Pteridine-2,4-diamine derivatives as radical scavengers and inhibitors of lipoxygenase that can possess anti-inflammatory properties

BACKGROUND: Reactive oxygen species are associated with inflammation implicated in cancer, atherosclerosis and autoimmune diseases. The complex nature of inflammation and of oxidative stress suggests that dual-target agents may be effective in combating diseases involving reactive oxygen species. RESULTS: A novel series of N-substituted 2,4-diaminopteridines has been synthesized and evaluated as antioxidants in several assays. Many exhibited potent lipid antioxidant properties, and some are inhibitors of soybean lipoxygenase, IC50 values extending down to 100 nM for both targets. Several pteridine derivatives showed efficacy at 0.01 mmol/kg with little tissue damage in a rat model of colitis. 2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)pteridin-4-amine (18f) at 0.01 mmol/kg exhibited potent anti-inflammatory activity (reduction by 41%). CONCLUSION: The 2,4-diaminopteridine core represents a new scaffold for lipoxygenase inhibition as well as sustaining anti-inflammatory properties

Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents

We report the synthesis, anti-inflammatory and antioxidant activities of novel quinoxaline and quinoxaline 1,4-di-N-oxide derivatives. Microwave assisted methods have been used in order to optimize reaction times and to improve the yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase. Two of the best lipoxygenase inhibitors (compounds 7b and 8f) were evaluated as in vivo anti-inflammatory agents using the carrageenin-induced edema model. One of them (compound 7b) showed important in vivo anti-inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug

Gel meloksikama za topičku primjenu: In vitro i in vivo vrednovanje

Skin delivery of NSAIDs offers several advantages over the oral route associated with potential side effects. In the present investigation, topical gel of meloxicam (MLX) was formulated using N-methyl pyrrolidone (NMP) as a solubilizer and Carbopol Ultrez 10® as a gelling polymer. MLX gel was evaluated with respect to different physicochemical parameters such as pH, viscosity and spreadability. Irritation potential of MLX gel was studied on rabbits. Permeation of MLX gel was studied using freshly excised rat skin as a membrane. Anti-inflammatory activity of MLX gel was studied in rats and compared with the commercial formulation of piroxicam (Pirox® gel, 0.5 %, m/m). Accelerated stability studies were carried out for MLX gel for 6 months according to ICH guidelines. MLX gel was devoid of any skin irritation in rabbits. After 12 h, cumulative permeation of MLX through excised rat skin was 3.0 ± 1.2 mg cm2 with the corresponding flux value of 0.24 ± 0.09 mg cm2 h1. MLX gel exhibited significantly higher anti-inflammatory activity in rats compared to Pirox® gel. Physicochemically stable and non-irritant MLX gel was formulated which could deliver significant amounts of active substance across the skin in vitro and in vivo to elicit the anti-inflammatory activity.Primjena nesteroidnih protuupalnih lijekova na kožu ima nekoliko prednosti nad peroralnim načinom primjene uz koju se vežu određene nuspojave. U radu je opisana priprava gela meloksikama (MLX) za topičku primjenu. U pripravi gela korišten je N-metil pirolidon (NMP) kao otapalo i Carbopol ultrez 10® kao polimer za geliranje. Određivani su različiti fizikokemijski parametri kao što su pH, viskoznost i razmazljivost. Potencijalna iritacija MLX gela testirana je na kunićima, a svojstvo permeacije na svježim izrescima kože štakora. Protuupalno djelovanje praćeno je na štakorima i uspoređeno s registriranim pripravkom piroksikama (Pirox® gel, 0,5 % m/m). Testovi ubrzanog starenja MLX gela rađeni su tijekom 6 mjeseci prema ICH protokolu. Dobiveni rezultati ukazuju da MLX gel nimalo ne iritira kožu kunića. Kumulativna permeacija nakon 12 h bila je 3,0 ± 1,2 mg cm2, s odgovarajućem vrijednošću fluksa 0,24 ± 0,09 mg cm2 h1. MLX gel pokazao je značajno jače protuupalno djelovanje u odnosu na Pirox® gel. Pripravljeni gel je stabilan, ne iritira kožu, te in vitro i in vivo doprema kroz kožu ljekovitu tvar u dovoljnoj količini da ispolji protuupalno djelovanje

Historical portrayal of Greek tourism through topic modeling on international newspapers

In this paper, we bridge computational linguistics with historical methods to explore the potential of topic modeling in historical newspapers. Our case study focuses on British and American newspapers published in the second half of the 20th century that debate issues of Greek tourism, but our method can be transposed to any diachronic data. We demonstrate that Non-negative Matrix Factorization (NFM) can generate interpretable topics within the historical period under examination providing a tangible example of how computational text analysis can assist historical research. Furthermore, we highlight the role of historical interpretation with regard to analyzing discourse dynamics through topic models. The results of our analysis provide interesting insights for academics and researchers in the field of (Digital) Humanities and Social Sciences, as well as for stakeholders in the tourism industry

