Danilenko, Nadezhda

Danilenko N.V., Lutsuk M.O., Khlebnikov A.I.

New 4-(benzoxazol-2-yl)phenyl 3-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl sulfate was synthesized via the SuFEx click reaction between fluorosulfate-containing 1,4-naphthoquinone and 2-(4-hydroxyphenyl)benzoxazole. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was used as an organic base, while triethylamine was inactive in this reaction.

Aseeva N.V., Danilenko N.V., Plotnikov E.V., Korotkova E.I., Lipskikh O.I., Solomonenko A.N., Erkovich A.V., Eskova D.D., Khlebnikov A.I.

This study presents the synthesis of new fluorosulfate derivatives of 1,4-naphthoquinone by the SuFEx reaction. Anticancer properties of obtained compounds were studied on PC-3 (prostate adenocarcinoma), SKOV-3 (ovarian cancer), MCF-7 (breast cancer), and Jurkat cell lines. All the studied compounds showed higher cytotoxic effects than Cisplatin. The DFT method was applied to determine the electronic structure characteristics of 1,4-naphthoquinone derivatives associated with cytotoxicity. A method of determination of 2,3-dichloro-1,4-naphthoquinone (NQ), 3-chloro-2-((4-hydroxyphenylamino)-1,4-naphthoquinone (NQ1), and 4-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl fluorosulfate (NQS) in a pharmaceutical substance using an impregnated graphite electrode (IMGE) was developed. The morphology of the IMGE surface was studied using scanning electron microscopy (SEM). The electrochemical behavior of NQ, NQ1, and NQS was studied by cyclic voltammetry (CV) in 0.1 M NaClO4 (96% ethanol solution) at pH 4.0 in a potential range from −1 to +1.2 V. Electrochemical redox mechanisms for the investigated compounds were proposed based on the determining main features of the electrochemical processes. Calibration curves were obtained by linear scan voltammetry in the first derivative mode (LSVFD) with the detection limit (LOD) 7.2 × 10−6 mol·L−1 for NQ, 8 × 10−7 mol·L−1 for NQ1, and 8.6 × 10−8 mol·L−1 for NQS, respectively.

Danilenko N.V., Lutsuk M.O., Patlasova S.E., Korotkova E.I., Khlebnikov A.I.

New 2-(4-(fluorosulfonyloxy)phenyl)benzoxazole (2) was synthesized through the SuFEx click reaction in a two-chamber reactor. The effect of silylation on the yield of the target compound was investigated. The fluorescent properties of compound 2 were determined using experimental and computational methods.

Danilenko N.V., Bolbasov E.N., Khlebnikov A.I., Schepetkin I.A., Tverdokhlebov S.I., Quinn M.T.

• Novel materials for tissue repair after surgical resection of tumors are needed. • Naphthoquinones have been reported to be effective for anticancer therapy. • Electrospun PCL-based scaffolds were loaded with a 1,4-naphthoquinone derivative. • Anticancer activity was retained, yet mechanical properties did not change for doped scaffolds. The development of bioresorbable scaffolds with anticancer properties for use in tissue repair after surgical resection of tumors is important. Naphthoquinones with high anticancer activity are promising compounds for creating anticancer scaffolds. Thus, electrospun polycaprolactone (PCL) scaffolds embedded with different concentrations of 2-chloro-3-((4-hydroxyphenyl)amino)-1,4-naphthoquinonone (NQCP4) were fabricated without changing the technological parameters of scaffold formation. Loading NQCP4 into the spinning solution at concentrations of 10 to 50 μg/mL did not cause changes in the structure, strength, or wettability of the scaffold. However, increasing NQCP4 concentrations in the spinning solution enhanced anticancer properties of the scaffolds in vitro . Thus, the use of NQCP4 makes it possible to obtain promising PCL scaffolds for tissue repair, which are in demand for surgical resection of malignant neoplasms, while still maintaining the technological advantages of “classical” electrospinning technology.

Aseeva N.V., Korotkova E.I., Lipskikh O.I., Khlebnikov A.I., Danilenko N.V.

In this work, we have studied the physicochemical behaviors of oxidation-reduction of 2,3-dichloro-1,4-naphthoquinone (NQ) and 2-chloro-3-((4-hydroxyphenyl) amino)-1,4-naphthoquinone (NQ1) synthesized on the basis of NQ, on impregnated graphite electrode. The nature of the electrochemical processes was determined and the mechanism of oxidation-reduction of substances was assumed. The operating conditions for the voltammetric determination of compounds on an impregnated graphite electrode were selected, such as the supporting electrolyte – 0.1 M NaClO4 solution in 96% ethanol (pH=2 for NQ, pH=10 for NQ1), V=100 mV·s-1, as well as the potential and time of accumulation (Eacc +1 V; tacc 50 s for NQ and Eacc -1 V; tacc 30 s for NQ1). It is shown that the pH of the supporting electrolyte has a high influence on NQ and NQ1 analytical signal. For NQ, the current reaches its maximum value at pH = 2. For NQ1, the opposite effect of pH on the current intensity is observed: the maximum current value is reached at pH = 12. The linear dependence of the reduction peak current at a potential of 0.12 V on the concentration of NQ is observed in the range 2·10-5 – 8·10-4 mol·l-1 with the regression equation I=3.14C - 0.35 (R2=0.9992). For NQ1, the linear range of the calibration curve of the electro oxidation current at a potential of -0.58 V on the concentration is maintained in the range 1·10-6 – 8·10-4 mol·l-1 with regression equation I=45.74C +0.37 (R2=0.9992). The detection limit (LOD) for NQ, calculated according to the 3S criterion, is 7.2·10-6 mol·l-1, for NQ1 8·10-7 mol·l-1. The accuracy of the method of analyzed compounds quantitative determination in the substance was checked by the "spiked test" method.

Cantini N., Schepetkin I.A., Danilenko N.V., Khlebnikov A.I., Crocetti L., Giovannoni M.P., Kirpotina L.N., Quinn M.T.

