Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry最新文献

Novel Corona Virus 2019 (COVID-19) is a new virus spread rapidly all over the world. It has specific respiratory or gastrointestinal tract symptoms. Its reported complications include respiratory distress, systemic inflammatory response syndrome, and septic shock. Due to heavy cytokines released by the virus; corticosteroids (40-120 mg / day) were given to severe cases to reduce pneumonia. It's a difficult task to control the spread of SARS-CoV-2, and to invent proper vaccines and treatments. In this review, the existing understanding of fatal, pandemic human coronavirus SARS-Cov2 (COVID-19), with special reference to its diagnosis, origin, transmission, and different approaches to develop its therapeutics, will be discussed.

Background: Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) production, which plays an important role in the regulation of febrile response. In our previous work, ligand-based pharmacophore models, built with mPGES-1 inhibitors, were employed to identify a novel series of compounds that reduce the febrile response in rats.

Objectives: The study aimed to evaluate the mechanism of action of the most active compound (1).

Methods: For in vivo assays, rats were pretreated with the antipyretic compounds 1-8, 30 min before LPS injection. For in vitro assays, RAW 264.7 macrophage cells were incubated with the antipyretic compounds 1-8 for 1 hour before LPS stimulus. After 16 h, quantitative real-time PCR was carried out. Additionally, the PGE₂ concentration in the hypothalamus was quantified by ELISA and the inhibitory effect of N-cyclopentyl-N'-[3-(3-cyclopropyl-1H-1,2,4-triazol- 5-yl)phenyl]ethanediamide (1) over human COX-2 enzymatic activity was determined with a COX Colorimetric Inhibitor Screening Assay Kit.

Results: Compound 1 and CAY10526 showed comparable efficacy to reduce the febrile response when injected i.v. (compound 1: 63.10%, CAY10526: 70.20%). Moreover, compound 1 significantly reduced the mPGES-1 mRNA levels, in RAW264.7 cells, under inflammatory conditions. A chemically-similar compound (8-) also significantly reduced the mRNA levels of the gene target. On the other hand, compounds 6 and 7, which are also somewhat similar to compound 1, did not significantly impact mPGES-1 mRNA levels.

Conclusions: PGE2 concentration reduction in the hypothalamus, due to compound 1 central injection, is related to decreased mPGES-1 mRNA levels but not to COX-2 inhibition (IC50> 50 μM). Therefore, compound 1 is a promising lead for innovative antipyretic drug development.

Background: Today, the effects of growth factors and mesenchymal stem cells (MSCs) in promoting wound healing has been confirmed.

Objective: This study aimed to investigate the effect of MSCs and platelet cryogel on wound healing.

Methods: 40 male wistar rats were randomly divided into five groups (n=8). The control group was just dressed, the second group received platelet cryogel, the third group received platelet cryogel containing MSCs, the fourth group received plasma, and the fifth group received plasma plus MSCs. The biopsy was obtained from the wounds in the 2, 4, 6, and 8 days of the treatment. Then, pathological evaluation was conducted. Finally, qRT-PCR was performed to determine angiogenesis.

Results: The intervention groups had faster wound healing and lower wound area than the control group (p<0.05). The highest wound healing rate and the smallest wound area was observed in the group receiving platelet cryogel plus MSCs. Angiogenesis, fibrosis, myoepithelial and epithelialization in the pathologic examination using H & E staining were not significantly different between the groups. The expression of Ang-1 in the intervention groups was higher than the control group and the highest expression was observed in the platelet cryogel plus MSCs, followed by the platelet cryogel group. The expression of VEGF in the plasma plus MSCs was higher than in the other groups.

Conclusion: Further studies require to determine the effects of combined use of platelet cryogel plus MSCs on other types of wound and evaluate mechanisms involved in wound healing like collagenesis and inflammatory factors.

Background: The dietary model of metabolic syndrome has continued to aid our understanding of its pathogenesis and possible management interventions. However, despite progress in research, therapy continues to be challenging for humans; hence, the search for newer treatment and prevention options continues.

Objective: The objective of this study was to evaluate the impact of dietary CQ10 supplementation on metabolic, oxidative, and inflammatory markers in a diet-induced mouse model of metabolic syndrome.

Methods: Mouse groups were fed a Standard Diet (SD), High-Fat High-Sugar (HFHS) diet, and SD or HFHS diet (with incorporated CQ10) at 60 and 120 mg/kg of feed. At the completion of the study (8 weeks), blood glucose levels, Superoxide Dismutase (SOD) activity, plasma insulin, leptin, adiponectin, TNF-α, IL-10, serum lipid profile, and Lipid Peroxidation (LPO) levels were assessed. The liver was either homogenised for the assessment of antioxidant status or processed for general histology.

