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  • Open access
  • 30 Reads
Design, synthesis, biophysical and antiprotozoal evaluation of new promising 2,9-bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives by targeting G-quadruplex
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A series of new 2,9-bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives was designed, synthesized, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the sub and mM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The substituted diphenylphenanthroline 1l was identified as the most potent antiplasmodial candidate with a ratio of cytotoxic to antiparasitic activities of 505.7 against the P. falciparum CQ-resistant strain W2. Against the promastigote forms of L. donovani, the phenanthrolines 1h, 1j, 1n and 1o were found the most active compounds with IC50 from 2.52 to 4.50 mM. The phenanthroline derivative 1o was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 91 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma could be considered as possible targets of this kind of nitrogen heterocyclic derivatives, their ability to stabilize the parasitic telomeric G-quadruplexes have been determined through the FRET melting assay and by native mass spectrometry.

  • Open access
  • 33 Reads
Novel anti-HMGB1 aptamers as potential drugs in anti-inflammatory and cancer therapies

High-Mobility Group Box 1 (HMGB1) is an abundant, highly conserved, non-histone nuclear protein present in almost all eukaryotic cells. In inflammatory conditions, HMGB1 is actively secreted from immune cells in the extracellular matrix, where it behaves as a proinflammatory cytokine. Once released, it can bind to cell-surface receptors, such as the Receptor for Advanced Glycation End products (RAGE) and Toll-Like Receptors (TLR) 2, 4 and 9, and mediate various cellular responses, including the induction of cell migration/proliferation and the release of other proinflammatory cytokines. Moreover, HMGB1 is able to contribute to the pathogenesis of various chronic inflammatory and autoimmune diseases as well as of cancer. Given the multiple roles of HMGB1 in these pathologies, identification of inhibitors of this protein is of considerable clinical interest. We here identified novel G-quadruplex (G4) forming aptamers as potential HMGB1 inhibitors. Using SELEX technology, we selected 14 G4-forming DNA sequences from a properly designed G-rich oligonucleotide library. These aptamers have been fully characterized in a biologically relevant buffer using several biophysical techniques to determine their preferred conformation as well as their thermal and enzymatic stability. Moreover, we evaluated the interaction between these aptamers and HMGB1, as well as their ability to inhibit HMGB1-induced migration in cancer cells so to identify the best candidates for future in vivo assays aimed at repressing the pathological functions induced by the target protein.

  • Open access
  • 24 Reads
Chemical Characterization and Antibacterial Activity of Artemisia herba-alba Asso Essential Oil from Southwestern Algeria (Naâma)
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The purpose of this study was to elucidate the chemical composition and to evaluate the Antibacterial activity of the Algerian Artemisia herba-alba Asso (Asteraceae) essential oil (EO) from arid region (Naâma, Algeria). Volatile components of Artemisia herba-alba Asso essential oil obtained by hydrodistillation were analyzed by gas chromatography coupled with mass spectroscopy (GC-MS). The Antibacterial activity was assessed against four bacterial strains referenced by the ATCC (American Type Culture Collection) using the disk diffusion assay and the agar dilution method. Detailed analysis of the essential oils led to the identification of 80 components amounting to 99.44 % of the total oil. Chrysanthenone (22.99%) followed by camphor (18.72 %), α-thujone (9.85%), camphene (3.25),1, 8-cineole (3.19 %) and β- Thujone (3.05%) are found to be the major compounds. The antibacterial effect of the essential oil of Artemisia herba alba shows high sensitivity to most bacteria used at 5µl of pure EO and at 10µl except for Pseudomonas aeruginosa, which proved to be resistant. The minimum values of the inhibitory concentration (MIC) varied between 3.12 to 6.25 % (v/v).This plant can be used as potential alternative remedies for the treatment of many infectious diseases.

  • Open access
  • 28 Reads
Effects of paroxetine chronic exposure to fish and its role in the response to other environmental contaminants
Published: 01 November 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Selective serotonin reuptake inhibitor (SSRI) antidepressants consumption has increased significantly worldwide leading to its environmental dissemination. Their frequent and increasing detection in different environmental matrices is thus an emerging environmental concern as these drugs are biologically active substances that, although designed to modulate human behaviour, have the ability to alter fish behaviour, physiology, and gene expression, even at low concentrations. The available studies with paroxetine are scarce and there is little information on how chronic exposure to SSRIs may influence the response to other environmental contaminants like nanoplastics (NPLs), which is an environmentally relevant condition as SSRIs do not exist alone in the environment. Accordingly, in this study, the effects of zebrafish 21 days exposure to 0, 40, and 400 µg/L of the antidepressant paroxetine (PAR) was assessed by studying fish behaviour. Moreover, this study also assessed how chronic exposure to PAR would affect the response to acute exposure to 1 and 10 µg/L of 50 nm polymethylmethacrylate NPLs (PMMA-NPLs).

