Proceedings of 4th International Electronic Conference on Medicinal Chemistry最新文献

{"title":"Conformational changes of secondary and tertiary structures of interferon under the influence of oligoribonucleotides-based drugs","authors":"R. Nikolaiev, M. Vivcharyk, S. Levchenko, S. Chernykh, N. Obernikhina, Z. Tkachuk","doi":"10.3390/ecmc-4-05629","DOIUrl":"https://doi.org/10.3390/ecmc-4-05629","url":null,"abstract":"","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82554775","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 vivo imaging of the activity of host defense peptide mimetics in a mouse model of invasive candidiasis","authors":"G. Diamond, L. Ryan, R. Parveen, A. Hise, K. Freeman, R. Scott","doi":"10.3390/ecmc-4-05628","DOIUrl":"https://doi.org/10.3390/ecmc-4-05628","url":null,"abstract":"Systemic fungal infections are increasingly common, especially in immune compromised patients. Even with newly developed drugs, there remain issues of limited spectrum, side effects, and the development of resistance. Host defense peptides (HDPs) have been examined recently for their utility as therapeutic antifungals, especially due to the low levels of resistance that develop. Unfortunately, the peptides exhibit poor pharmacologic properties in vivo. We have demonstrated the potent activity of nonpeptidic compounds that mimic HDPs in both structure and function against clinical strains of Candida albicans associated with oral and invasive candidiasis in mouse models. However, to test numerous compounds in vivo requires large numbers of mice, with multiple time points, and requires immunosuppression of the mice using cyclophosphamide, which can influence pharmacological parameters. We have identified a strain of mouse that develops invasive candidiasis without the need for immunosuppressive drugs. When we infect these mice with a strain of C. albicans that constitutively expresses Red Fluorescent Protein, we can quantify the infection in real time by in vivo imaging. We can further observe the reduction in fluorescence in infected mice after treatment with an HDP mimetic. Together our results demonstrate a novel in vivo method for screening new antifungal drugs.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87507111","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":"pKa modulation of a bis(2-aminoimidazoline) DNA minor groove binder that targets the kinetoplast of Trypanosoma brucei","authors":"Jorge Jonathan Nué Martinez, C. Millan, G. Ebiloma, H. D. Koning, L. Campos, C. Dardonville","doi":"10.3390/ecmc-4-05626","DOIUrl":"https://doi.org/10.3390/ecmc-4-05626","url":null,"abstract":"The parasite Trypanosoma brucei, ethiologic agent of human African trypanosomiasis (i.e. sleeping sickness), contains a kinetoplast with the mitochondrial DNA (kDNA) comprising of >70 % AT base pairs. Hence, DNA minor groove binding molecules have been investigated as antitrypanosomal agents. Diphenyl-based bis(2-iminoimidazolidines) are promising DNA minor groove binders that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late(CNS)-stage disease, possibly due to poor brain penetration caused by their dicationic nature. \u0000As a strategy to reduce the pKa of the basic 2-iminoimidazolidine groups, halogen atoms (R1 = Cl, F) were introduced in the structure of lead compound 1 and the pKa of the new compounds was determined . A reduction of 1–2 pKa units for the imidazolidine group linked to the substituted phenyl ring was observed. In vitro activities (EC50) against wild type and resistant strains of T. b. brucei were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340).1 The chloro-substituted derivative 5a, which was curative in vivo in a mouse model of stage 1 infection by T. b. rhodesiense, appeared as a new promising lead compound.2 \u0000Mechanistic studies were performed to identify the cellular target of these dicationic compounds. Altogether, our results show that 1 and 5a share the same mechanism of action against T. brucei, acting specifically on the integrity of the kinetoplast by altering the structure and replication of kDNA.2","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74944490","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":"A