Synthesis, bioactivity, pharmacokinetic and biomimetic properties of multi-substituted coumarin derivatives

A series of novel multi-substituted coumarin derivatives were synthesized, spectroscopically characterized, and evaluated for their antioxidant activity, soybean lipoxygenase (LOX) inhibitory ability, their influence on cell viability in immortalized human keratinocytes (HaCaT), and cytotoxicity in adenocarcinomic human alveolar basal epithelial cells (A549) and human melanoma (A375) cells, in vitro. Coumarin analogues 4a–4f, bearing a hydroxyl group at position 5 of the coumarin scaffold and halogen substituents at the 3-phenyl ring, were the most promising ABTS•+ scavengers. 6,8-Dibromo-3-(4-hydroxyphenyl)-4-methyl-chromen-2-one (4k) and 6-bromo-3-(4,5-diacetyloxyphenyl)-4-methyl-chromen-2-one (3m) exhibited significant lipid peroxidation inhibitory activity (IC50 36.9 and 37.1 µM). In the DCF-DA assay, the 4′-fluoro-substituted compound 3f (100%), and the 6-bromo substituted compounds 3i (80.9%) and 4i (100%) presented the highest activity. The 3′-fluoro-substituted coumarins 3e and 4e, along with 3-(4-acetyloxyphenyl)-6,8-dibromo-4-methyl-chromen-2-one (3k), were the most potent lipoxygenase (LOX) inhibitors (IC50 11.4, 4.1, and 8.7 µM, respectively) while displaying remarkable hydroxyl radical scavenging ability, 85.2%, 100%, and 92.9%, respectively. in silico docking studies of compounds 4e and 3k, revealed that they present allosteric interactions with the enzyme. The majority of the analogues (100 µM) did not affect the cell viability of HaCaT cells, though several compounds presented over 60% cytotoxicity in A549 or A375 cells. Finally, the human oral absorption (%HOA) and plasma protein binding (%PPB) properties of the synthesized coumarins were also estimated using biomimetic chromatography, and all compounds presented high %HOA (>99%) and %PPB (60–97%) values. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Synthesis and Biological Evaluation of Substituted Fused Dipyranoquinolinones

New methyl-substituted, and diphenyl-substituted fused dipyranoquinolinones are prepared in excellent yields via the triple bond activation and 6-endo-dig cyclization of propargyloxycoumarin derivatives by gold nanoparticles supported on TiO2 in chlorobenzene under microwave irradiation. In the absence of gold nanoparticles, the methyl-substituted propargyloxycoumarin derivatives resulted in fused furopyranoquinolinones through Claisen rearrangement and 5-exo-dig cyclization. The intermediate propargyloxy-fused pyridocoumarins are prepared by propargylation of the corresponding hydroxy-fused pyridocoumarins. The methyl-substituted derivatives of the latter are synthesized in excellent yield by the three-component reaction of amino hydroxycoumarin with n-butyl vinyl ether under iodine catalysis. The diphenyl-substituted derivatives of hydroxy-fused pyridocoumarins are obtained, also, by the three-component reaction of amino hydroxycoumarin with benzaldehyde and phenyl acetylene catalyzed by iron (III) chloride. Preliminary biological tests of the title compounds indicated lipoxygenase (LOX) (EC 1.13.11.12) inhibitory activity (60–100 μM), whereas compound 28a, with IC50 = 10 μM, was found to be a potent LOX inhibitor and a possible lead compound. Only compounds 10b and 28b significantly inhibited lipid peroxidation

A novel and easy two-step, microwave-assisted method for the synthesis of halophenyl pyrrolo 2,3-b quinoxalines via their pyrrolo precursors. Evaluation of their bioactivity

A novel, two-step, facile route for the synthesis of pyrrolo[2,3-b]quinoxalines via 2,3-dioxopyrroles, enhanced by microwave irradiation, is presented. The newly synthesized 2,3-dioxo-5-halophenyl pyrrolo precursors 4a-c as well as the non-aromatized ethyl 2-(4-halophenyl)-1-methyl-2,4-dihydro-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylates 6a-c and the aromatized ethyl 2-(4-halopheny1)-1-methyl-1H-pyrrolo[2,3-b]quinoxaline-3-carboxylates 7a-c were evaluated for their antioxidant, cytostatic, and antiviral properties. Most of them proved to be potent hydroxyl radical scavengers and inhibited in vitro lipid peroxidation. The compounds showed moderate antiproliferative activity, while 6a inhibited vaccinia virus at an EC50 value of 2 [mu M, and 4c and 6c inhibited Sindbis virus at EC50 values of 4 mu M. (C) 2014 Elsevier Ltd. All rights reserved