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  • 146 Reads
Synthesis of Squaramides with Anti-tumor Activity
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

In this study, the cytotoxic effects of different squaramides were tested against diverse cancer cells, such as HGC-27, HeLa, T98 and U87 cells, and non-cancer cells, such as EK293, MDCK and Vero cells. The best results were observed in a disubstituted squaramide that showed an IC50 of 1.81 μM against HGC-27 cells, which is a considerably lower value than the IC50 values observed in the rest of the cell lines. Therefore, this squaramide and its derivatives could be promising molecules for the treatment of gastric carcinoma.

Furthermore, the mechanism of action of this compound was evaluated. The outcomes indicated that the decrease in cell viability produced by the squaramide is probably caused by G0/G1 cell cycle arrest and caspase-mediated apoptosis. Additionally, the cell death produced by this compound was accompanied by autophagy induction and no signs of cathepsin-mediated cell death and necroptosis were observed.

  • Open access
  • 98 Reads
Synthesis and Antimicrobial Activity of Benzofuroxans and Structurally Related N-oxide-Containing Heterocycles
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Synthesis of new organic compounds possessing biological activity is very challenging and is a current trend in medicinal chemistry. In recent studies benzofuroxan derivatives have been described as drugs active against bacteria and fungi, based on the ability of these compounds to induce intracellular release of nitric oxide (II). Consequently, many substances arising from reactions between(di)сhloro(di)nitrobenzofuroxans and different aliphatic, aromatic amines, amino acids, aminoalcohol nitrates, sulfanilamides, polyene antibiotics and other nucleophiles have been prepared. Novel 2H-benzimidazole 1,3-dioxides were also obtained by interaction of benzofuroxans with alcohols in sulfuric or perchloric acidsWe also proposed a new method for the preparation of 2H-benzimidazole 1,3-dioxides by reaction of o-benzoquinonedioxime with ketones. Further nitration of the obtained compounds yielded a wide range of Sepin-1 analogues (separase inhibitors) with various substituents in the 2-position.

Beside their high biological activity,  2H-benzimidazole 1,3-dioxides can be involved into thermal reactions. Heating of 2Н-benzimidazole 1,3-dioxides resulted in the formation of 3Н-[2,1,4]benzoxadiazine 4-oxides, which are unstable and easily transformed into initial 2H-benzimidazole 1,3-dioxides on exposure to sunlight. More prolonged heating of 3Н-[2,1,4]benzoxadiazine 4-oxides caused sequential elimination of the N-oxide oxygen atom to form 2H-benzimidazole mono N- oxides as final products of thermal reactions at moderate temperatures.

  • Open access
  • 137 Reads
Optimization of Conditions for the Chromatographic Isolation of Isohexenyl Naphthazarin Derivatives from the Rhizome Callus of Echium vulgare
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Recently, naphthazarin derivatives have attracted huge attention due to their broad variety of biological activity. The wide spectra of their biological activity includes wound healing, anti-inflammatory effects, antitumor, antimicrobial and antithrombotic activity, etc. The importance of these compounds does not only lie in their biological activity (and medicinal applications), but in industry as well (food coloring, cosmetics, wood coating, etc.)

In this study, three naphthazarin derivatives have been isolated and identified (deoxyshikonin, acetylshikonin and β-hydroxylisovalerylshikonin). The plant, Echium vulgare, is abundant on the territory of Serbia as a self-sown and cultivated species. The plant itself has been characterized as having a low naphthazarin pigment content compared to Onosma visianii, Onosma paniculata, Alkanna tinctoria and Lithospermum erythrorhizon, which are used for mass production of these pigments. The isolation method described in this study makes preparation of a concentrated extract from Echium vulgare possible. This concentrated extract can complement the extracts of plants with higher naphthazarin pigment content that either are non native or endangered on the territory of Europe.