Persistent inflammation contributes to a number of diseases; therefore, control of the inflammatory response is an important therapeutic goal. In an effort to identify novel anti-inflammatory compounds, we screened a library of pyridazinones and structurally related derivatives that were used previously to identify N-formyl peptide receptor (FPR) agonists. Screening of the compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP1-Blue monocytic cells identified 48 compounds with anti-inflammatory activity. Interestingly, 34 compounds were FPR agonists, whereas 14 inhibitors of LPS-induced NF-κB activity were not FPR agonists, indicating that they inhibited different signaling pathways. Further analysis of the most potent inhibitors showed that they also inhibited LPS-induced production of interleukin 6 (IL-6) by human MonoMac-6 monocytic cells, again verifying their anti-inflammatory properties. Structure–activity relationship (SAR) classification models based on atom pair descriptors and physicochemical ADME parameters were developed to achieve better insight into the relationships between chemical structures of the compounds and their biological activities, and we found that there was little correlation between FPR agonist activity and inhibition of LPS-induced NF-κB activity. Indeed, Cmpd43, a well-known pyrazolone-based FPR agonist, as well as FPR1 and FPR2 peptide agonists had no effect on the LPS-induced NF-κB activity in THP1-Blue cells. Thus, some FPR agonists reported to have anti-inflammatory activity may actually mediate their effects through FPR-independent pathways, as it is suggested by our results with this series of compounds. This could explain how treatment with some agonists known to be inflammatory (i.e., FPR1 agonists) could result in anti-inflammatory effects. Further research is clearly needed to define the molecular targets of pyridazinones and structurally related compounds with anti-inflammatory activity and to define their relationships (if any) to FPR signaling events.

Popkov A.V., Kulbakin D.E., Popkov D.A., Gorbach E.N., Kononovich N.A., Danilenko N.V., Stankevich K.S., Choynzonov E.L., Zheravin А.А., Khlusov I.A., Bondar L.N., Perelmuter V.M., Bolbasov E.N., Tverdokhlebov S.I.

Composite poly-L-lactide acid-based scaffolds with hydroxyapatite (HAp) content up to 75 wt.% were fabricated via solution blow spinning. The influence of HAp concentration on structure, wettability, mechanical properties and chemical and phase composition of the produced materials was examined. It was found that with an increase of HAp content the average fiber diameter was increased, the uniaxial strength and relative elongation were reduced, while the phase composition and surface wettability did not change. The performance of the scaffolds during implantation in the parietal bone of a rat skull for a period from 15 to 90 days was studied. The materials have shown high ability to integrate with both soft and hard tissues. It was found that scaffolds with 25 wt.% HAp content significantly enhance osteogenesis during scarification (damage) of the periosteum. Overall, the fabricated scaffolds proved to be highly efficient for replacing bone defects in long tubular bones.

Danilenko N., Shmalyuk V., Khlebnikov A.

The fluorosulfate derivatives of benzoxazole attract attention since benzoxazole-based compounds have a wide range of biological activities, and the ability of the –SO2F group to react with various functional groups makes it possible to synthesize various new derivatives. The new 2-(2-(fluorosulfonyloxy)phenyl)benzoxazole (2) has been synthesized by the SuFEx click reaction in a two-chamber reactor. Compound 2 is the first example of a benzoxazole derivative with a fluorosulfate-containing substituent at position two of the benzoxazole heterocycle. The anti-cancer potency of 2 was evaluated in silico using molecular docking. The docking results suggest that title compound 2 is of great interest for further studies as a possible anaplastic lymphoma kinase inhibitor.

Kolesnik I., Tverdokhlebova T., Danilenko N., Plotnikov E., Kulbakin D., Zheravin A., Bouznik V., Bolbasov E.

• Porous PTFE membranes are formed by electrospinning from a spinning solution containing a suspension of PTFE and PVA. • The effect of the content of a suspension of PTFE in solution on the physicochemical properties of PTFE membranes before and after heat treatment has been studied. • It was found that membranes containing 50 wt% PTFE suspension have the highest strength after heat treatment. • A hypothesis has been put forward about the plasticizing effect of PVA degradation products on PTFE particles forming membrane fibers. • High biocompatibility of PTFE membranes has been demonstrated in vitro and in vivo. The structure and properties of polytetrafluoroethylene (PTFE) polymeric membranes obtained by electrospinning from a suspension of PTFE in a solution of polyvinyl alcohol (PVA) with subsequent thermal treatment were presented. The effect of the PTFE suspension ratio in spinning solutions on the morphology, crystal structure, chemical composition, strength, and cytotoxicity of the formed PTFE membranes was evaluated. We found that a decrease in the PTFE suspension content in spinning solutions leads to a decrease in the number of defects in the membrane fibers, which increasing the strength and elongation. Membranes made from spinning solutions with a lower content of PTFE suspension have a higher degree of crystallinity and a more perfect crystal structure. It has been suggested that the products of PVA destruction during the heat treatment of PTFE/PVA membranes are capable of plasticizing effects on PTFE particles, improving the strength of PTFE membranes. The membranes after thermal treatment were not cytotoxic regardless of the PTFE suspension content in the spinning solutions. High biocompatibility of membranes was established during implantation into soft tissues.

Goreninskii S., Danilenko N., Bolbasov E., Evtina A., Buldakov M., Cherdyntseva N., Saqib M., Beshchasna N., Opitz J., Filimonov V., Tverdokhlebov S.

Poly(ε-caprolactone)/polyvinylpyrrolidone (PCL/PVP) scaffolds with various composition were fabricated from 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) solution using the same electrospinning parameters in order to reveal the effect of polymer ratio on the material properties. The obtained materials were characterized using scanning electron microscopy, contact angle measurements, X-ray diffraction, Fourier-transformed infrared spectroscopy, and tensile testing. The strengthening effect of PVP was observed: Young modulus of PCL/PVP scaffold with 50/50 polymer ratio was found at 105.4 ± 8.4 MPa which is six times higher comparing to those of PCL scaffold. PVP-containing scaffolds were extremely hydrophilic with PVP concentration of 5 wt% (vs. 25 wt% in previous reports) leading to full wetting of the material. in vitro studies showed an improved viability of HeLa cells cultured with the composites containing higher concentrations of PVP. Owing to the application of HFIP, PCL-based materials were loaded with cyclophosphamide for the first time and the PVP-containing materials demonstrated the intensified initial release of the model compound. Utilizing HFIP for the fabrication of PCL/PVP scaffolds significantly widens their application for drug delivery systems due to a good solubility of proteins, drugs, and other biologically active compounds in this solvent.

Schepetkin I.A., Karpenko A.S., Khlebnikov A.I., Shibinska M.O., Levandovskiy I.A., Kirpotina L.N., Danilenko N.V., Quinn M.T.

