinol, fucoxanthin and fucoidan as promising therapeutic agents against breast cancer. Phytochem Lett, 2015. 14: p. 91-98.

[3] Kumar, S.R., M. Hosokawa, and K. Miyashita, Fucoxanthin: a marine carotenoid exerting anti-cancer effects by affecting multiple mechanisms. Mar Drugs, 2013. 11(12): p. 5130-47.

[4] Santo, V.E., S.P. Rebelo, M.F. Estrada, P.M. Alves, E. Boghaert, and C. Brito, Drug screening in 3D in vitro tumor models: overcoming current pitfalls of efficacy read-outs. Biotechnol J, 2017. 12(1): p. 1600505.

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Food for celiacs with black quinoa (Chenopodium petiolare kunth)
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session Posters

The aim of this work was the evaluation of the possibility of preparing gluten-free food (T.A.C.C.) with regional raw materials from southern Patagonia Argentina. It was decided to make cereal bars under the form of rectangle-shaped molded dough composed of cereals of different types and other binder ingredients. In this test, the bars were made with black seeds of wild quinoa (Chenopodium petiolare kunth) that are born naturally in low areas, in Gobernador Gregores, Santa Cruz, Argentina (48 ° 78 'S - 70 ° 23' W). It is a variety of small grain, bitter taste and high content of phenolic compounds. It was also used in the formulation of white quinoa bars (Chenopodium album). Quinoa provides 16 to 25 g of proteins of high biological value and 3% of lipids, highlighting the presence of omega 6 and omega 3 acids. For the preparation of the bars in a beaker, the sugar and honey were mixed and heated to a boil. Then the beaker was removed from the fire and the fatty matter (soybean oil) and ground quinoa were added in fine granulometry, gentle agitation was always maintained. This still hot mixture was molded and allowed to cool to room temperature. The determinations in the bars were: proteins 7.4%, carbohydrates 60.8%, lipids 6.8% humidity 25%. Each 100g quinoa bar provides 368.1 calories. It was possible to develop a product potentially suitable for coeliacs, rich in nutrients, using natural raw material from the Gobernador Gregores area, Santa Cruz, Argentina.

  • Open access
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The effect of the caffeine on the binding of haloperidol to human serum albumin
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session Posters

Caffeine belongs to a group of purine alkaloids. Complexes that albumin build with drug molecules represent a depot from which the drug is gradually released. Haloperidol (HPD) belongs to the group of atypical antipsyhotics and it is binding to human serum albumin (HSA) more than 90 %. The aim of this study was to determine the effect of caffeine on the binding of haloperidol to HSA. Reviewing the results will determine whether and how the caffeine affects the binding of haloperidol to HSA. Binding of haloperidol and caffeine was investigated by fluorescence spectroscopy. All fluorescent spectra were recorded in the range of 300 to 550 nm at a wavelength of excitation of 295 nm on two temperatures (303 and 310 K). Fluorescence spectroscopic data showed that the fluorescence quenching of HSA resulted from the formation of the HPD-HSA-Caffeine complex. Spectroscopic analyses on different therapeutic agents indicate that the mechanics of quenching human serum albumin with haloperidol and caffeine are a static process. Estimated constants (Ksv, Ka) and binding sites (n), between haloperidol, caffeine and human serum albumin, are Ksv 2.71 × 103 l/mol, Ka = 9.27 × 103 l/mol at a temperature of 303K, and Ksv 1.83 × 103 l/mol, Ka = 9.33 × 103 l/mol at a temperature of 310K. The number of operating points is 1. Caffeine affects the binding of haloperidol to HSA. It leads to a greater stabilization of the HSA-HPD complex. These results indicate the possible impact and significance of the interaction of medicinal products.

  • Open access
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GalNAc mimetics: from synthesis to potential inhibitors in Alzheimer’s Disease
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

N-acetylgalactosamine(GalNAc) belongs to the group of 2-amino-2-deoxysugars which are found in a wide range of biological structures playing a role in in cell-cell interaction and receptor induced cell signaling, among other biological processes in health and disease.

Alzheimer’s disease (AD) is a protein misfolding pathology, causing dementia in over 40 million people worldwide. Cellular prion protein (PrP) has a high-affinity binding with amyloid β (Aβ) oligomers, the most toxic species in Alzheimer’s pathology1. It has been demonstrated that O-glycosylated GalNAc, attached to Ser/Thr side chain of PrP via an α-glycosidic linkage, promotes the inhibition of amyloidogenesis in AD2. In this context, we have synthesized new GalNAc mimetics, including phenyl selenogalactosides with additional contacts in the GalNAc core structure, to improve the interactions with the prion peptide and to investigate the binding affinity with Aβ1-42. The study of the intermolecular interactions of the new chemical structures and Aβ1-42 oligomers was investigated by NMR methods, namely saturation transfer difference NMR (STD-NMR) and 19Fluorine NMR (F-NMR) protocols. Different methods, such as rapid equilibrium diffusion (RED) were applied for the evaluation of interactions. At the same time, competition and metabolic experiments were carried out. In this communication, synthetic approaches to the GalNAc mimetics will be presented and interaction results regarding C2 substitution and anomeric heteroatoms, such as O, S and Se with Aβ1-42 oligomers will be discussed.