  • Open access
  • 122 Reads
Organocatalytic Synthesis of Chiral 1,4-Dihydropyridines with Potential Biological Properties
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

The 1,4-dihydropyridine core is a widely studied privileged scaffold. Molecules containing this structure are well known calcium channel blockers and are being used already as drugs in the treatment of heart disease. Moreover, recent advances have demonstrated their potential to act against many other diseases. The recent research concerning their activity as multidrug-resistance reversing agents should be highlighted. In the chemistry field, they are soft reducing agents and their chiral analogues have been used in asymmetric reductions with good results.

As shown before, these molecules contain a chiral center in their C4 position. The control of the selectivity in chemical transformations has been a crucial challenge to organic chemists. Nowadays, is well known that the living matter can actually discern between stereoisomers of the same compound. Nevertheless, there are scarce examples of procedures leading to enantiomerically enriched 1,4-DHPs, being most of them based on the use of chiral auxiliaries or chiral resolutions. Finding new and more environmental-friendly processes is also an interesting matter in chemistry, organocatalytic procedures are a perfect tool to achieve this goal.

Herein, we report our recent advances in the development of new organocatalytic methodologies to produce enantiomerically enriched 1,4-DHPs. Interestingly, one of them, brings out another privileged scaffold, such as the oxindole motif. Our methodologies could be perfect keystones leading to further research on the biological properties of these promising compounds.

  • Open access
  • 118 Reads
2-Amino-7(8)-fluorophenazine N5,N10-dioxide: Scale-up and Toxicity Evaluation
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session Posters

Breast cancer is a solid tumor characterized by a high level of hypoxic areas which are difficult to treat. The rate of this disease in women is elevated, mainly in developing countries since the diagnosis is made in the later stages of the disease. We have developed bioreductive prodrugs under conditions of hypoxia in which the compound 2-amino-7(8)-fluorophenazine N 5 ,N 10 - dioxide (FNZ) stands out as a potent and selective anticancer agent. In order to improve the ADME properties the FNZ was vehiculated in physiological serum:tween (PS:T). This work presents the optimization of the synthesis of FNZ, the evaluation of the mutagenic potential in vitro (AMES test) and the acute toxicity (Up & Down) of free-FNZ and its encapsulated. The optimization of the procedure to scale-up 5 g was done according to the synthesis already described. Washing and drying conditions of the benzofuroxan intermediate and FNZ allowed an overall yield of 60 %, five times higher than the micro-scale procedure. We performed the Ames assay on five strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537, TA102) recommended for drug development. The preliminary results indicate that all the systems under study (Free-FNZ, PS:T/FNZ) exhibited mutagenicity in the five Salmonella strains. The most mutagenic system was the free-FNZ being the encapsulation using (PS:T) the least. The acute toxicity showed that the vehiculated FNZ had a maximum dose of 2000 mg/kg of mouse weight. The vehiculated FNZ was not toxic in the Up & Down assay transforming it in a good formulation to be used in vivo studies.

Acknowledgement: The authors want to thank the ANII for financial support.

  • Open access
  • 134 Reads
Theoretical Exploration of Nanoparticles Targeting Bacterial Prostatitis

Prostatitis describes a combination of infectious diseases (acute and chronic bacterial prostatitis), chronic pelvic pain syndrome (CPPS) or asymptomatic prostatitis Most men with “chronic prostatitis” have chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), characterized by pelvic pain. The etiology of this syndrome is not fully known, the evaluation has been controversial and treatment is, unfortunately, frequently unsuccessful. Focused multimodal therapy appears to be more successful than empiric monotherapy. In that sense, it is important to know how nanoparticles will function in an animal model. The present paper reviews promising methods to capture prostate targeting.