Cell division cycle 25 (Cdc25) and mitogen-activated protein kinase kinase 7 (MKK7) are enzymes involved in intracellular signaling but can also contribute to tumorigenesis. We synthesized and characterized the biological activity of 1,4-naphthoquinones structurally similar to reported Cdc25 and(or) MKK7 inhibitors with anticancer activity. Compound 7 (3-[(1,4-dioxonaphthalen-2-yl)sulfanyl]propanoic acid) exhibited high binding affinity for MKK7 (Kd = 230 nM), which was greater than the affinity of NSC 95397 (Kd = 1.1 μM). Although plumbagin had a lower binding affinity for MKK7, this compound and sulfur-containing derivatives 4 and 6-8 were potent inhibitors of Cdc25A and Cdc25B. Derivative 22e containing a phenylamino side chain was selective for MKK7 versus MKK4 and Cdc25 A/B, and its isomer 22f was a selective inhibitor of Cdc25 A/B. Docking studies performed on several naphthoquinones highlighted interesting aspects concerning the molecule orientation and hydrogen bonding interactions, which could help to explain the activity of the compounds toward MKK7 and Cdc25B. The most potent naphthoquinone-based inhibitors of MKK7 and/or Cdc25 A/B were also screened for their cytotoxicity against nine cancer cell lines and primary human mononuclear cells, and a correlation was found between Cdc25 A/B inhibitory activity and cytotoxicity of the compounds. Quantum chemical calculations using BP86 and ωB97X-D3 functionals were performed on 20 naphthoquinone derivatives to obtain a set of molecular electronic properties and to correlate these properties with cytotoxic activities. Systematic theoretical DFT calculations with subsequent correlation analysis indicated that energy of the lowest unoccupied molecular orbital E(LUMO), vertical electron affinity (VEA), and reactivity index ω of these molecules were important characteristics related to their cytotoxicity. The reactivity index ω was also a key characteristic related to Cdc25 A/B phosphatase inhibitory activity. Thus, 1,4-naphthoquinones displaying sulfur-containing and phenylamino side chains with additional polar groups could be successfully utilized for further development of efficacious Cdc25 A/B and MKK7 inhibitors with anticancer activity.

Goreninskii S.I., Guliaev R.O., Stankevich K.S., Danilenko N.V., Bolbasov E.N., Golovkin A.S., Mishanin A.I., Filimonov V.D., Tverdokhlebov S.I.

In the present study, we report a simple and efficient method of gelatin immobilization on the surface of PLA electrospun fibers using pre-treatment with a mixture of toluene and ethanol allowing to form swelled surface layer followed by gelatin adsorption from its solution in PBS. Our results demonstrate that gelatin immobilization leads to a decrease in the water contact angle from 120° to 0°, enhances scaffold strength up to 50%, and doubles the number of adhered cells and their average area. We observed that the maximum amount of gelatin (0.07 ± 0.01 mg per cm3 of the scaffold) was immobilized during the first five minutes of exposure to the gelatin solution. Modified scaffolds demonstrated increased strength.

Goreninskii S.I., Stankevich K.S., Bolbasov E.N., Danilenko N.V., Filimonov V.D., Tverdokhlebov S.I.

Three dimensional nanofiber materials made of poly-L-lactic acid (PLLA) and produced by electrospinning are commonly used in regenerative medicine and as a base for drug delivery systems. Surface modification of such materials allows manipulating their chemical, physical, and biological properties. Previously, our group reported a number of modification strategies for thin PLLA films, based on the “solvent/non-solvent” technique. Most biologically active agents may not be adsorbed on the surface of PLLA. Proposed treatment allows partially dissolving the polymer surface in order to adsorb biologically active molecules or linkers. The aim of this work was to investigate the influence of solvent/non-solvent mixture composition on the morphology and crystal structure of the electrospun PLLA scaffolds and to select the solvent system for further scaffolds modification in order to impart them biological activity. PLLA scaffolds were treated with mixtures of toluene and ethanol in different compositions. By means of scanning electron microscopy, it was shown that solvent/non-solvent treatment had no critical effect on the morphology of the scaffolds. The results of X-ray diffraction analysis revealed that treatment of the scaffolds with investigated solvent systems did not lead to the formation of the additional phases and the size of the polymer crystallites as well. Thus, selected solvent system will be used for modification of the PLLA electrospun nanofiber material for biomedical application.

Stankevich K.S., Danilenko N.V., Gadirov R.M., Goreninskii S.I., Tverdokhlebov S.I., Filimonov V.D.

A new approach for the immobilization of poly(acrylic) acid (PAA) as a chemically reactive cross-linker on the surface of poly(lactic) acid-based (PLA) biomaterials is described. The proposed technique includes non-covalent attachment of a PAA layer to the surface of PLA-based biomaterial via biomaterial surface treatment with solvent/non-solvent mixture followed by the entrapment of PAA from its solution. Surface morphology and wettability of the obtained PLA-PAA composite materials were investigated by AFM and the sitting drop method respectively. The amount of the carboxyl groups on the composites surface was determined by using the fluorescent compounds (2-(5-aminobenzo[d]oxazol-2-yl)phenol (ABO) and its acyl derivative N-(2-(2-hydroxyphenyl)benzo[d]oxazol-5-yl)acetamide (AcABO)). It was shown that it is possible to obtain PLA-PAA composites with various surface relief and tunable wettability (57°, 62° and 66°). The capacity of the created PAA layer could be varied from 1.5nmol/cm2 to 0.1μmol/cm2 depending on the modification conditions. Additionally, using bovine serum albumin (BSA) it was demonstrated that such composites could be modified with proteins with high binding density (around 0.18nmol/cm2). Obtained fluoro-labeled PLA-PAA materials, as well as PLA-PAA composites themselves, are valuable since they can be used for biodegradable polymer implants tracking in living systems and as drug delivery systems.

Goreninskii S., Stankevich K., Bolbasov E., Danilenko N., Filimonov V., Tverdokhlebov S.

Electrospun biodegradable scaffolds (matrixes) made of poly(e-caprolactone) (PCL) and poly(L-lactic acid) (PLLA) are three-dimensional fibrous structures that are commonly used in regenerative medicine and drug delivery systems. Modification of such structures allows manipulating with biological and immune response. Previously, our team suggested a number of surface modification strategies for thin films made of PLLA. One of the proposed strategies are based on treatment of the material with “solvent/non-solvent” mixture that allows absorbing biologically active molecules or linkers on the surface of the sample. The aim of this work was to compare the influence of “solvent/non-solvent” treatment on the structure and crystallinity of the elecrospun biodegradable PCL and PLLA scaffolds. For that purpose, original PCL and PLLA scaffolds were treated with mixture of toluene and ethanol in different proportions. Morphology of the obtained samples was studied using scanning electron microscopy. It was shown that “solvent/non-solvent” treatment doesn’t lead to changes in scaffolds morphology such as gluing or cutting of the matrix fibers. By means of X-ray diffraction analysis it was shown that treatment of the samples with selected mixtures doesn’t change material crystallinity. Thus, it was demonstrated that proposed composition of the “solvent/nonsolvent” mixture can be used for the modification of electrospun PCL and PLLA scaffolds.

Villegas C., González-Chavarría I., Burgos V., Cabrera-Pardo J.R., Schmidt B., Paz C.