Practical Access to New Pyrazole SKF-96365 Analogues as Potential Store-Operated Calcium Entry (SOCE) Inhibitors","authors":"Bazureau Jean Pierre, C. D. Dago, L. Voli, T. Roisnel, C. Brigaudeau, Y. Bekro, Janat Mamybékova, O. Mignen","doi":"10.3390/ECMC-4-05618","DOIUrl":"https://doi.org/10.3390/ECMC-4-05618","url":null,"abstract":"The racemic synthesis in four steps of pyrazole SKF-96365 analogues without substituent (CF3 group) on the pyrazole platform was realized in moderate to good yields. The separation of (±) hydroxyl enantiomers 4 was developed successfully using the method of \"half-concentration\" with commercial (+)-(1S)- and (-)-(1R)-10-camphorsulfonic acid (CSA) followed by neutralization of diastereomers with MeONa in dry MeOH solution. With the pure enantiomers (-)-(1S)-4b and (+)-(1R)-4b, initial attempts to obtain the crystallized (-)-(1S)-7d and (+)-(1R)-7d after treatment of intermediate 6d with a solution of 1M HCl (for precipitation of hydrochloride salt 7d) failed. We have also investigated the effects of compounds 7(a-d) on endoplasmic reticulum (ER) Ca2+ and SOCE on PLP-B lymphocyte cell line and compound 7d was identified as a better SOCE inhibitor than SKF-96365. This preliminary SAR study showed that the MeO group in para-position of the phenethyl-1H-pyrazolium skeleton or for the Cbeta-phenylpropoxy side chain of 7 influenced the SOCE activity.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75079483","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":"Identification of degradation products of saquinavir mesylate by LC-MS: Molecular docking and in silico ADME prediction studies","authors":"Kiran Gangarapu, Julakanti Venu, Mulagada Monja, T. Gouthami, V. Bakshi","doi":"10.3390/ecmc-4-05627","DOIUrl":"https://doi.org/10.3390/ecmc-4-05627","url":null,"abstract":"Saquinavir mesylate (SQM) is subjected to forced degradation under conditions of hydrolysis, oxidation, dry heat, photolysis as recommended by International conference on Harmonization guideline Q1A (R2). In total, (I-V) degradation products (DPs) were formed in acidic hydrolytic, alkaline hydrolytic and oxidative conditions. Successful separation of SQM and its DPs was achieved on C18(4.6mm×75mm) 3.5μg column at ambient temperature (30 ̊C) with mobile phase A (10mM ammonium acetate in water), B100% acetonitrile at 2.0ml/min flow rate in the gradient mode. The injection volume was fixed at 20μl and detection wavelength at 238nm. The HPLC method was found to be linear, accurate, precise, sensitive, specific, rugged, and robust for quantification of SQM as well as degradation products. The major degradation products (DP-1) formed in hydrolytic acid conditions was identified and characterized by LC-MS/MS and proposed the fragmentation patterns by comparing with SQM. Further, DP-1 were isolated through column chromatography and analyzed by 1H NMR. In Silico molecular docking studies on HIV protease (PDB: 4qgi) for DPs and SQM was estimated and found to be pharmacologically inactive than SQM. Prediction of Toxicity and ADME properities were performed for DP-1 and SQM and found to less toxic.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83573452","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":"Bicyclic lactams as potential inhibitors of the NMDA receptor","authors":"Margarida Espadinha, Jorge Dourado, Rocío Lajarín-Cuesta, Clara Herrera Arozamena, Lídia M D Gonçalves, João A Lopes, M. I. Rodríguez-Franco, D. J. V. A. Santos, C. Ríos, Maria M. M. Santos","doi":"10.3390/ecmc-4-05631","DOIUrl":"https://doi.org/10.3390/ecmc-4-05631","url":null,"abstract":"The family of ionotropic glutamate receptors (iGluRs) is localized in the cell membrane of neurons and has crucial roles in the normal development of the central nervous system (CNS). Sustain healthy memory, learning, and cognitive processes are fundamental functions of these receptors. [1] N-Methyl-D-aspartate (NMDA) receptors belong to the family of iGluRs and its over-activation is associated to neuronal loss and, consequently, to major neurological disorders such as Parkinson and Alzheimer’s