  • Open access
  • 79 Reads
Looking for Novel p24 Multimerization Inhibitors of FIV
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Feline immunodeficiency virus (FIV) is a member of the retroviridae family of viruses. It causes an acquired immunodeficiency syndrome (AIDS) in domestic and non-domestic cats worldwide, representing an important veterinary issue. Genome organization of FIV and clinical characteristics of the disease caused by the virus are similar to those of human immunodeficiency virus (HIV). Both viruses infect T lymphocytes, monocytes and macrophages, and their replication cycle in infected cells is analogous. Thus, infection of cats with FIV is also a useful tool to study and develop novel drugs and vaccines against HIV. Anti-retroviral drugs studied extensively in HIV infection have targeted different steps of the virus replication cycle: 1) intervention of host cell surface receptors and co-receptors; 2) inhibition of fusion of the virus membrane with the cell membrane; 3) blockade of reverse transcription of viral genomic RNA; 4) interruption of nuclear translocation and viral DNA integration into host genomes; 5) prevention of viral transcript processing and nuclear export; and 6) inhibition of virion assembly and maturation. Despite much success of anti-retroviral therapy in slowing HIV progression in humans, similar therapy has not been thoroughly investigated for FIV infection in cats. FIV capsid protein (CA) drives the assembly of the viral particle, which is a critical step in the viral replication cycle. During this step, the CA protein oligomerizes to form a protective coat that surrounds the viral genome. In this article we perform a large screening of four hundred molecules from our in-house library. We used an in vitro assembly assay of p24, combined with microscale thermophoresis to estimate binding affinity. This screening led to the discovery of around 5 novel hits to drug development and drug design for new antiviral drugs.

  • Open access
  • 137 Reads
Novel N-(2-Mercaptobenzenesulfonyl)guanidine Derivatives Modified by Nitrogen-containing Heterocycles – Synthesis and Antiproliferative Activity Against Human Cancer Cell Lines
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session Posters

Benzenesulfonylguanidine derivatives have been known to inhibit growth of different types of human cancer cell lines. According to this fact, new compounds with structures based on benzenesulfonylguanidine scaffold and modified by important pharmacophores such as morpholine, 4-methylpiperazine or piperidine, have been designed and synthesized. The planned
N-(2-mercaptobenzenesulfonyl)guanidine derivatives  have been obtained by reaction of the appropriate N-(2-mercaptobenzenesulfonyl)cyanamide potassium salt with
1-aminopiperidine, 4-aminomorpholine or 1-amino-4-methylpiperazine; p-toluenesulfonic acid has been used as a protonating agent. The obtained compounds have been evaluated in MTT assay for an antiproliferative activity against human cancer cell lines HCT-116 (colon carcinoma), MCF-7 (breast cancer) and HeLa (cervical cancer). The results indicated that compounds containing the 4-methylpiperazine ring were the most potent growth inhibitors. The obtained IC50 values for these derivatives were lower than 35 μM against all tested cancer cell lines, with the best activity at level of IC50 ≤ 15 μM for compound with a methyl group at the position 5, and a (2-fluorophenyl)methylthio group at the position 2 of benzenesulfonyl scaffold.  Moderate antiproliferative effect (IC50 ~ 40 μM) was observed for derivatives containing a piperidine residue. Compounds with a morpholine fragment, in contrast, did not show significant growth inhibition.





  • Open access
  • 110 Reads
Chiral Liquid Chromatography in Analysis of the Stereochemistry of Marine Natural Compounds: Contribution for Medicinal Chemistry
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

In Medicinal Chemistry many naturally occurring peptides have been used as pharmaceuticals or as models for drugs used in therapeutics. Thus, marine-derived peptides are certainly an interesting source for new drugs. Taking into account the mechanisms of molecular recognition and the influence of molecular three-dimensionality in this process, it is essential to define the amino acids components of the peptide fractions isolated from marine sources.

Chiral liquid chromatography (LC) it has become a very helpful and highly applicable method for preparative resolution of racemates [1], determination of the enantiomeric purity [2], monitoring enantiomeric reactions [3], analysis of the stereochemistry of natural compounds [4, 5], among other applications.

Herein, we describe the determination of the stereochemistry of the amino acid residues of three bioactive marine natural products [4, 5], by chiral LC analysis of their acidic hydrolysates, using appropriate D and L amino acids standards. The enantioseparations of the amino acids were successfully performed with the Chirobiotic TTM column under reversed-phase elution conditions. Actually, the teicoplanin selector of this column has several characteristic features that make it suitable for amino acid analysis [6]. The elution order of the enantiomers of all the standards amino acids was confirmed by injecting the solutions of the racemic or enantiomeric mixtures and then each enantiomer separately.