Germacranes are a type of sesquiterpene lactones with anti-inflammatory and cytotoxic properties against cancer cell lines. In this in vitro study, erioflorin and erioflorin acetate were isolated and purified from the leaves of Podanthus mitiqui Lindl (Mitique or Mitriu), a shrub endemic to Chile and traditionally used in Mapuche medicine to treat urinary and digestive disorders. Their effects on advanced prostate cancer cell lines (DU-145 and 22Rv1) were evaluated. Cytotoxicity was assessed using real-time cell death and clonogenic assays. Apoptosis was determined by measuring reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and apoptotic cell percentage through flow cytometry. Gene expression of BAX and BCL-2 was analyzed via RT-qPCR, while NF-κB activation was studied in DU-145 cells and human monocytic NF-κB reporter assays using LPS stimulation and alkaline phosphatase activity quantification. Erioflorin acetate exhibited the highest cytotoxicity, with IC50 values of 35.1 µM (22Rv1) and 27.3 µM (DU-145), compared to erioflorin, which had IC50 values of 50.3 µM and 56.5 µM, respectively. Both compounds increased ROS levels, reduced ΔΨm, and induced apoptosis. RT-qPCR analysis revealed that erioflorin elevated the BAX/BCL-2 ratio, and both compounds inhibited NF-κB activation by preventing IκBα phosphorylation. In conclusion, the findings demonstrate that erioflorin and erioflorin acetate exert significant in vitro cytotoxic and cytostatic effects on prostate cancer cells, supporting their potential as natural candidates for prostate cancer therapy.

Xiang S., Li Y., Khan S.N., Zhang W., Yuan G., Cui J.

Cancer remains a primary cause of mortality, with over 18.1 million new cases and 9.6 million deaths globally in 2018. Chemotherapy, which utilizes a spectrum of cytotoxic drugs targeting the rapidly dividing cancer cells, is a predominant treatment modality. However, the tendency of chemotherapeutics to induce drug resistance and exhibit non-specific cytotoxicity necessitates the development of new anticancer agents with heightened efficacy and minimized toxicity. In recent years, the discovery of safe and effective antibacterial/antiviral agents has also been a hot spot in medicinal chemistry. This paper comprehensively reviews the synthesis, anticancer/antibacterial/antiviral activity, and structure–activity relationships of natural 1,4-naphthoquinones and their derivatives. It highlights their potential as efficient and low-toxicity antitumor and anti-infectious drug candidates.

Golovina E.L., Serebryakova V.A., Vaizova O.E.

Introduction. Cancer is the leading cause of death worldwide. Naphthoquinones are a group of natural organic compounds with a wide range of activity, including cardio-, hepato-, neuroprotective effects, as well as antimicrobial, anti-inflammatory and antitumor activity. 1,4-naphthoquinone is easily oxidized, reduced, and may be easily attached with nucleophiles. Well-developed methods of chemical modification of naphthoquinones make them attractive for the development of new types substances. It is known about the antitumor effect of natural naphthoquinone compounds – plumbagin, shikonin, lapachol. Antitumor antibiotics such as doxorubicin and daunorubicin have a 1,4-naphthoquinone fragment in their structure.Text. This review is devoted to the analysis of information on the mechanisms of antitumor action of synthetic derivatives of 1,4-naphthoquinone. Possible targets of their antitumor action are discussed.Conclusion. An analysis of the literature data showed that synthetic compounds based on the 1,4-naphthoquinone molecule have antitumor activity. The mechanism of antitumor action may be associated with the induction of apoptosis through the signaling pathway of mitogen-activated protein kinase (MAPK) and the pathway of the signal transducer and activator of transcription 3 (STAT3), inhibition of cell division cycle phosphatase (Cdc25), accumulation of reactive oxygen species (ROS), inhibition of angiogenesis. The data obtained by researchers from different countries confirm the prospects of searching for new compounds with antitumor activity among synthetic derivatives of 1,4-naphthoquinone for the development of new medicines based on them.

Sk M.S., Mwangomo R., Daniel L., Gilmore J.

ABSTRACTApplication of one‐dimensional nanofibers have witnessed exponential growth over the past few decades and are still emerging with their excellent physicochemical and electrical properties. The driving force behind this intriguing transition lies in their unique high surface‐to‐volume ratio, ubiquitous nanodomains, improved tensile strength, and flexibility to incorporate deliberate functionalities required for specific and advanced applications. Besides numerous benefits, nanomaterials may adversely interact with biological tissues and potentially be cytotoxic and carcinogenic. However, precisely engineered design can outperform the risk with myriad benefits. Wound care technologies are evolving, and products involved in wound care management have a yearly market value of $15–22 billion. Solution blow spinning (SBS) is a facile technique to synthesize biocompatible nanofibers with scalable processing variables for multidirectional biomedical applications. SBS is feasible for a wide range of thermoplastic polymers and nanomaterials to fabricate nanocomposites. This review will focus on the relevance of SBS technology for wound care, including dressings, drug delivery, tissue engineering scaffolds, and sensors.

Madani M., Cruz C.D., Gounani Z., Baniasadi H., Tammela P., Laaksonen T., Niskanen J., Seppälä J.

Stoykov I.I., Antipin I.S., Burilov V.A., Kurbangalieva A.R., Rostovsky N.V., Pankova A.S., Balova I.A., Remizov Y.O., Pevzner L.M., Petrov M.L., Vasily A.V., Averin A.D., Beletskaya I.P., Nenaydenko V.G., Beloglazkina E.K., et. al.

An overview of the main scientific achievements of Russian universities in the field of organic chemistry for the period 2018–2023 is presented.

Danilenko N.V., Lutsuk M.O., Khlebnikov A.I.

New 4-(benzoxazol-2-yl)phenyl 3-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl sulfate was synthesized via the SuFEx click reaction between fluorosulfate-containing 1,4-naphthoquinone and 2-(4-hydroxyphenyl)benzoxazole. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was used as an organic base, while triethylamine was inactive in this reaction.

Aseeva N.V., Danilenko N.V., Plotnikov E.V., Korotkova E.I., Lipskikh O.I., Solomonenko A.N., Erkovich A.V., Eskova D.D., Khlebnikov A.I.