diseases. Recently, targeting the NMDA receptor was considered a promising strategy in the medicinal chemistry field and the development of effective NMDA receptor antagonists become an attractive therapeutic approach. [2] In the last years, Santos’ group has been involved in the design and development of potent NMDA receptor antagonists, more precisely enantiopure bicyclic lactams. [3-5] To evaluate the activity of the potential NMDA receptor antagonists, was measured their capacity to inhibit NMDA-induced increase of intracellular Ca2+ levels in in vitro cultures of embryonary rat cortical neurons, using the Ca2+-sensitive fluorescent dye Fluo-4. The first molecule that showed some interesting results was a (S)-phenylalaninol oxazolopyrrolidone. [3] After, based on the oxazolopyrrolidone scaffold, a hit-to-lead optimization was carried out in the search for more potent NMDA receptor antagonists. A new library of enantiopure phenylalaninol bicyclic lactams was developed and most of the new compounds displayed NMDA receptor antagonism. It was even more interesting the significant difference in activities between the two enantiomers. The most promising compound showed an IC50 value of 27 μM, on the same order of magnitude as that of memantine (47 μM), an NMDA receptor antagonist in clinical use for the treatment of Alzheimer’s disease. [5] More recently, we also extended our interest to more rigid molecules, also containing a bicyclic lactam core. Interestingly, this new family of compounds showed to be even more potent as NMDA receptor antagonists (4-fold more active than memantine). Additional biological tests indicated that the promising compounds can cross the blood-brain barrier (determined by an in vitro assay) and non-hepatotoxic, as well. Furthermore, the synthesis of the interesting aminoalchool-based libraries is easy to perform, resulting in moderate to good yields, and excellent stereoselectivities.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77592577","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":"Enantiopure oxazoloisoindolinones: Promising small molecules for p53-based therapy with potential anticancer properties","authors":"Valentina Barcherini, Margarida Espadinha, J. Soares, S. Gomes, A. Antunes, L. Saraíva, Maria J. Santos","doi":"10.3390/ECMC-4-05630","DOIUrl":"https://doi.org/10.3390/ECMC-4-05630","url":null,"abstract":"Cancer is a group of diseases that can affect any part of the body via an uncontrolled and anomalous cellular proliferation. In this research field, the tumor protein p53 is a widely-studied therapeutic target in cancer treatment, as this transcription factor is inactivated in all types of human cancers. In 50% of malignancies, p53 is found expressed in its wild-type form and generally inhibited by two major negative regulators, MDM2 and MDMX. In the remaining 50% of cases, p53 is inactivated by contact and conformational mutations principally on its DNA-binding site, thus not exercising its regulatory function. [1] In the last years, our research group has been actively involved in the synthesis of small molecules to reactivate the p53 pathway. Starting from the enantiopure aminoalcohol tryptophanol, we have recently developed several small molecules that reactivate p53 (Figure 1). Here we present our most updated results on the development of a chemical library of (S)- and (R)-tryptophanol-derived oxazoloisoindolinones. This class of compounds may be accessed by cyclocondensation reaction of enantiopure forms of tryptophanol and several achiral oxoacids. In this synthetic approach, the chiral inductor (tryptophanol) is responsible for the stereo-outcome of the final product and it is part of the main skeleton of the bioactive molecules. For those reasons, this asymmetric reaction is highly efficient/atom economic. Interestingly, this specific one-step synthetic strategy allows to the construction of a new chiral center. [2] From this work tryptophanol-derived bicyclic lactams SLMP53-1 and DIMP53-1 were identified as the most promising p53 reactivators. [3] Further hit-to-lead optimization is ongoing, and assessment of the antiproliferative activity of the optimized oxazoloisoindolinones against four different cancer cells lines highlights that this chemical family displays selectively potent antitumor activity towards p53 with no apparent toxic effects.