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Development of new 2-heteroaryl-4-quinolones as potential antibiotics targeting multi-​drug resistant ESKAPEE pathogens
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Multi-drug resistant ESKAPEE pathogens are responsible for various nosocomial infections. Considering this serious threat to public health, new efficient treatments are urgently needed.1 The bacterial communication systems, called quorum sensing (QS), constitute a pool of new promising pharmacological targets for the development of antimicrobial molecules. The inhibition of QS could disrupt several intra/inter-species protective interactions (bacterial multiplication, biofilm formation) and virulence pathways.

The intervention of three main small signaling molecules was described in the pqs intercellular communication system of P. aeruginosa : the Pseudomonas quinolone signal (PQS), its precursor 2-heptyl-4(1H)-quinolone (HHQ) and the 2‑heptyl‑4‑hydroxyquinoline-N-oxide (HQNO) as a secondary metabolite from this pathway.2 Interestingly, HQNO appears to be a potent respiratory chain inhibitor for various competing microorganisms such as S. aureus.3 Furthermore, HHQ analogues and different 2-heteroaryl-4-quinolone series revealed efficient as QS inhibitors (PQS receptor antagonists) or as type II NADH/quinone oxidoreductase inhibitors.4,5,6

Taking these studies into account, the interest of the quinolone scaffold in the design of QS and respiratory chain inhibitors has emerged. In this context, we aim to develop new antibacterial 2‑heteroaryl‑4‑quinolone series. The synthesis of the first series carrying out pallado-catalyzed C-C or C-N coupling reactions from 2-bromo-4-chloroquinoline precursors will be described in the presentation.

Bibliographic references: (1) Expert Rev. Anti Infect. Ther., 2013, 11(3), 297-308 ; (2) Org. Biomol. Chem., 2018, 16, 169-181 ; (3) Curr. Biol., 2016, 26, 195-206 ; (4) Org. Biomol. Chem., 2017, 15, 4620-4630 ; (5) J. Med. Chem., 2012, 55, 1844-1857; (6) J. Med. Chem., 2017, 60, 3703-3726.

  • Open access
  • 243 Reads
Development of silica nanoparticles for 1H MRI and optical imaging
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Among the numerous imaging techniques, magnetic resonance imaging (MRI) has become the most powerful tool for diagnosis owing to its high spatial resolution, unlimited tissue penetration, and nonionizing nature. Nevertheless, one can mention its lack of sensitivity, which constitutes a major drawback especially in the field of molecular imaging. The combination of MRI and optical imaging (OI), detecting the luminescence emitted by a tracer, offers the high spatial resolution of the former and the high sensitivity of the latter. In this context, this study focused on the improvement of the relaxation properties of a commercial gadolinium chelate, Gd-HP-DO3A, bya non-covalent confinement of the complex in a semi-permeable nanosystem. To induce the bimodality, a fluorescent compound, i.e. ZW800-1, has been co-encapsulated inside the nanoparticle in a one-pot process. Thanks to their exceptional properties (i.e. biocompatibility, chemical stability, low toxicity) silica nanoparticles (SiO2NPs) have been chosen as a matrix. Narrow size distribution SiO2NPs were obtainedby a reverse microemulsion process (DH: 80 nm). Relaxometric measurements of the synthesized nanoplatforms have proven its efficiency to decrease T1,2of water proton molecules. The fluorescent properties were kept after the encapsulation of the fluorophore. The final system was characterized by Dynamic Light Scattering (DLS), Nuclear Magnetic Resonance (NMR) spectroscopy, relaxometry measurements, UV-Vis and IR spectroscopies and Transmission electron microscopy (TEM).