This study presents the synthesis of new fluorosulfate derivatives of 1,4-naphthoquinone by the SuFEx reaction. Anticancer properties of obtained compounds were studied on PC-3 (prostate adenocarcinoma), SKOV-3 (ovarian cancer), MCF-7 (breast cancer), and Jurkat cell lines. All the studied compounds showed higher cytotoxic effects than Cisplatin. The DFT method was applied to determine the electronic structure characteristics of 1,4-naphthoquinone derivatives associated with cytotoxicity. A method of determination of 2,3-dichloro-1,4-naphthoquinone (NQ), 3-chloro-2-((4-hydroxyphenylamino)-1,4-naphthoquinone (NQ1), and 4-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl fluorosulfate (NQS) in a pharmaceutical substance using an impregnated graphite electrode (IMGE) was developed. The morphology of the IMGE surface was studied using scanning electron microscopy (SEM). The electrochemical behavior of NQ, NQ1, and NQS was studied by cyclic voltammetry (CV) in 0.1 M NaClO4 (96% ethanol solution) at pH 4.0 in a potential range from −1 to +1.2 V. Electrochemical redox mechanisms for the investigated compounds were proposed based on the determining main features of the electrochemical processes. Calibration curves were obtained by linear scan voltammetry in the first derivative mode (LSVFD) with the detection limit (LOD) 7.2 × 10−6 mol·L−1 for NQ, 8 × 10−7 mol·L−1 for NQ1, and 8.6 × 10−8 mol·L−1 for NQS, respectively.

Zhou S., Liu Z., Jin Y., Huang Y., Fang Y., Tian H., Wu H.

Traditional dressings have shortcomings such as poor moisture absorption and easy to adhere, making the development of new dressings crucial. In this work, a PLA/PVP crosslinked drug-loaded nanofiber membrane was prepared through electrospinning and ultraviolet crosslinking, with poly (lactic acid) (PLA), polyvinylpyrrolidone (PVP), and salicylic acid (SA) as starting materials. The results demonstrated that the inclusion of PVP notably boosted the viscosity and conductivity of the blend spinning solution. The roughness of the fabricated fiber was elevated, and the diameter of the fibers was more uniform. Additionally, the incorporation of PVP not only enhanced the porosity of the fiber membrane but also effectively decreased its contact angle. Notably, when the PVP content reached 40 %, the contact angle underwent a substantial reduction, decreasing significantly from 125.4° to 82.2°. The SA drug-loaded fiber membrane exhibited a notable bacteriostatic effect against Escherichia coli and Staphylococcus aureus, with its release behavior adhering to Fick's diffusion law. In the cell viability experiment, the cell proliferation rate increased from 94 % to 129 % after 3 days. This shows that the prepared membrane has good antibacterial effect and cell compatibility, which provides a theoretical basis for the construction of a new medical dressing.

da Silva V.C., Gomes D.D., de Medeiros E.L., Santos A.M., de Lima I.L., Rosa T.P., Rocha F.S., Filice L.D., Neves G.D., Menezes R.R.

This work presents the successful production of highly porous 3D nanofibrous hybrid scaffolds of polylactic acid (PLA)/polyethylene glycol (PEG) blends with the incorporation of calcium phosphate (CaP) bioceramics by a facile two-step process using the solution blow spinning (SBS) technique. CaP nanofibers were obtained at two calcium/phosphorus (Ca/P) ratios, 1.67 and 1.1, by SBS and calcination at 1000 °C. They were incorporated in PLA/PEG blends by SBS at 10 and 20 wt% to form 3D hybrid cotton-wool-like scaffolds. Morphological analysis showed that the fibrous scaffolds obtained had a randomly interconnected and highly porous structure. Also, the mean fiber diameter ranged from 408 ± 141 nm to 893 ± 496 nm. Apatite deposited considerably within 14 days in a simulated body fluid (SBF) test for hybrid scaffolds containing a mix of hydroxyapatite (HAp) and tri-calcium phosphate-β (β-TCP) phases. The scaffolds with 20 wt% CaP and a Ca/P ration of 1.1 showed better in vitro bioactivity to induce calcium mineralization for bone regeneration. Cellular tests evidenced that the developed scaffolds can support the osteogenic differentiation and proliferation of pre-osteoblastic MC3T3-E1 cells into mature osteoblasts. The results showed that the developed 3D scaffolds have potential applications for bone tissue engineering.

Baklan D., Bilousova A., Pitak Y.

Piskunov M., Piskunova A., Ashikhmin A., Melnik E., Bolbasov E.

This study deals with the impact of a microgel particle-laden drop of the water–agar solution onto nanofiber mats of different wettability at Weber numbers in the range of 14–502 and initial velocities in the range of 0.32–1.83 m/s. We examined the effects of inertia and the competition between the wetting and antiwetting pressures within the liquid impalement on the hydrodynamic behavior of drops in the spreading and contraction phases. Hydrophilic mat representing a full water absorption coating is manufactured by electrospinning from a mixture of polycaprolactone and polyvinylpyrrolidone; hydrophobic—from polytetrafluoroethylene. The micro- and nanoscale characteristics of nanofiber mats are analyzed by scanning electron microscopy and atomic force microscopy, respectively. A physical model of liquid flow under an impacting microgel particle-laden drop along and inside the micro- and nanostructures of nanofiber mats is proposed. Empirical expressions for the prediction of drop impact hydrodynamics are derived. By introducing the impalement factor, which is physically close to the Euler number, they take into account the difference between wetting and anti-wetting pressures in addition to inertia. Microgel particle-laden drop deposition accounting for the effect of liquid impalement inside nanofiber materials with different wettability is expected to enhance the efficiency of bioprinting polymer layers in tissue engineering.

Goreninskii S.I., Melnik E.Y., Plotnikov E.V., Eskova D.D., Zvyagin A.V., Bolbasov E.N., Tverdokhlebov S.I.

Sharma B., Dhiman C., Hasan G.M., Shamsi A., Hassan M.I.

Plumbagin (PLB) is a naphthoquinone extracted from Plumbago indica. In recent times, there has been a growing body of evidence suggesting the potential importance of naphthoquinones, both natural and artificial, in the pharmacological world. Numerous studies have indicated that PLB plays a vital role in combating cancers and other disorders. There is substantial evidence indicating that PLB may have a significant role in the treatment of breast cancer, brain tumours, lung cancer, hepatocellular carcinoma, and other conditions. Moreover, its potent anti-oxidant and anti-inflammatory properties offer promising avenues for the treatment of neurodegenerative and cardiovascular diseases. A number of studies have identified various pathways that may be responsible for the therapeutic efficacy of PLB. These include cell cycle regulation, apoptotic pathways, ROS induction pathways, inflammatory pathways, and signal transduction pathways such as PI3K/AKT/mTOR, STAT3/PLK1/AKT, and others. This review aims to provide a comprehensive analysis of the diverse pharmacological roles of PLB, examining the mechanisms through which it operates and exploring its potential applications in various medical conditions. In addition, we have conducted a review of the various formulations that have been reported in the literature with the objective of enhancing the efficacy of the compound. However, the majority of the reviewed data are based on in vitro and in vivo studies. To gain a comprehensive understanding of the safety and efficacy of PLB in humans and to ascertain its potential integration into therapeutic regimens for cancer and chronic diseases, rigorous clinical trials are essential. Finally, by synthesizing current research and identifying gaps in knowledge, this review seeks to enhance our understanding of PLB and its therapeutic prospects, paving the way for future studies and clinical applications.