\u0000Acknowledgements\u0000Fundacao para a Ciencia e a Tecnologia (FCT) through PTDC/DTP-FTO/1981/2014, PTDC/QUI-QOR/29664/2017, UID/DTP/04138/2013, PD/BI/135334/2017 and IF/00732/2013.\u0000References\u0000[1]. Espadinha M, Barcherini V, Lopes E A, Santos M M M (2018). Curr Top Med Chem 18: 647-60.\u0000[2]. Dourado J, Perez M, Griera R, Santos M M M (2016). RSC, Chapter 3.1.19, 198-201.\u0000[3]. a) Soares J, Raimundo L, Pereira N A L, Monteiro A, Gomes S, Bessa C, Pereira C, Queiroz G, Bisio A, Fernandes J, Gomes C, Reis F, Goncalves J, Inga A, Santos M M M, Saraiva L (2016). Oncotarget 7(4): 4326-43; b) Soares J, Espadinha M, Raimundo L, Ramos H, Gomes A S, Gomes S, Loureiro J B, Inga A, Reis F, Gomes C, Santos M M M, Saraiva L (2017). Molecular Oncology 11(6): 612-27.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79960597","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, characterization and an extensive biological evaluation of 5-​[2-​(methylthio)​ethyl]​-​3-​(2-​propen-​1-​yl)​-​2-​thioxo-4-​imidazolidinone","authors":"Biljana M Šmit, P. Stanić, Marijana Zivkovic","doi":"10.3390/ecmc-4-05625","DOIUrl":"https://doi.org/10.3390/ecmc-4-05625","url":null,"abstract":"Ever since their discovery, hydantoins have attracted huge attention due to their intriguing properties, vast chemical diversity and potential, as well as their broad spectra of biological activity. The wide set of their biological activity includes antimicrobial, antitumor, antiandrogen, anticonvulsant, antiteratogenic activity, etc. They are also used in the treatment of cachexia, psoriasis, wounds in general and also as muscle relaxants. There are many synthetic routes to hydantoins and some of them involve amino acids. As rigorous chemical conditions are not required, these reactions can be manifested in physiological conditions too, especially in the cases when protein consumption is increased and thus hydantoins have been isolated from urine. With all this in mind, elucidation of biological implications of hydantoins gains importance. In this study, an amino acid derived 2-thiohydantoin, 5​[2-​(methylthio)​ethyl]​​3-​(2​propen​1​yl)​​2-​thioxo-4​imidazolidinone, has been synthesized and fully characterized by NMR and IR spectroscopy, as well as X-ray crystallography. An extensive antimicrobial study has been carried out on ten bacterial isolates (Grampositive and Gram-negative), as well as on five fungal isolates. Cytotoxicity has been tested on the cell lines of the normal lung fibroblasts, as well as breast, colon and lung tumor cell lines. Ultimately, a fish embryo toxicity (FET) assay has been carried out in vivo on the zebrafish model, testing for lethal and teratogenic effects and cardiotoxicity. Based on the found biological activity in previously mentioned assays, a determination of therapeutic potential has been carried out to show whether the compound is toxic in antimicrobial and anticancer doses.","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82427315","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 multifunctional diamine AGE/ALE inhibitors to prevent oxidative and carbonyl stress exacerbation in Alzheimer's disease","authors":"Elodie Lohou, N. Sasaki, A. Boullier, P. Sonnet","doi":"10.3390/ECMC-4-05622","DOIUrl":"https://doi.org/10.3390/ECMC-4-05622","url":null,"abstract":"","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87608932","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":"Hepatoprotective and antioxidant effects of oligoribonucleotides-D-mannitol complexes against thioacetamide-induced liver fibrosis","authors":"T. Marchyshak, Z. Tkachuk, L. Semernikova, T. Yakovenko","doi":"10.3390/ecmc-4-05624","DOIUrl":"https://doi.org/10.3390/ecmc-4-05624","url":null,"abstract":"","PeriodicalId":20450,"journal":{"name":"Proceedings of 4th International Electronic Conference on Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81186174","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}