Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 17, Issue 1, 2018

Background: phthalazine derivatives were reported to possess anticonvulsant , cardiotonic , antibacterial, analgesic , anti-inflammatory, and anti-microbial activity. In the current study, we applied the QSAR for prediction of newly phthalazinediones incorporating thioamide moiety aiming to reach a more potent anti-inflammatory and Analgesic agent. Methods: Phthalazinediones 10-15 have been synthesized through condensation of dibenzobarallene 3 with thiosemicarbazides 4-8. One equation was predicted using quantitative structure activity relationship (QSAR) and regression analysis for the anti-inflammatory activity with a regression correlation (R) close to unity. The docking studies were performed to investigate the biological trends of the organic compounds (thiol form) against cyclooxygenas- 2 enzyme, which is a responsible inflammation mediator by using Molgro Virtual Docker (MVD) software. The anti-inflammatory activity and analgesic effect of the thioamides 10-15 were determined by collagen II-adjuvant induced paw edema test in rats. Results: Compounds 10, 11, 12, and 14, exhibited promising anti-inflammatory activity. Furthermore, in the pain scoring, compounds 10, 11 and 12 were found to be more effective than piroxicam and the order of the analgesic effect of the investigated compounds is as followed 14 >12 > 10 > 11 > 15. Conclusion: It is clear from the foregoing that the compound 14 is a promising compound if future pharmacological detailed studies. This is consistent with what has been predictable equation 1 in this study.

Background: The benzimidazole ring is an important pharmacophore in modern drug discovery. Mannich reaction is one of the versatile reaction widely used in organic synthesis. Mannich base derivatives play an important role in medical field with diverse biological actions. Objective: A series of N-(benzimidazol-1-ylmethyl)-4-chlorobenzamide derivatives (3a- 3m) were synthesized and evaluated for anti-inflammatory and antimicrobial potential. Method: Mannich reaction was used to synthesize N-(benzimidazol-1-ylmethyl)-4- chlorobenzamide analogues. The structures of novel target compounds were elucidated by spectral and analytical techniques and screened for in vivo anti-inflammatory activity and ulcerogenic activity. In addition, the prepared derivatives were also evaluated for in vitro antimicrobial activity against gram negative, gram positive and fungal strains. Further, in silico studies were carried out to define the interaction of the title compounds with COX-2 enzyme and microbial protein. Results: The results revealed that out of thirteen molecules, compound 3a (containing chloromethyl substituent at 2-position of benzimidazole) showed significant antiinflammatory effect at a dose of 100 mg/kg p.o. and the experimental data was statistically significant at p≤0.05 level. Diclofenac sodium was taken as standard drug for antiinflammatory activity. Furthermore, derivative 3e (containing 2-chlorophenyl moiety at 2- position of benzimidazole scaffold) was found to be the most effective antimicrobial compound among the synthesized derivatives. Ciprofloxacin and clotrimazole were used as reference antimicrobial agents. Results from in vivo and in vitro studies of synthesized analogues were found to be in good correlation with in silico study. Conclusion: These results designate that N-(Benzimidazol-1-ylmethyl)-4-chlorobenzamide analogues, substituted with halogen functionality, could be used as potential lead for designing more potent anti-inflammatory and antimicrobial agents.

Background: Recently, pyrazole derivatives have shown significant antiinflammatory activity. Non-steroidal anti-inflammatory drugs have some side effects, mainly gastric irritation and gastric ulceration during the treatment of inflammation. So the current study deals with the synthesis and pharmacological evaluation of a series of novel pyrazole derivatives as anti-inflammatory agents. Methods: A series of novel ethyl 5-(substituted)-1H-pyrazole-3-carboxylate (2a-j) were synthesized and evaluated for anti-inflammatory activity using carrageenan-induced inflammation in rat paw edema model. In the first step, diethyl oxalate react with acetophenone derivatives in presense of sodium ethoxide to form substituted ethyl-2,4-dioxo-4- phenyl butanoate derivatives as intermediate (1a-j). Further the suspension was prepared from dioxo-esters with hydrazine hydrate in glacial acetic acid yielded novel ethyl 5- (substituted)-1H-pyrazole-3-carboxylate (2a-j) derivatives. The structure of the final analogues (2a-j) has been confirmed on the basis of elemental analysis, IR, 1 H NMR and mass spectra. Results: All the values of elemental analysis, FTIR, 1H NMR, and mass spectra were found to be prominent. The anti-inflammatory activity test revealed that Ethyl 5-(3,4- dimethoxyphenyl)-1H-pyrazole-3-carboxylate (2f) and ethyl 5-(2,3-dimethoxyphenyl)-1Hpyrazole- 3-carboxylate (2e) exhibited significant anti-inflammatory activity as compared to control group. Conclusion: The results of the current study indicate that the substitution at pyrazole scaffold could improve anti-inflammatory activity.