Baklan D., Bilousova A., Wesolowski M.

In this work, the resistance of polylactide-based non-wovens produced by solution blow spinning to environmental factors was investigated. An average contact angle of up to 136° was achieved with an average fiber diameter of 340 nm at the optimal material density and nozzle–substrate distance. When exposed to ultraviolet (UV) radiation, the polylactide non-wovens rapidly lose their hydrophobic properties due to changes in surface morphology resulting from fiber melting. It was demonstrated that the influence of surface structural features on hydrophobicity is greater than that of the material itself. The stability of the wetting properties under UV irradiation was assessed using the derivative parameters of the Owens–Wendt technique, which can serve as an additional method for estimating surface polarity.

Aseeva N.V., Danilenko N.V., Plotnikov E.V., Korotkova E.I., Lipskikh O.I., Solomonenko A.N., Erkovich A.V., Eskova D.D., Khlebnikov A.I.

This study presents the synthesis of new fluorosulfate derivatives of 1,4-naphthoquinone by the SuFEx reaction. Anticancer properties of obtained compounds were studied on PC-3 (prostate adenocarcinoma), SKOV-3 (ovarian cancer), MCF-7 (breast cancer), and Jurkat cell lines. All the studied compounds showed higher cytotoxic effects than Cisplatin. The DFT method was applied to determine the electronic structure characteristics of 1,4-naphthoquinone derivatives associated with cytotoxicity. A method of determination of 2,3-dichloro-1,4-naphthoquinone (NQ), 3-chloro-2-((4-hydroxyphenylamino)-1,4-naphthoquinone (NQ1), and 4-((3-chloro-1,4-naphthoquinon-2-yl)amino)phenyl fluorosulfate (NQS) in a pharmaceutical substance using an impregnated graphite electrode (IMGE) was developed. The morphology of the IMGE surface was studied using scanning electron microscopy (SEM). The electrochemical behavior of NQ, NQ1, and NQS was studied by cyclic voltammetry (CV) in 0.1 M NaClO4 (96% ethanol solution) at pH 4.0 in a potential range from −1 to +1.2 V. Electrochemical redox mechanisms for the investigated compounds were proposed based on the determining main features of the electrochemical processes. Calibration curves were obtained by linear scan voltammetry in the first derivative mode (LSVFD) with the detection limit (LOD) 7.2 × 10−6 mol·L−1 for NQ, 8 × 10−7 mol·L−1 for NQ1, and 8.6 × 10−8 mol·L−1 for NQS, respectively.

de Oliveira J.C., Abreu B.U., Paz E.R., Almeida R.G., Honorato J., Souza C.P., Fantuzzi F., Ramos V.F., Menna-Barreto R.F., Araujo M.H., Jardim G.A., da Silva Júnior E.N.

AbstractHerein, we describe the Ru‐catalyzed C−H alkenylation of 1,4‐naphthoquinones (1,4‐NQs), resulting in 1,4‐naphthoquinoidal/SuFEx hybrids with moderate to good yields. This method provides a novel route for direct access to ethenesulfonyl‐fluorinated quinone structures. We conducted mechanistic studies to gain an in‐depth understanding of the elementary steps of the reaction. Additionally, we evaluated the prototypes against trypomastigote forms of T. cruzi, leading to the identification of compounds with potent trypanocidal activity.

Ishikawa T., Eguchi Y., Igarashi M., Okajima T., Mita K., Yamasaki Y., Sumikura K., Okumura T., Tabuchi Y., Hayashi C., Pasqua M., Coluccia M., Prosseda G., Colonna B., Kohayakawa C., et. al.

AbstractWaldiomycin is an inhibitor of histidine kinases (HKs). Although most HK inhibitors target the ATP-binding region, waldiomycin binds to the intracellular dimerization domain (DHp domain) with its naphthoquinone moiety presumed to interact with the conserved H-box region. To further develop inhibitors targeting the H-box, various 2-aminonaphthoquinones with cyclic, aliphatic, or aromatic amino groups and naphtho [2,3-d] isoxazole-4,9-diones were synthesized. These compounds were tested for their inhibitory activity (IC50) against WalK, an essential HK for Bacillus subtilis growth, and their minimum inhibitory concentrations (MIC) against B. subtilis. As a result, 11 novel HK inhibitors were obtained as naphthoquinone derivatives (IC50: 12.6–305 µM, MIC: 0.5–128 µg ml−1). The effect of representative compounds on the expression of WalK/WalR regulated genes in B. subtilis was investigated. Four naphthoquinone derivatives induced the expression of iseA (formerly yoeB), whose expression is negatively regulated by the WalK/WalR system. This suggests that these compounds inhibit WalK in B. subtilis cells, resulting in antibacterial activity. Affinity selection/mass spectrometry analysis was performed to identify whether these naphthoquinone derivatives interact with WalK in a manner similar to waldiomycin. Three compounds were found to competitively inhibit the binding of waldiomycin to WalK, suggesting that they bind to the H-box region conserved in HKs and inhibit HK activity.

Abhishek Singh T., Sharma V., Thakur N., Tejwan N., Sharma A., Das J.

In the present study, we prepared novel and multifunctional carbon dots/magnesium oxide (CDs/MgO) nanocomposites with varied amount of CDs (0.5–5 wt%) via a facile hydrothermal process. The nanocomposites were then utilized for the fabrication of CDs/MgO-modified screen printed carbon electrodes (CDs/MgO/SPCE) for highly sensitive and selective electrochemical detection of the anticancer drug doxorubicin (DOX) using cyclic voltammetry. All the prepared CDs/MgO nanocomposites possess excellent efficiency towards the electrochemical oxidation of the DOX at the surface of SPCE by facilitating electron transfer reaction with increasing concentration of CDs in comparison with bare MgO nanoparticles (NPs) and CDs due to increased electroactive surface area. Besides, the oxidation peak current was also found to be increased with increasing scan rate from 50 to 150 mV/s−1. The CDs-5.0/MgO nanocomposite exhibited maximum oxidation response for the detection of DOX (10 µM) at pH 5 and at a scan rate of 50 mV/s−1. Under the optimized conditions, CDs-5.0/MgO modified SPCE exhibited a linear response for the determination of DOX in the concentration range of 0.1–1 µM (correlation coefficient, R2 = 0.99) with a low detection limit of 0.09 µM. Furthermore, a negligible effect of the common interfering agents validated the superior selectivity of the sensor (CDs-5.0/MgO/SPCE) towards DOX. The suitable linear range, low detection limit, rapid response, and excellent sensitivity of the proposed sensor (CDs/MgO/SPCE) make it a promising tool for the determination of DOX in biological, clinical, and pharmaceutical fields.