  • Open access
  • 37 Reads
Spectral studies of oligoribonucleotide-based drugs
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Recently, oligoribonucleotide (ORN)-based preparations have become increasingly popular. ORNs have a wide range of biological properties. They are used as antiviral drugs and have antitumor and anti-inflammatory action. They act on both RNA and DNA-containing viruses and stimulate the innate antiviral immunity system. The biological activity of such drugs can partly be correlated with their spectral properties

As samples, we took the "Nuclex" pharmaceutical drugs based on an ORN and alcohol sugar D-mannitol (D-M), and the main components of these drugs (active substance - ORN and excipient - D-M). We measured the UV-Vis absorption (Specord 210 Plus two-beam spectrophotometer; Analytik Jena), fluorescence (Fluoromax-Plus spectrofluorimeter; HORIBA Instruments Inc.), and fluorescence excitation spectra for solutions in degassed bi-distillated water at room temperature.

Control of the ORN concentration was performed by measuring the absorption spectra and monitoring the maximum at 260 nm. The shape of the spectrum and the position of the absorption peak of ORN and Nuclex coincided and corresponded to the absorption spectrum of adenosine. During the study, a possible complexation between the active substance and the excipient (ORN-D-M) was identified. By excitation of ORN and Nuclex at a wavelength of 260 nm, we obtained a wide range of fluorescence in the region of 280-550 nm with a maximum at 380 nm. Measuring the fluorescence spectrum and the fluorescence excitation of the Nucleus and ORN, two large emission centers were detected with a maximum luminescence at 380 nm for an excitation wavelength of 290 nm (emission at 310-550 nm) and a maximum at 440 nm, with excitation at 360 nm (emission at 350-610 nm). In the absorption spectrum, those maxima did not appear, but we observed a strong emission compared to the excitation at a wavelength of 260 nm. In Nuclex, the excitation peak at 290 nm is significantly dominated by the intensity of the excitation peak at 360 nm, and in the ORN, the ratio between similar centers is reversed. When D-M is added, the ratio between the emission peaks at 380 and 440 nm changed, what might indicate the complexation of ORN and D-M. When D-M wa added to the ORN, the position of the emission peaks and the shape of the peaks did not change.

In the course of our research, we found fluorescence centers of Nuclex, and identified the possibility of complexes between ORN and D-M.

  • Open access
  • 23 Reads
Pharmacokinetics of Gestobutanoil in rat serum using HPLC-APCI-MS
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Pilot studies of the pharmacokinetics of Gestobutanoil (GB) showed that it undergoes rapid biotransformation forming two metabolites, which quantitative analysis was significant. An HPLC-MS technique was developed for the simultaneous quantification of GB and its two metabolites in rat serum. Due to the nature of GB and one of its metabolites, the ESI-MS-detection was ineffective. The ionization problem was solved with APCI. The detection of GB and one of its metabolites was carried out by the fragments of their molecules formed in the ionization chamber. The second metabolite formed [M+H]+ ions. During the method validation following characteristics were checked out: specificity, linearity, precision, accuracy, matrix effect, stability. The limit of quantification for each analyte was 10 ng/ml. Pharmacokinetics studies have shown that biotransformation of GB is so fast that it wasn't detected in rat serum even in 15 minutes after administration. The pharmacokinetics of two metabolites of GB was described.

  • Open access
  • 32 Reads
Conformational, fluorescence and energy parameters of Interferon α2b under the influence of mono and oligoribonucleotides-based drug
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Oligonucleotides antiviral drugs have been actively used in medicine over the last decades, but the molecular mechanism of their action remains unclear. The RNA-based drug is known to increase interferon production and stimulate nonspecific antiviral protection. As shown in our previous works, the combination of oligonucleotides with alcoholic sugar D-mannitol leads to changes in their biological activity and efficiency.

We studied the interactions between Interferon α2b and mononucleotides (NMP), yeast oligoribonucleotides (ORNs), their Na+ salts (ORNsNa), and complex with D­mannitol (ORNs:D­M). To investigate the interaction and conformational changes of IFN with ligands the quenching and lifetime of fluorescence, circular dichroism spectroscopies and isothermal titration calorimetry (ITC) were used.