Background: Dracocephalum kotschyi is traditionally used for its anti-inflammatory effects. We aimed to investigate the effects of ethyl acetate extract of D. kotschyi on the expression of key inflammatory mediators and main signaling molecules involved in the regulation of inflammation. Methods: Lipopolysaccharide (LPS)-stimulated J774.1 mouse macrophages were cultured in the presence of the plant extract and examined by the real time-PCR for gene expressions of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. Cytokine levels and phosphorylated forms of stressactivated protein kinases/c-Jun N-terminal kinase (SAPK/JNK), signal transducer and activator of transcription (STAT)-3, p38, IΚB-α and nuclear factor (NF)-ΚB p65 were determined using ELISA. Results: The extract significantly reduced the expression of key mediators of inflammation. iNOS expression level decreased from 138±8.5 fold in LPS-only treated cells to 6.5±2.6 fold after treatment with 25 μg/ml of the extract (p<0.001). Similarly, COX-2 expression decreased from 632 ±98.8 fold in control to 124 ±24.6 fold (p<0.01). Treatment of cells with the extract significantly reduced IL-1β and TNF-α cytokines at both gene and protein expression levels. The extract at 25 μg/ml caused significant decreases in phospho- SAPK/JNK and phospho-STAT3 levels in macrophages (p<0.01). Proteins of phospho-p38, NFΚB-p65 and phospho-NF-ΚB p65 had a reduced level in treated cells (p<0.05). No significant change in phospho-IΚB level was observed. Conclusion: These findings suggested that D. kotschyi with inhibition of NF-ΚB, SAPK/JNK, STAT-3 and p-38 might have reduced the expression levels of key inflammatory mediators and thus possibly have potential beneficial impact on inflammatory diseases.

Background: Current therapies for against inflammatory bowel disease (IBD) are sometimes limited by high costs, high toxicities and/or undesirable side effects, reasons for which new treatments are constantly being developed and studied. In this regards, an increasing mass of data has demonstrated that fecal transplantations and probiotic supplementations have shown promising effects and could be considered as adjunct IBD treatments to decrease some of the unwanted side effects caused by primary treatments. Furthermore, there is also mounting evidence that suggests that certain vitamins could provide antiinflammatory effects and it has been shown that certain strains of lactic acid bacteria (LAB), the most commonly used probiotic microorganisms, can produce biologically active forms of certain vitamins. Objective: To discuss the potential role of the vitamin-producing LAB on intestinal inflammatory diseases. Method: A thorough search of bibliographic databases for peer-reviewed research on the effect of vitamins produced by LAB on inflammatory processes was performed. Results: There is mounting research that vitamin producing LAB could provide antiinflammatory effects. Conclusion: The potential role of vitamin producing LAB was discussed not only because they could be used to decrease inflammation but also because they could provide the host with essential nutrients that are normally deficient in IBD patients due to altered intestinal morphologies.

Background: The skin toxicity-induced by ionizing radiation may limit the duration of treatment and may lead to discomfort in quality of life of patients during radiotherapy. Objective: The purpose of this randomized, placebo-controlled, double-blind study was to investigate the preventive effect of oral administration of celecoxib (CLX) on the acute radiation- induced skin toxicity in patients with breast cancer. Methods: Sixty breast cancer patients were randomly assigned to use CLX (400 mg per day) or placebo capsules during radiotherapy. Radiation-induced dermatitis was classified according to the radiation therapy oncology group (RTOG) criteria, as well as pain and itching were scored according to the VAS (Visual Analogue Scale) for six weeks of treatment. Breast swelling was evaluated through increase in the size of the breast during radiotherapy. Results: Oral administration of CLX capsule during and after radiotherapy reduced significantly radiation-induced itching and pain in patients with breast cancer. CLX reduced the frequency of increased breast size caused by radiotherapy in patients as compared with placebo; however, this difference was statistically not significant. Patients who received CLX had insignificantly skin dermatitis when compared with placebo group. Conclusion: However, CLX was unable to reduce the dermatitis caused by ionizing radiation; it significantly reduced itching and pain in patients during radiotherapy. CLX may have beneficial effects in the quality life of breast cancer patients for treatment.