Navarro-Tovar G., Vega-Rodríguez S., Leyva E., Loredo-Carrillo S., de Loera D., López-López L.I.

Natural product derivatives are essential in searching for compounds with important chemical, biological, and medical applications. Naphthoquinones are secondary metabolites found in plants and are used in traditional medicine to treat diverse human diseases. Considering this, the synthesis of naphthoquinone derivatives has been explored to contain compounds with potential biological activity. It has been reported that the chemical modification of naphthoquinones improves their pharmacological properties by introducing amines, amino acids, furan, pyran, pyrazole, triazole, indole, among other chemical groups. In this systematic review, we summarized the preparation of nitrogen naphthoquinones derivatives and discussed their biological effect associated with redox properties and other mechanisms. Preclinical evaluation of antibacterial and/or antitumoral naphthoquinones derivatives is included because cancer is a worldwide health problem, and there is a lack of effective drugs against multidrug-resistant bacteria. The information presented herein indicates that naphthoquinone derivatives could be considered for further studies to provide drugs efficient in treating cancer and multidrug-resistant bacteria.

Rahman M.M., Islam M.R., Akash S., Shohag S., Ahmed L., Supti F.A., Rauf A., Aljohani A.S., Al Abdulmonem W., Khalil A.A., Sharma R., Thiruvengadam M.

One of the leading global causes of death is cancer; even though several treatment methods have improved survival rates, the incidence and fatality rates remain high. Naphthoquinones are a type of quinone that is found in nature and has vital biological roles. These chemicals have anticancer (antineoplastic), analgesic, anti-inflammatory, antimalarial, antifungal, antiviral, antitrypanosomal, antischistosomal, leishmanicidal, and anti-ulcerative effects. Direct addition of a substituent group to the 1,4-naphthoquinone ring can alter the naphthoquinone's oxidation/reduction and acid/base characteristics, and the activity can be altered. Because of their pharmacological properties, such as anticancer activity and probable therapeutic application, naphthoquinones have greatly interested the scientific community. Some chemicals having a quinone ring in malignant cells have been found to have antiproliferative effects. Naphthoquinones' deadly impact is connected with the inhibition of electron transporters, the uncoupling of oxidative phosphorylation, the creation of ROS, and the formation of protein adducts, notably with -SH enzyme groups. This review article aims to discuss naphthoquinones and their derivatives, which act against cancer and their future perspectives. This review covers several studies highlighting the potent anticancer properties of naphthoquinones. Further, various proposed mechanisms of anticancer actions of naphthoquinones have been summarized in this review.

Leote R.J., Sanz C.G., Diculescu V.C.

• Shikonin, a natural compound with pharmaceutical properties; • Shikonin reduction results in semiquinone radical and superoxide; • Shikonin induces DNA conformational modification. • In-situ shikonin reduction leads to occurrence 8-oxo-guanine. • Shikonin-DNA interaction mechanism proposed. Shikonin, a natural compound with pharmaceutical properties, has attracted interest due to its anti-oxidant properties, potential anti-cancer activity and activity over several biological pathways, such as dsDNA transcription/replication of cancer cells and inhibition of pyruvate kinase M2. The electrochemical behavior of shikonin in aqueous media was investigated at glassy carbon electrodes by cyclic and differential pulse voltammetry. The reduction involves the quinone moiety and formation of a semiquinone intermediate. In the absence of dissolved oxygen, the reduction is reversible while in normal atmosphere leads to formation of superoxide cation. The oxidation occurs at the dihydroxy moiety and reversibility was only observed in acid electrolytes. A redox mechanism was proposed. The interaction between shikonin and ds DNA was evaluated in incubated solutions and in situ with the dsDNA-electrochemical biosensor. The mechanism of interaction is time-dependent and follows an initial binding step at the grooves of the double strand leading to conformational modifications recognized through the variation of guanine and adenine oxidation peaks. The in-situ electrochemical production of the semiquinone intermediate leads to a preferential interaction with guanine residues, promoting their oxidation and consequently occurrence 8-oxo-guanine. An interaction mechanism was proposed.

Zhang Z., Chen L., Tian H., Liu M., Jiang S., Shen J., Wang K., Cao Z.

A deepening understanding of the relationship between transient receptor potential canonical channel 5 (TRPC5) and chronic kidney disease (CKD), has led to the emergence of several types of TRPC5 inhibitors displaying clear therapeutic effect. Herein, we report the synthesis and biological evaluation of a series of pyrroledione TRPC5 inhibitors, culminating in the discovery of compound 16g with subtype selectivity. Compared with GFB-8438, a potent TRPC5 inhibitor (Goldfinch Bio), compound 16g showed improved inhibition of TRPC5 and enhanced protective effect against protamine sulfates (PS)-induced podocyte injury in vitro. In addition, compound 16g did not induce cell death in primary cultured hepatocytes and immortalized podocytes in a preliminary toxicity assessment, indicating its utility as a potent and safe inhibitor for studying the function of TRPC5.

Richter K., Papke R.L., Stokes C., Roy D.C., Espinosa E.S., Wolf P.M., Hecker A., Liese J., Singh V.K., Padberg W., Schlüter K., Rohde M., McIntosh J.M., Morley B.J., Horenstein N.A., et. al.

Activation of nicotinic acetylcholine receptors (nAChRs) expressed by innate immune cells can attenuate pro-inflammatory responses. Silent nAChR agonists, which down-modulate inflammation but have little or no ionotropic activity, are of outstanding clinical interest for the prevention and therapy of numerous inflammatory diseases. Here, we compare two silent nAChR agonists, phosphocholine, which is known to interact with nAChR subunits α7, α9, and α10, and pCF3-N,N-diethyl-N′-phenyl-piperazine (pCF3-diEPP), a previously identified α7 nAChR silent agonist, regarding their anti-inflammatory properties and their effects on ionotropic nAChR functions. The lipopolysaccharide (LPS)-induced release of interleukin (IL)-6 by primary murine macrophages was inhibited by pCF3-diEPP, while phosphocholine was ineffective presumably because of instability. In human whole blood cultures pCF3-diEPP inhibited the LPS-induced secretion of IL-6, TNF-α and IL-1β. The ATP-mediated release of IL-1β by LPS-primed human peripheral blood mononuclear leukocytes, monocytic THP-1 cells and THP-1-derived M1-like macrophages was reduced by both phosphocholine and femtomolar concentrations of pCF3-diEPP. These effects were sensitive to mecamylamine and to conopeptides RgIA4 and [V11L; V16D]ArIB, suggesting the involvement of nAChR subunits α7, α9 and/or α10. In two-electrode voltage-clamp measurements pCF3-diEPP functioned as a partial agonist and a strong desensitizer of classical human α9 and α9α10 nAChRs. Interestingly, pCF3-diEPP was more effective as an ionotropic agonist at these nAChRs than at α7 nAChR. In conclusion, phosphocholine and pCF3-diEPP are potent agonists at unconventional nAChRs expressed by monocytic and macrophage-like cells. pCF3-diEPP inhibits the LPS-induced release of pro-inflammatory cytokines, while phosphocholine is ineffective. However, both agonists signal via nAChR subunits α7, α9 and/or α10 to efficiently down-modulate the ATP-induced release of IL-1β. Compared to phosphocholine, pCF3-diEPP is expected to have better pharmacological properties. Thus, low concentrations of pCF3-diEPP may be a therapeutic option for the treatment of inflammatory diseases including trauma-induced sterile inflammation.