The most active quenching and decrease INF, when titrated with NMPs and ORNs, was obtained using acid forms in combination with mannitol lifetime of fluorescence. The quenching and lifetime of fluorescence INF when titrated saline forms slightly different from control. Thus, when using the ORN:D­M, quenching was 28%. INF has a lifetime of 2.95 ns, after interacting with ORN and ORN:D-M INF has a fluorescence lifetime of 2.37 and 2.32 ns, respectively. The quenching and lifetime of fluorescence INF when titrated AMP:D­M - 17% and 1.92 ns, respectively, GMP:D­M - 45% and 2.53 ns, CMP:D-M - 42% and 2.24ns, UMP:D-M - 13% and 2.25 ns. The analysis of the IFN secondary structure by Bestsel shows the decrease in the structure of the number of secondary elements when interacting between INF and acidic forms nucleotides. On the other hand, an increase in the number of secondary elements in the interaction between INF and salt forms NMPs and ORNs were obtained. The ITC curves titration of INF with ORNs and NMPs indicate that the reaction of the interaction between protein and acidic ligands is exothermic and with saline endothermically. It is known that exothermic protein-ligand interaction increases the conformational mobility of the protein and endothermic decrease.

Different effects of different forms of ORNs and NMPs on the secondary structure of the INF can be explained by various binding sites. The ORNs and ribonucleotides have the advantage of interacting with proteins, unlike salt ORNs and nucleotide monophosphates, because they have a stronger binding. Thus, we assume the same compound in various forms may act as an inhibitor and activator for the protein. To test this assumption in the case of nucleotide ligands, we plan to conduct studies with the interferon receptor.

  • Open access
  • 36 Reads
The influence of oligoribonucleotide complexes with D-mannitol on tumor formation in a murine model of B16 melanoma
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Malignant melanoma is considered to be one of the most aggressive forms of skin cancer - about 80% of skin cancer deaths are associated with this disease. Because melanoma is an immunogenic tumor, effective treatment is based on strategies to enhance the body's immune response. Recent studies have shown that oligoribonucleotides-D-mannitol (ORNs-D-M) complexes possess exhibit in particular antiviral, anti-inflammatory and immunomodulatory actions due to the activation of immune responses. Given the wide range of biological effects, we aimed to investigate the effect of ORNs-D-M on the development of B16 melanoma in mice by controlling tumor growth and genetic analysis of marker genes.

Methods. Adult female mice of a C57BL/6J line were used. Suspension of B16 mouse melanoma cell was subcutaneously introduced into the right posterior paw. For the experimental groups, the ORNs-D-M solution (in PBS) was injected once at concentrations of 1.4; 0.7; 0.35; 0.175 mg on animal. The control group received 100 μl of PBS. Tumor size was monitored during the experiment. Expression of T-cell markers (CD3, CD4, CD8, CD247), macrophage markers (CD68, CD163, NOS2), immunotherapy target genes (PDCD1, CD274, CTLA4, CTLA4 / del) and cytokine (IFNB1) were evaluated by real-time qPCR assay in peripheral blood of mice.

Results. Our investigations show that different concentrations of ORNs-D-M have the opposite effect on the growth of melanoma B16 tumors. In the group where animals received 1.4 mg of ORNs-D-M, the formation of the solid tumors was not observed; however, in the group with 0.7 mg dose, the average tumor volume was 97% lower than the non-drug group. In the case of lower concentrations, the average tumor size was 2-3 times higher than in the non-drug group. Also, we observed the changes in the expression of major marker genes. The mRNA expression levels of markers of T-cell counts CD3, CD4, CD8, and CD247, in groups with high concentrations of ORNs-D-M approached those of healthy animals. However, in mice, bearing melanoma recorded a decrease in mRNA levels of these genes. As well ORNs-D-M increases in the immune response to cancer and generally decreases the level of immunosuppression, which reflect in the increased expression of CD274, PDCD1, and IFNB1.