Overall, chronic exposure to PAR decreased fish basal locomotor activity during both light and dark periods and interfered with stress response. When considering fish that were pre-exposed to PAR and then subjected to PMMA acute exposure, a significant interaction between PAR and PMMA-NPLs was found when considering fish swimming behaviour under light conditions. These results highlight the ability of SSRIs to modulate effects of other contaminants and the need to consider organisms’ previous contamination history.

  • Open access
  • 60 Reads
Design, synthesis and antimicrobial activities of quinoline-based FabZ inhibitors as promising antimicrobial drugs
Published: 01 November 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General

Up to now, antimicrobial resistance is one of the biggest public health challenges. Multi-resistance is particularly worrying in both Gram-negative bacteria, Pseudomonas aeruginosa and Escherichia coli for instance, and parasites such as Plasmodium falciparum.

Consequently, developing new compounds with original and selective antimicrobial modes of action is critical. Fatty acids are essential to maintain the vital integrity of the bacterial membrane. Their biosynthesis involves the fatty acid synthase-II (FAS-II) system which is exclusively found in germs. Furthermore, the amino-acid sequences of the FAS-II enzymes active site are well conserved in the microbial pathogens. As proves of concept, Isoniazid, a well-known antituberculous compound, and Afabicin – currently in clinical development to treat drug resistant staphylococci infections- target InhA or FabI, FAS‑II enzymes. In this work, we focus on another important FAS-II enzyme, FabZ, to design new antimicrobials with limited side effects and minimal chances of cross resistance with existing drugs targeting other pathways.

In the Protein Data Bank (PDB), several FabZ 3D structures from different organisms have been reported. Among known FabZ inhibitors, the NAS91 family, with a quinoline core, inhibits PfFabZ with IC50 in the micromolar range. Additionally, co-crystal NAS91 family-PfFabZ complex structures are described in the PDB. Based on these data, we have started a FabZ-based drug design study to develop novel quinoline structures. Herein, the in silico study, synthesis of new quinolines and biological results will be exposed.

  • Open access
  • 18 Reads
Using Machine Learning-Based Hierarchical Support Vector Regression Approach to Predict skin permeability

Skin is the largest organ in the human body and works as the natural barrier against the external environment. Furthermore, topical and transdermal drug delivery has been emerged as the new effective and safer administration. A variety of in vitro, in vivo, and ex vivo assays have been adopted to evaluate the retention of the drug in the skin layers and skin permeability, in which the ex vivo excised human skin has been considered as the gold standard to assess the skin penetration despite its potential of ethical issues. In this study, the novel machine learning-based hierarchical support vector regression (HSVR) was adopted to generate a nonlinear quantitative structure-activity relationship (QSAR) model, which can predict the Kp values based on the ex vivo human skin permeability data. The HSVR model showed consistent performance with the experimental data and among the training set, test set, outlier set, and mock test, which was designated to mimic the real challenges. In addition, the HSVR exhibited better prediction performance than the classical partial least squares (PLS). Thus, it can be concluded that the novel HSVR model can be utilized to facilitate the assessment of skin permeability of the novel compounds in drug discovery.

  • Open access
  • 16 Reads
Ionic derivatives of insulin-mimetic vanadium(V) complexes with Schiff base ligands.

The biological activity of the vanadium Schiff base complexes, which can be potentially used as insulin-mimetic compounds, was extensively studied in the last decade. Pharmacological data showed that these compounds produced a significant decrease in blood glucose level and improved liver and kidney function after two weeks of daily use. The vanadium complexes obtained so far with Schiff bases create problems, most often with cytotoxicity, very low solubility in water, difficulties in studying the crystal structure, instability at pH = 2 and in transport to cells. Therefore, it is necessary to search for new organic vanadium compounds to optimize their pharmaceutical activity. Lastly, several hundred vanadium(III- V) complexes with Schiff bases were tested, controlling both the starting vanadium compound for the synthesis of complexes, as well as changing the substituents in the aromatic ring of aldehyde and hydrazide - Schiff base components. The obtained neutral compounds were highly soluble in organic solvents, however, they were insoluble in water. Therefore, the DMSO-H2O mixture was used to test the stability of the complexes. In the last studies, the synthesis and physicochemical characterization of the vanadium(V) complex with triethylamine as a cation - HTEA[VO2(L)] (where L = Schiff base formed from 5-bromosalicylaldehyde and 2-hydroxybenzhydrazide) was described. In the formed ionic complexes, the crystal studies show additional hydrogen interactions between the cation and the complex anion. The ionic structure of such compounds should increase the solubility of the complexes in water, thus maximizing their availability in the biological systems studied.