Tan Y., Chu Z., Shan H., Zhangsun D., Zhu X., Luo S.

The α7 nicotinic acetylcholine receptor (nAChR) is widely distributed in the central and peripheral nervous systems and is closely related to a variety of nervous system diseases and inflammatory responses. The α7 nAChR subtype plays a vital role in the cholinergic anti-inflammatory pathway. In vivo, ACh released from nerve endings stimulates α7 nAChR on macrophages to regulate the NF-κB and JAK2/STAT3 signaling pathways, thereby inhibiting the production and release of downstream proinflammatory cytokines and chemokines. Despite a considerable level of recent research on α7 nAChR-mediated immune responses, much is still unknown. In this study, we used an agonist (PNU282987) and antagonists (MLA and α-conotoxin [A10L]PnIA) of α7 nAChR as pharmacological tools to identify the molecular mechanism of the α7 nAChR-mediated cholinergic anti-inflammatory pathway in RAW264.7 mouse macrophages. The results of quantitative PCR, ELISAs, and transcriptome analysis were combined to clarify the function of α7 nAChR regulation in the inflammatory response. Our findings indicate that the agonist PNU282987 significantly reduced the expression of the IL-6 gene and protein in inflammatory macrophages to attenuate the inflammatory response, but the antagonists MLA and α-conotoxin [A10L]PnIA had the opposite effects. Neither the agonist nor antagonists of α7 nAChR changed the expression level of the α7 nAChR subunit gene; they only regulated receptor function. This study provides a reference and scientific basis for the discovery of novel α7 nAChR agonists and their anti-inflammatory applications in the future.

Crocetti L., Vergelli C., Guerrini G., Giovannoni M.P., Kirpotina L.N., Khlebnikov A.I., Ghelardini C., Di Cesare Mannelli L., Lucarini E., Schepetkin I.A., Quinn M.T.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, cartilage damage and bone destruction. Although the pharmacological treatment of RA has evolved over the last few years, the new drugs have serious side effects and are very expensive. Thus, the research has been directed in recent years towards new possible targets. Among these targets, N-formyl peptide receptors (FPRs) are of particular interest. Recently, the mixed FPR1/FPR2 agonist Cpd43, the FPR2 agonist AT-01-KG, and the pyridine derivative AMC3 have been shown to be effective in RA animal models. As an extension of this research, we report here a new series of pyridinone derivatives containing the (substituted)phenyl acetamide chain, which was found to be essential for activity, but with different substitutions at position 5 of the scaffold. The biological results were also supported by molecular modeling studies and additional pharmacological tests on AMC3 have been performed in a rat model of RA, by repeating the treatments of the animals with 10 mg/kg/day of compound by 1 week.

Potyrak K., Wiatrak B., Krzyżak E., Szczukowski Ł., Świątek P., Szeląg A.

Alzheimer's disease is one of the most serious disorders of the 21st century. There is still no effective therapy for this condition. The study investigated the potential regenerative effect of four pyrrolo[3,4-d]pyridazinone derivatives in cultures of SH-SY5Y neuron-like cells preincubated with lipopolysaccharide (LPS) or cocultured with microglia-like cells. In addition to the traditional investigation of the effect on viability, the level of free radicals and nitric oxide, the average length of neurites was also measured. Via in silico studies, the possibility of penetration of the blood-brain barrier (BBB) by the tested compounds was assessed. The administration of LPS to the culture of SH-SY5Y cells as well as coculturing with microglia-like cells had a significant negative effect on the results of all the assays performed. The treatment with the tested derivatives in most cases significantly reduced this negative effect. The obtained results suggest that the compound L2 may have a beneficial impact on neuronal damage caused by LPS or proinflammatory cytokines secreted by microglia-like cells. Importantly, tested compounds can pass through the BBB, which allows them to enter the brain.

Peregrym K., Szczukowski Ł., Wiatrak B., Potyrak K., Czyżnikowska Ż., Świątek P.

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, we decided to modify the structure of already reported 1,3,4-oxadiazole based derivatives of pyrrolo[3,4-d]pyridazinone in order to obtain effective COX inhibitors. Herein we present the synthesis, biological evaluation and molecular docking studies of 12 novel compounds with disubstituted arylpiperazine pharmacophore linked in a different way with 1,3,4-oxadiazole ring. None of the obtained molecules show cytotoxicity on NHDF and THP-1 cell lines and, therefore, all were qualified for further investigation. In vitro cyclooxygenase inhibition assay revealed almost equal activity of new derivatives towards both COX-1 and COX-2 isoenzymes. Moreover, all compounds inhibit COX-2 isoform better than Meloxicam which was used as reference. Anti-inflammatory activity was confirmed in biological assays according to which title molecules are able to reduce induced inflammation within cells. Molecular docking studies were performed to describe the binding mode of new structures to cyclooxygenase. Investigated derivatives take place in the active site of COX, very similar to Meloxicam. For some compounds, promising druglikeness was calculated using in silico predictions.

Danilenko N., Shmalyuk V., Khlebnikov A.

The fluorosulfate derivatives of benzoxazole attract attention since benzoxazole-based compounds have a wide range of biological activities, and the ability of the –SO2F group to react with various functional groups makes it possible to synthesize various new derivatives. The new 2-(2-(fluorosulfonyloxy)phenyl)benzoxazole (2) has been synthesized by the SuFEx click reaction in a two-chamber reactor. Compound 2 is the first example of a benzoxazole derivative with a fluorosulfate-containing substituent at position two of the benzoxazole heterocycle. The anti-cancer potency of 2 was evaluated in silico using molecular docking. The docking results suggest that title compound 2 is of great interest for further studies as a possible anaplastic lymphoma kinase inhibitor.

Vergelli C., Khlebnikov A.I., Crocetti L., Guerrini G., Cantini N., Kirpotina L.N., Schepetkin I.A., Cilibrizzi A., Quinn M.T., Rossi P., Paoli P., Giovannoni M.P.

N-formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4-(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6-membered compounds, all exhibiting the same 4-bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five-membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site.