  • Open access
  • 42 Reads
Synthesis and lipooxigenase inhibition of coumarin derivatives
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session Posters

Coumarin derivatives are an important group of biologically active compounds that have found a wide range of application in pharmacy and medicine. For this reason, their extraction from plants, as well as the synthesis in laboratories have been increased lately. Many studies have been conducted and various coumarins shown different biological activities such as antibacterial, antifungal, anti-inflammatory, anticoagulant, antioxidant, anticancer, anti-HIV and much more. Coumarins can also act as enzyme inhibitors. It has been proven that coumarins inhibit many enzymes, including lipoxygenases. Lipoxygenases are iron-containing enzymes that convert polyunsaturated fatty acids into biologically active compounds involved in the inflammatory and immune responses. Sometimes it is necessary to inhibit those enzymes to avoid adverse reactions in plants and animals as well as in humans. During compounds synthesis in laboratory, it is important to minimize environmental contamination. Therefore, use of deep eutectic solvents is preferable, due to their desirable properties (low toxicity, high availability, low inflammability, high recyclability, low volatility and low price).

The aim of this work was to obtain coumarin derivatives, with potential lipoxygenase inhibiting activity, by environmentally friendly synthetic methods . Synthesis of coumarins were performed via Knoevenagel condensation between different substituted salicylaldehydes and active methylene compounds in deep eutectic solvents, which have role of the solvent and the catalyst. Synthesized coumarin derivatives showed enzyme inhibition in range from 45% to 96%.


This work has been supported in part by Croatian Science Foundation under the project “Green Technologies in Synthesis of Heterocyclic Compounds” (UIP-2017-05-6593).

  • Open access
  • 65 Reads
Synthetic cathinones: Chiral resolution and enantioselectivity studies
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Synthetic cathinones, analogs of cathinone (found in plant Catha edulis), are very interesting bioactive compounds and the most representative constituents of "legal highs" [1]. Their consumption has serious health concerns such as hallucinations, hypertension, tachycardia, and may lead to acute liver and/or kidney failure and rhabdomyolysis [2]. For all these reasons, and the fact that new cathinones continue to be synthesized and consumed, the study of these compounds has an enormous interest. All the synthetic cathinone are chiral and, consequently, their biological and toxicological activities could differ for each of the enantiomers. Despite the growing interest regarding synthetic cathinones, there are only few examples of studies concerning their potential enantioselectivity on bioactivity/toxicity [3]. To perform enantioselectivity studies, it is necessary to obtain both enantiomers with very high enantiomeric purity. Recently, we reported the enantiomeric resolution of several synthetic cathinones by liquid chromatography using two analytical chiral stationary phases based on polysaccharide derivatives [4,5]. The enantioresolution of MDPV, pentedrone and methylone (three of the most commonly used synthetic cathinones worldwide) were scaled up to multi-milligrams for further enantioselectivity studies [4,5]. Both enantiomers of the three cathinones were isolated with high enantiomeric purity. Additionally, the absolute configuration of the enantiomers of pentedrone and methylone was determined by electronic circular dichroism (ECD) spectroscopy, with the aid of theoretical calculations [5]. The toxicity of both enantiomers of MDPV was evaluated using primary cultures of rat hepatocytes, showing similar behavior [4]. Nevertheless, enantioselectivity was observed for pentedrone and methylone enantiomers in dopaminergic SH-SY5Y cells cytotoxicity and reactive species production. Moreover, kinetic studies to evaluate the ability of pentedrone and methylone enantiomers to pass across the intestinal barrier model revealed a differentiated passage of the cathinones enantiomers through intestinal membrane.

Financial supported from Universidade do Porto/FMUP through FSE-Fundo Social Europeu, NORTE 2020-Programa Operaconal Regional do Norte (NORTE-08-5369-FSE-000011). Partially supported by the Strategic Funding UID/Multi/04423/2019 through national funds provided by FCT and ERDF, in the framework of the programme PT2020. Partially supported by FEDER funds through the Operational Programme for Competitiveness and Internationalisation (COMPETE 2020), Portugal, and UID/MULTI/04378/2013 - POCI/01/0145/FEDER/07728.

[1] EMCDDA, New psychoactive substances in Europe. European Monitoring Centre for Drugs and Drug Addiction, 2015.