  • Open access
  • 9 Reads

In dairy sector, mastitis is one of the most important and costly disease because due to it the world’s economy faces about 35 billion dollar loss each year. Bacterial pathogens that cause mastitis are called mastitogens. Among these bacterial species Escherichia coli, Staphylococcus aureus, Streptococcus uberis, Streptococcus agalactia and Streptococcus dysgalactia are the most important. Mastitis is treated with antibiotics however; due to their improper, excessive and irrational usage, these pathogens have become resistant to them. Drug residues in milk is also a factor resulting in multi-drug resistance (MDR) in mastitogens that cause treatment to become ineffective. In Pakistan, several ethnoveterinary plants such as Allium sativum (Garlic) and Chenopodium album (Goosefoot) are used for the treatment of mastitis in cattle and buffalo. For this purpose, we prepared aqueous and methanol extracts of A. sativum and C. album. In the agar well diffusion method, the aqueous A. sativum showed strong activity against Staphylococcus aureus i.e. 20mm. whereas, the methanolic extract of C. album gave 11mm zone of inhibition against Staphylococcus aureus. By combining the extracts of A. sativum and C. album then they give a synergistic effect especially against E.coli. Results showed that zone of inhibition against Staphylococcus aureus was 16mm, against E.coli 22mm and against Streptococcus uberis was 5mm. Our study is in agreement with the use of A. sativum and C. album in cases of mastitis and recommend their combined use for better results.

  • Open access
  • 26 Reads

Foodborne diseases (FBD) are a serious issue that affect not only human health but also has an impact on the global economy. They remain a persistent problem due to the continuing changes in global food trade trends, dietary patterns, food manufacturing, and the emergence of foodborne microbes in the food chain. In Pakistan, where meat is considered as an essential component of our meal but due to high nutrient concentration levels, high water activity, minerals and vitamins, and other growth factors such as pH microbes thrive in it. The extensive use of antibiotics has resulted in antimicrobial resistant (AMR) bacteria in E. coli, Salmonella, Campylobacter and Listeria spp. Traditional medicinal practices especially the use of plant extracts continue to play a crucial role in addressing basic healthcare needs in underdeveloped countries. The purpose of our study was to check the antibacterial potential of Jasminum sambac (Jasmine) and Hibiscus rosa sinensis (China rose) extracts against foodborne pathogens i.e. E. coli, Salmonella and Campylobacter. The hot and cold extracts were prepared using ethanol and distilled water and the antibacterial activity were observed by agar well diffusion method. The minimum inhibitory concentration (MIC) was also carried out the plant extracts gave MIC values of 6 and 12 µg/ml for E. coli and Salmonella respectively. The minimum bactericidal concentration (MBC) showed that ethanol extracts of both plants possessed bactericidal activity. Our study indicates that the native plants of Pakistan have significant bioactivity against foodborne pathogens.

  • Open access
  • 18 Reads
MARSplines approach for quantitative relationships between structure and pharmacological activity of potential drug candidates

An approach of multivariate adaptive regression splines (MARSplines) was applied for the quantitative structure-activity relationship studies of antitumor activity against murine leukemia L1210 of anthrapyrazoles as well as activated coagulation factor X (FXa) inhibitory activity of isosteviol analogues. These two different sets of molecules in the first stage underwent molecular modelling studies, i.e. geometrical optimization by the MM+ and the AM1 method using the Polak-Ribiere algorithm and finally about 5’000 molecular descriptors encoding structural features were calculated. Afterwards, statistical analysis using MARSplines algorithm was performed, which led to an establishment of a portfolio of submodels. As a result, the statistically significant MARS model for each set of the studied compounds that best describes quantitative structure-activity relationships was chosen. Elaborated models reveal, which molecular properties affect the most the pharmacological activity of anthrapyrazole and isosteviol compounds. Among the independent variables appearing in the statistically significant MARS models, descriptors belonging 2D Atom Pairs, 2D autocorrelations, 3D-MoRSE, GETAWAY, burden eigenvalues, RDF and WHIM descriptors, may be distinguished. The studies confirmed the benefit from using MARSplines algorithm, since high predictive power of obtained models make them useful for the prediction of antitumor and FXa inhibitory activity and possibly this approach can be considered as a tool for searching new drug candidates.