Chiral LC technique demonstrated to be decisive leading to the unambiguous elucidation of the amino acid constituents of the three bioactive marine natural products.

Acknowledgements: This work was partially supported through national funds from Foundation for Science and Technology (FCT) and European Regional Development Fund (ERDF) and COMPETE under the projects UID/Multi/04423/2013, PTDC/MAR-BIO/4694/2014 (POCI-01-0145-FEDER-016790), and INNOVMAR (Innovation and Sustainability in the Management and Exploitation of Marine Resources) - NORTE-01-0145-FEDER-000035, Research Line NOVELMAR. War War May Zin thanks the Lotus Unlimited Project under the ERASMUS MUNDUS ACTION 2-EU-Asia Mobility Project for a Ph.D. scholarship. Chadaporn Prompanya thanks the Faculty of Pharmaceutical Sciences, Burapha University, Thailand for her scholarship to the University of Porto. War War May Zin and Chadaporn Prompanya equally contributed to this work.

[1] M.E. Sousa, M.E. Tiritan, K.R.A. Belaz, M. Pedro, M.S.J. Nascimento, Q.B. Cass, M.M.M. Pinto, J. Chromatogr. A, 1120 (2006) 75-81.

[2] B. Silva, C. Fernandes, M.E. Tiritan, M.M.M. Pinto, M.J. Valente, M. Carvalho, P.G. de Pinho, F. Remião, Forensic Toxicol., (2016) 1-14.

[3] C. Fernandes, P. Brandão, A. Santos, M.E. Tiritan, C. Afonso, Q.B. Cass, M.M. Pinto, J. Chromatogr. A, 1269 (2012) 143-153.

[4] C. Prompanya, C. Fernandes, S. Cravo, M.M.M. Pinto, T. Dethoup, A.M.S. Silva, A. Kijjoa, Mar. Drugs, 13 (2015) 1432-1450.

[5] W.W.M. Zin, S. Buttachon, T. Dethoup, C. Fernandes, S. Cravo, M.M.M. Pinto, L. Gales, J.A. Pereira, A.M.S. Silva, N. Sekeroglu, A. Kijjoa, Mar. Drugs, 14 (2016).

[6] A. Berthod, Y. Liu, C. Bagwill, D.W. Armstrong, J. Chromatogr. A, 731 (1996) 123-137.

  • Open access
  • 189 Reads
Searching Bioactive Molecules in Prostate Cancer from Mayan Traditional Medicinal Plants
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session ECMC-3

Prostate cancer (PC) is the most common cancer in men around the word. It is a complex and heterogeneous disease in which androgens and their receptor play a crucial role in the progression and development. The current treatment for PC is a combination of surgery, radiation and chemotherapy. Therapeutic agents commonly used in the clinic include steroidal and non- steroidal antiandrogens, such as cyproterone acetate. These few agents have multiple adverse effects and are not 100% effective. Several plant compounds and mixtures, including grape seed polyphenol extracts, lycopene and tomato preparations, soy isoflavones, and green tea extracts, have been shown to be effective against PC cell growth. Some isolated compounds were reported with in vivo activity on CP murine model like capsaicin and curcumin. We prepared a library of plant extracts from traditional Mayan medicine. These plants were selected for their use in the contemporaneous Maya communities with application in different types of diseases and treatments. These extracts were used in a phenotypic screening in LNCaP (androgen sensitive) prostate cancer cells in a fixed dose (25 μg / mL). Ten plants out of 11 were identified with cytotoxic activity in these cells. With the active extracts, a bioguided fractionation method was performed until the elucidation of the major components. We identified 3 compounds with activity and design one hybrid molecule with the natural product structure and steroid analog to enhance the antiproliferative activity.