References:

1. Blázquez-Sánchez, M.T., Matos, A.M., Rauter, A.P., Exploring Anti-Prion Glyco-Based and Aromatic Scaffolds: A Chemical Strategy for the Quality of Life, Molecules, (2017), 22-26;

2. Lin, C., Chen, E., Lee, L., Hsu, R., Luh, F., Yand, L., Chou, C., Huang, L., Lin, C., Chen, R., Comparison of the anti-amyloidogenic effect of O-mannosylation, O-galactosylation and O-GalNAc glycosylation, Carbohydr. Res.,(2014), 46-53.

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Disclosing the effect of doxorubicin and mitoxantrone on cardiac mitochondrial proteome: an in vivo approach using a murine model
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

In the last decades, the number of cancer survivors has increased considerably due to the huge efficacy of anticancer therapies. Nevertheless, the side effects in these patients are still a major concern, namely in the cardiac tissue[1,2]. The mechanisms underlying the cardiotoxicity of doxorubicin (DOX) and mitoxantrone (MTX) are not completely understood, although they seem to disturb the mitochondrial dynamics and lead to oxidative stress[3]. Our goal was to study the effects of DOX and MTX in the molecular mechanisms harbored in the heart of adult male CD-1 mice (3 months). A total of 6 intraperitoneal administrations were given to the animals, twice a week for three weeks: control mice received saline solution and DOX- and MTX-treated received a total cumulative dose of 9 mg/kg and 6 mg/kg, respectively. During the entire experimental period, animal welfare was assessed daily. Mice were euthanized one week after the last administration. The experiments were performed with the approval of the Portuguese National Authority for Animal Health (reference number 0421/000/000/2016) and of the ORBEA of ICBAS-UP (project number 140/2015). After excising, aliquots of whole cardiac tissue and corresponding enriched mitochondrial fractions were prepared and analyzed by immunoblot and enzymatic techniques. Additionally, enriched mitochondrial fractions were studied by mass spectrometry-based proteomics (GeLC-MS/MS). From this analysis 693 different proteins were identified, assigned to the biological processes “small molecule metabolic process”, “oxidation-reduction process” and “carboxylic acid metabolic process” according to String[4]. The distribution analysis of the mitochondrial proteome data (using partial least squares-discriminant analysis; PLS-DA) showed clustering among the conditions. Indeed, MTX treatment presented less similarities with control. Comparative analysis of the mitochondrial proteomes revealed upregulation of fatty acid metabolism induced by DOX administration and upregulation of antioxidant activity in response of MTX treatment. Moreover, DOX and MTX administration promoted a decrease on mitochondrial density, given by citrate synthase activity. Concomitantly, metabolic adaptations were noticed, more evident in the heart of DOX treated mice. Indeed, increased glyceraldehyde-3-phosphate dehydrogenase-to-ATP and electron transfer flavoprotein dehydrogenase-to-ATP ratios were observed. Thus, more than differences in cardiac mitochondrial proteome, these drugs seem to decrease this organelle density.

References:

  1. Hrynchak I, Sousa E, Pinto M, Costa VM. The importance of drug metabolites synthesis: the case-study of cardiotoxic anticancer drugs. Drug Metab Rev. 2017;49(2):158–96.
  2. Colombo A, Sandri MT, Salvatici M, Cipolla CM, Cardinale D. Cardiac complications of chemotherapy: role of biomarkers. Curr Treat Options Cardiovasc Med. 2014;16(6):313.
  3. McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther. 2017;31(1):63–75.
  4. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP. STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(D1):D447–52.

Acknowledgments:

This work was supported by national funds by Fundação para a Ciência e a Tecnologia (FCT, Portugal) and co-financed by FEDER and COMPETE for the project “PTDC/DTP-FTO/1489/2014 – POCI-01-0145-FEDER-016537” and the QOPNA research unit (FCT UID/QUI/00062/2019). SRB, ARM and VMC acknowledge FCT for their grants (SFRH/BD/138202/2018, SFRH/BD/129359/2017 and SFRH/BPD/110001/2015) and VMC’s grant is funded by FCT, I.P., under the Norma Transitória – DL57/2016/CP1334/CT0006.

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Chemical imaging in pharmaceutics for formulation analysis, quality control, and monitoring of formulation interactions with biological tissue

Raman microspectroscopy is an elegant and efficient tool for chemical analysis of the samples since it provides information about the structure, conformation, and changes of molecules both in pharmaceutical formulation and in the biological tissue. It is especially useful for samples containing water since water absorption is not dominating the Raman spectrum, as it happens in the case of infrared spectroscopy. Analysis of several formulations for onychomycosis treatment is shown as the example of Raman microspectroscopy application in pharmaceutics. Differences between the formulations are shown to be linked to their efficiency in the infection treatment. Comparison of Raman microspectroscopy as the tool to analyze pharmaceutical formulations, their efficiency and stability is made in relation to the other spectroscopical and microscopical methods and the advantages and disadvantages of several techniques are discussed. The application of the results obtained in this study is demonstrated on further improvement of the formulation in development.