[2] M.J. Valente, et al., Khat and synthetic cathinones: a review. Arch Toxicol, 2014. 88(1): p. 15-45.

[3] B. Silva, et al., Chiral Resolution and Enantioselectivity of Synthetic Cathinones: A Brief Review, J Anal Toxicol, 2018. 42: p. 17-24.

[4] Silva, B., et al., Chiral enantioresolution of cathinone derivatives present in “legal highs”, and enantioselectivity evaluation on cytotoxicity of 3,4-methylenedioxypyrovalerone (MDPV). Forensic Toxicol, 2016. 34(2): p. 372-385.

[5] Silva, B., et al., Multi-milligram resolution and determination of absolute configuration of pentedrone and methylone enantiomers. J Chromatogr B Analyt Technol Biomed Life Sci, 2018. 1100-1101: p. 158-164.

  • Open access
  • 32 Reads
Nutrient composition, antioxidant and antiproliferative activities of Clausena excavata and Murraya koenigii leaves
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Clausena excavata (CE) and Murraya koenigii (MK) have shown potential medicinal values of herbal plants, thus they were investigated for their nutrient composition. MK possessed higher carbohydrate but lower fiber than CE. Vitamin A is higher in MK but lower vitamin C and E than CE. Antioxidant and antiproliferative activities of CE and MK crude extracts and essential oils and the composition of essential oil were also examined. The hydrodistilled essential oil was analysed by GC/MS. CE and MK leaf oils were made up of safrole and β-farnesene. Phenolic contents of the methanolic extracts of both plants were higher than the water extracts with CE exhibited higher phenolic content. Antioxidant activities were measured via inhibition of linoleic acid oxidation and scavenging of DPPH radicals. The methanolic extracts exhibited significant activities in both assays. MK methanolic extract and oil significantly inhibited linoleic acid oxidation but weakly scavenged DPPH radical than CE. Antiproliferative activities against HepG2, MCF-7, MDA-MB-231, HeLa and CAOV3 were determined using MTT assay. MK methanolic extract and oil possessed the most potent antiproliferative effects. In conclusion, the methanolic extracts especially MK have the great potential in antioxidant and antiproliferative activities. Further investigations are required to explain the underlying mechanisms.

  • Open access
  • 45 Reads
Surface display of human cytochrome P450 enzymes 3A4, 1A2, 2C9, 2C19 and 2D6 with cytochrome P450 reductase for drug metabolism studies
Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5

Cytochrome P450 monooxygenases (CYPs) are responsible for the biotransformation of most known drugs and xenobiotics in human body [1]. As part of the phase-I-metabolism they catalyze a broad diversity of oxidation reactions in an extensive spectrum of substrates. The utilization of CYPs as biocatalysts is limited due to their low stability and their requirement of a membrane surrounding to fold into an active form [2]. Autodisplay of CYPs on the surface of E. coli has been shown an appropriate tool to overcome these limitations [3, 4].

In order to establish an in vitro system to study drug metabolism, the five most important CYPs, CYP 3A4, CYP 1A2, CYP 2C9, CYP 2C19 and CYP 2D6 were displayed on the surface of E. coli. The catalytic activity of CYP 3A4 was shown by testosterone as a substrate using a HPLC assay with external addition of the cytochrome P450 reductase (CPR) [5]. A co‑expression of CYP 1A2 and CPR was established with both enzymes being displayed on the surface of E. coli. Surface display was confirmed by a protease accessibility test and by flow cytometry. Surface displayed CYP 1A2 with co-expressed CPR was able to convert phenacetin to paracetamol, as well as 7‑ethoxyresorufin and 3-cyano-7-ethoxycoumarin to the fluorescent products resorufin [6] and 3-cyano-7-hydroxycoumarin. CYP 2C9, CYP 2C19 and CYP 2D6 were co‑expressed with CPR on the surface of E. coli as well. Combining cells with these five CYP enzymes in an active form on the bacterial cell surface is supposed to provide a suitable approach for the in vitro simulation of drug metabolism.