Proceedings of 5th International Electronic Conference on Medicinal Chemistry最新文献

{"title":"In silico studies towards new BACE1 inhibitors","authors":"E. Sousa, M. Maia, A. Palmeira, D. Resende, L. Kiss","doi":"10.3390/ecmc2019-06363","DOIUrl":"https://doi.org/10.3390/ecmc2019-06363","url":null,"abstract":"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. 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 Lipinski's rule of 5 and additional attributes crucial for central nervous system (CNS) drugs were also considered. 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.","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"173 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116131682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro toxicity of α-amanitin in human kidney cells and evaluation of protective effect of polymyxin B","authors":"R. Malheiro, V. M. Costa, M. Bastos, F. Carvalho","doi":"10.3390/ecmc2019-06360","DOIUrl":"https://doi.org/10.3390/ecmc2019-06360","url":null,"abstract":"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 αamanitin toxicity and that the associated renal damage is largely decreased by this antibiotic. 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) at different time-points and cytotoxicity evaluated by the MTT reduction and neutral red 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 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.","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130538718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticancer drugs-induced toxicity in different age male CD-1 mice","authors":"Ana Reis-Mendes, M. Duarte-Araújo, J. Duarte, S. Gonçalves-Monteiro, F. Remião, F. Carvalho, E. Sousa, M. Bastos, V. M. Costa","doi":"10.3390/ecmc2019-06365","DOIUrl":"https://doi.org/10.3390/ecmc2019-06365","url":null,"abstract":"","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"39 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128230731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New heterocyclic polyphenols with skin anti-aging potential","authors":"D. Resende, E. Sousa, Mariana C. Almeida, B. Maciel, H. Carmo, I. Almeida, J. S. Lobo, Carlotta Pozzo, S. Cravo, G. Rosa, A. Kane-Pagès, M. Barreto, M. Pinto","doi":"10.3390/ecmc2019-06362","DOIUrl":"https://doi.org/10.3390/ecmc2019-06362","url":null,"abstract":"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. \u0000Considering 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. \u0000The 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. \u0000 \u0000Acknowledgements: \u0000This 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.","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"83 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132881361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, biological evaluation, and docking study of indole aryl sulfonamides as aromatase inhibitors","authors":"M. Fantacuzzi","doi":"10.3390/ecmc2019-06361","DOIUrl":"https://doi.org/10.3390/ecmc2019-06361","url":null,"abstract":"","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125819079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The membrane/aqueous partitioning as an essential tool for pharmacokinetic profiling to support drug design","authors":"E. Fernandes, Telma B. Soares, Andreia Almeida, M. E. C. R. Oliveira, B. Sarmento, M. Lúcio","doi":"10.3390/ecmc2019-06357","DOIUrl":"https://doi.org/10.3390/ecmc2019-06357","url":null,"abstract":"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.","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132822225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug (re-)design guided by biophysical characterization of interactions with biomimetic membranes","authors":"E. Fernandes, S. Benfeito, M. E. Oliveira, F. Borges, M. Lúcio","doi":"10.3390/ecmc2019-06377","DOIUrl":"https://doi.org/10.3390/ecmc2019-06377","url":null,"abstract":"Successful drug development requires not only the optimization for specific and potent recognition by its pharmacodynamical targets, but also efficient delivery to these target sites. Drug-biomembrane reciprocal interactions are a key determinant to understand how a compound performs at a barrier with relevant implications in its pharmacokinetic behaviour especially in Absorption, Distribution, Metabolism and Excretion (ADME). Concerning this, a rational drug design, where medicinal chemists can envision how a structure can be optimized aiming an improved pharmaceutical profile, can be the solution to avoid bigger investments in drugs that might not be effective. Lipid biomimetic membrane models with different lipid constitution are increasingly employed as alternative platforms with very well defined and controlled conditions to predict structural, biophysical and chemical aspects involved in the compounds’ penetration and/or interaction with biomembranes. As a proof-of-concept, in this study several biomimetic membrane models (cell membrane and epithelial membrane of blood-brain barrier) were used and different biophysical techniques (derivative spectroscopy; quenching of steady-state and time-resolved fluorescence; dynamic light scattering; differential scanning calorimetry and small and wide angle x-ray diffraction) were applied to characterize the pharmacokinetic profile of a newly synthesized drug in order to support drug screening process decisions.","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134503938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drugs and PAINs: A DrugBank analysis of pan-assay interference compounds","authors":"George Nicolae Daniel Ion, G. Nițulescu","doi":"10.3390/ecmc2019-06378","DOIUrl":"https://doi.org/10.3390/ecmc2019-06378","url":null,"abstract":"","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116813010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of Aptamers to deliver therapeutic genetic sequences in muscle","authors":"L. Phylactou","doi":"10.3390/ecmc2019-06367","DOIUrl":"https://doi.org/10.3390/ecmc2019-06367","url":null,"abstract":"There are several types of muscular dystrophy which have as a common characteristic muscle weakness and wasting.\u0000Antisense oligonucleotide approaches hold promise for the development of rational therapeutic approaches against muscular dystrophy.\u0000There is need to improve the delivery of such oligonucleotides in a tissue such as the muscle which is highly abundant in the human body.\u0000During the presentation, I am describing the identification and use of aptamers to enhance delivery in muscle.","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"223 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122520796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The main products of cyclophosphamide bioactivation exert a cardiotoxic effect at clinical important concentrations in AC16 cardiac cells","authors":"F. Dionísio, V. M. Costa, Ana Margarida Araújo, Margarida Araújo, P. Pinho, M. Bastos, F. Carvalho","doi":"10.3390/ecmc2019-06366","DOIUrl":"https://doi.org/10.3390/ecmc2019-06366","url":null,"abstract":"Cyclophosphamide is used against lymphomas, solid tumors, namely breast, ovarian, bone and soft tissue tumors, in bone marrow transplant conditioning regimens and also in the treatment of autoimmune diseases. Despite its broad use, the application of cyclophosphamide is dose limited by its cardiotoxic effects, which have been linked to its intricate bioactivation process. In this study, we evaluated the cytotoxicity of cyclophosphamide (100 to 10000 μM) and two of its main metabolites, 4-hydroxycyclophosphamide (1 to 25 μM) and acrolein (5 to 100 μM) in AC16 cells, a human cardiomyocyte cell line. Furthermore, metabolomic evaluation was conducted in proliferative and differentiated cells after their incubation for 24h with subtoxic concentrations LC05 of cyclophosphamide, 4-hydroxycyclophosphamide and acrolein.","PeriodicalId":312909,"journal":{"name":"Proceedings of 5th International Electronic Conference on Medicinal Chemistry","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125287916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}