  • Open access
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Enhancing anticancer activity of spiropyrazoline oxindoles by disrupting p53-MDMs PPIs
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Cancer is a major public health problem worldwide with 18.1 million new cases of cancer and 9.6 million deaths worldwide in 20181.

The protein p53 is involved in many biological processes that are important to maintain the normal function of the cells (e.g. apoptosis, cell arrest, and DNA repair). It is an attractive target in oncology because it can modulate several additional cellular processes that are relevant for the suppression of tumour development, such as opposing oncogenic metabolic reprogramming, activating autophagy, and restraining invasion and metastasis. In all types of human cancers, the p53 tumour suppressor function is inactivated by mutation or gene deletion or by negative regulators such as MDM2 and MDMX. In the last years, the most popular approach among medicinal chemists to activate the wild-type p53 was the inhibition of p53-MDM2 protein-protein interaction (PPI) using small molecules. However, it is currently known that the full reactivation of p53 is only achieved when the interactions of p53 with both negative regulators are inhibited. Due to the lack of dual p53-MDM2/X PPIs inhibitors in clinical trials, it is urgent to develop small molecules that inhibit p53-MDMs PPIs2.

Our research team has been working on the development and optimization of spiropyrazoline oxindoles to obtain dual p53-MDM2/X PPIs inhibitors. Hence, we have already developed derivatives with good antiproliferative activities in HCT-116 p53(+/+) human colorectal carcinoma cell line, which induce apoptosis and cell cycle arrest at G0/G1 phase, upregulate p53 steady-state levels, and lead to a decrease of MDM2 levels3. In this communication, we report the structure-based computational optimization of this chemical family for the development of novel p53-MDM2/X interactions inhibitors. Our studies will shed light on the possible binding mode of spirooxindole derivatives to MDM2 and MDMX and will drive the hit-to-lead optimization strategy. Furthermore, we report our most recent optimization of the synthesis of these new spiropyrazoline oxindoles derivatives and the first preliminary biological results.

Acknowledgements: This work was supported by National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) through UID/DTP/04138/2019 (iMed.ULisboa), project PTDC/QUI-QOR/29664/2017, Principal Investigator grant CEECIND/01772/2017 (M. M. M. Santos) and PhD fellowships SFRH/BD/137544/2018 (E.A. Lopes) and SFRH/BD/117931/2016 (M. Espadinha).

1Ferlay, J., Colombet, M., Soerjomataram, I., Mathers, C., Parkin, D., Piñeros, M., Znaor, A. and Bray, F., Int. J. Cancer, 2019, 144, 1941-1953.

2Espadinha M., Barcherini V., Lopes E. A., Santos M. M. M., Curr. Top. Med. Chem. 2018, 18, 647-660.

3a) Nunes R., Ribeiro C. J. A., Monteiro Â., Rodrigues C. M. P., Amaral J. D., Santos M. M. M., Eur. J. Med. Chem., 2017, 139, 168-179. b) Amaral J. D., Silva D., Rodrigues C. M. P., Solá S., Santos M. M. M., Front. Chem., 2019, 7, article 7

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Antiviral activity of fluorinated compounds against DNA- and RNA-containing viruses
Published: 31 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Viral infections occupy an important place in human infectious pathology, as one of the most common and poorly controlled infections. At present, Influenza A virus (IAV) and Epstein-Barr virus (EBV) cause different infections, thereby imposing a huge toll on both human health and the economy worldwide. Thus, caused by the influenza virus, influenza or flu is a seasonal disease affecting millions of people in the world every year. The EBV is one of the world's most disseminated viruses and has been associated with a post-transplant lymphoproliferative disease, together with several cancers including Burkitt’s lymphoma, gastric cancer, Hodgkin’s lymphoma, lung carcinoma, nasopharyngeal carcinoma. Therefore, screening new effective drugs is an urgent and important problem.

Our study aimed to determine cytotoxicity and antiviral effect of fluorinated compounds against the Influenza A virus and Epstein-Barr virus. The cytotoxicity was studied in two cell lines (B95-8 and MDCK) by MTT assay. The cytotoxicity of the compounds the rate was 41 – 990 μg/ml in the B95-8 cell culture, which produces EBV, and 200 – 478 μg/ml in MDCK cells.

Compounds 10S-47 and 10S-49 were able to inhibit reproduction of IAV with EC50 (effective concentration inhibiting reproduction of the virus by 50%) of 38 μg/ml and 50 μg/ml, respectively. It was shown that fluorinated compounds showed low effectiveness against the Epstein-Barr virus, and inhibited the reproduction of the virus at 20% in the concentration range of 1 – 100 μg/ml. Also, we studied the potency of compound 10S-47 to make an apoptosis induction because it exhibited a significant cytotoxic effect on the growth of transformed cells. It was established that for compound 10S-47 at 40 mg/ml, the percentage of apoptotic cells exceeded the control and was 10%.

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