Results: Dietary CQ10 mitigated HFHS diet-induced weight gain, decreased glucose, insulin, and leptin levels, and increased adiponectin levels in mice. Coenzyme-Q10 improved the antioxidant status of the liver and blood in HFHS diet-fed mice while also decreasing lipid peroxidation. Lipid profile improved, level of TNF-α decreased, and IL-10 increased following CQ10 diet. A mitigation of HFHS diet-induced alteration in liver morphology was also observed with CQ10.

Conclusion: Dietary CQ10 supplementation mitigates HFHS diet-induced changes in mice, possibly through its anti-oxidant, anti-lipaemic, and anti-inflammatory potential.

Background: Computer-aided drug design is among the most effective methods of medicinal chemistry. The above mentioned approach is used for the purposeful search of antiinflammatory agents among quinazoline condensed derivatives.

Objective: The study aimed to conduct a purposeful synthesis of novel 3-R-2,8-dioxo-7,8-dihydro- 2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)carboxylic acids and their salts as promising anti-inflammatory agents, evaluate their structure by physicochemical methods and establish their anti-inflammatory activity.

Methods: The structures of target compounds were proposed due to their structure similarity to existing drugs and experimental agents with anti-inflammatory activities. The features of the synthesized compounds structures were evaluated by IR-, NMR spectroscopy and chromatography-mass spectrometry and discussed in detail. Probable molecular mechanisms of activity were predicted by molecular docking. The anti-inflammatory activity was determined by their ability to reduce the formalin- and carrageenan-induced paw edema in rats.

Results: It was found that the condensation of 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)ones with 2-oxoglutaric acid yielded 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline- 5a(6H)carboxylic acids which may be considered as a promising anti-inflammatory agent. An in silico study showed that the obtained compounds revealed affinity to the molecular targets and corresponded to the drug-like criteria. Additionally docking study allowed to estimate the nature of interactions between synthesized compounds and molecular targets. The in vivo experiments showed that the obtained compounds demonstrated significant anti-inflammatory activity comparable or higher than the activity of the reference drug Diclofenac.

Conclusion: The developed and implemented search strategy of the anti-inflammatory agents was justified. 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline5a(6H)carboxylic acids possessed the anti-inflammatory activity and additional introduction of fluorine atoms in position 11 or 12 of the heterocyclic system led to amplification of this activity.

Objective: This study investigated the antinociceptive and anti-inflammatory activities of the aqueous extract of Ficus capensis (AEFC) by bio-guided fractionation.

Methods: The anti-nociceptive and anti-inflammatory effects of AEFC (250, 500, 1000 mg/kg, i.p) were assessed using acetic acid-induced writhing, hot plate, tail-flick, formalin tests, and carrageenan- induced paw edema, respectively. The AEFC was fractionated base on polarity difference into butanol, ethyl acetate, and n-hexane fractions. The fractions (500 mg/kg) obtained were subjected to the same experimental procedures mentioned above. The EAF, which exerted the most productive activities, was further subjected to fractionation procedures that yielded six fractions (labeled CF1-CF6). These fractions (200 mg/kg) were tested for potential antinociceptive and anti-inflammatory activities. Notable antagonists (Naloxone and atropine) of the nociceptive pathway were used to evaluate the mechanism of the antinociceptive action of F. capensis.

Results and discussion: The AEFC, BF, EAF, and CF4 caused a significant (p<0.05) reduction in the number of abdominal writhes, an increase in reaction time against the hot plate, tail-flick tests, and a significant (p<0.05) inhibition in both phases of formalin test. The AEFC, BF, EAF, CF4, and CF6 caused a significant (p<0.05) inhibition of paw edema development due to carrageenan. Atropine significantly reversed the antinociceptive effect of CF4 in both phases of the formalin test. The results obtained revealed that CF4 produced central and peripheral antinociceptive effects, while CF6 is peripherally mediated.

Conclusion: The results support the traditional uses of F. capensis in the treatment of various diseases associated with pain and inflammation. The column fraction CF4 exhibited muscarinic receptor- mediated antinociceptive activity.

Introduction: Pain is an immunological response to an infection or inflammation and long-term use of pain management therapy includes the use of Nonsteroidal anti-inflammatory drugs, which is associated with the occurrence of toxicity as well as gastrointestinal bleeding. Therefore, the investigation of new analgesic and anti-inflammatory agents remains a major challenge.

Aims: The objective of this research study is to undergo the pharmacological evaluation of newly synthesized benzoxazole derivatives. These novel derivatives were evaluated for anti-nociceptive, anti-inflammatory and cytotoxic activity using various in-vivo and ex-vivo methods Methods: The study was carried out using swiss mice (adult male) weighing between 20gm to 30gm and were divided into groups containing (n=6) six animals in each group for treatment. The anti-nociceptive activity was performed by using 0.1ml of 0.6% v/v acetic acid as nociception inducer and evaluated by the diminished number of abdominal writhes. The anti-inflammatory activity was done using 0.1 ml of 2% w/v Carrageenan induced paw edema method was observed which was evaluated by calculating the percent maximum possible effect. Histopathological evaluation and cytotoxic activity of the compounds were carried out.

Results: The results of this research study revealed that synthesized derivatives (a, b, c, d and e) showed promising anti-nociceptive and anti-inflammatory effects along significantly higher cytotoxic activity in MCF-7 cell lines.

Conclusion: It can be concluded that synthesized derivatives (a, b, c, d and e) have potential anti- nociceptive and anti-inflammatory effects along with cytotoxic activity and certain modification in structure may result in the potent activity.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disease manifested by core symptoms of loss of motor control and postural instability. Loss of dopaminergic neurons is the cause of PD, thus enhancing dopamine level by pharmacological treatment is one of the key treatment strategies for PD. However, the limitations of current treatment strategies open the possibility of novel drug candidates for the treatment of PD.

Objective: To investigate the anti-PD potential of Harmine and Harmaline. We aim to evaluate the therapeutic potential of Harmine and Harmaline by in-silico approaches; molecular docking, pharmacokinetic and Prediction of Activity Spectra for Substances (PASS) analysis were used for evaluating the therapeutic potential of Harmine and Harmaline and standard drug levodopa (L-DOPA).

Methods: Auto dock vina was used for molecular docking of all three compounds against D2- and D3- dopamine receptors. The pharmacokinetics (PKs) and toxicity profile were predicted by pkCSM, and the pharmacological activity was predicted by PASS analysis.

Results: Molecular docking showed a higher binding affinity of Harmine and Harmaline as compared to L-DOPA, and these results were supported by in-silico pharmacokinetic and toxicity profiling. Moreover, PASS analysis showed anti-PD activity of Harmine and Harmaline.

Conclusion: Harmine and Harmaline exhibit higher binding affinity towards D2- and D3- dopamine receptors compared to L-DOPA, and PKs and toxicity profile support their potential as drug candidates for PD therapy.

Background: Daucus gracilis Steinh belongs to the Apiaceae family. The flowers of this plant have been used by the population of western Algeria for the treatment of mouth ulcers. However, very few studies exist concerning the biological properties of essential oil of Daucus gracilis Steinh flowers.

Objectives: The purpose of this work was to study the chemical composition of the essential oil of Daucus gracilis flowers and to evaluate their antimicrobial, insecticidal and anti-inflammatory properties.

Methods: The distilled essential oil was analyzed by GC and GC-MS. The antimicrobial activity of the essential oil was evaluated using two methods i) diffusion method, and ii) micro dilution technique. The insecticidal activity of essential oil was evaluated against adults of Tribolium confusum by fumigant test. The in vitro assessment of the anti-inflammatory property of essential oil was assessed by the protein denaturation method.

Results: Daucus gracilis flowers essential oil mainly represented oxygenated monoterpenes such as geranyl acetate (18.3%), lavandulyl acetate (15.2%), lavandulyl isobutyrate (13.6%) and citronellyl isobutyrate (6.8%). According to the results of antimicrobial activity, the essential oil of flowers presented prominent inhibitory action against Aspergillus flavus (0.06 μg/mL), followed by Staphylococcus aureus, Escherichia faecalis, Bacillus cereus and Candida albicans with MIC values of 0.125 μg/mL. The Daucus gracilis essential oil flowers proved to be very biocidal toward adults of Tribolium confusum; mortality of 100% of the population was noted with a dose of 2 μl/L air after 24 hours of exposure. Furthermore, the oil has shown a very good inhibition of protein denaturation comparable to Diclofenac at a concentration of 30 μL/mL.

Conclusion: Daucus gracilis essential oil can be used as a pharmacological tools for inflammatory, antimicrobial and insecticidal properties.

Background: For the first time, the inhibitory effects on the human salivary alpha-amylase activity of the anti-inflammatory drugs indomethacin, diclofenac sodium, ketoprofen, diclofenac potassium, diclofenac, triamcinolone acetonide, and the antihistamine drugs levocetirizine dihydrochloride, desloratadine, cycloheptadine hydrochloride, have been investigated to confirm the other properties of these drugs.

Objective: This study aimed to determine the effect of nine known drugs on human salivary α-amylase in vitro and the nature of interactions with structure-activity relationship using molecular docking experiments.

Methods: The inhibition of human salivary alpha amylase by the six anti-inflammatory and three antihistamine drugs has been carried out using the new method that has been proved in our previous work. Molecular docking has been achieved for the first time for these drugs using the Auto- Dock Vina program.

Results: Cyproheptadine hydrochloride presented the highest inhibitory activity against α-amylase with IC₅₀=0.7 mg/ml, while the other drugs showed weak activities (IC₅₀ > 2 mg/ml).

Conclusion: We conclude that Cyproheptadine hydrochloride, which was studied by docking experiments, exhibited the best inhibitory activity on salivary α-amylase in vitro & in silico.