Design,synthesis, docking and anti-inflammatory evaluation of novel series of benzofuran based prodrugs

Several new benzofuran derivatives were synthesized, via appropriate synthetic route as anti-inflammatory agents. The anti-inflammatory activity of the prepared compounds was evaluated using carrageenan rat model. Among the synthesized compounds, some compounds showed comparable anti-inflammatory activity to nimesulide, the standard drug taken for anti-inflammatory studies. Docking study of the prepared compounds was performed for the study of interaction of molecules with the active site of COX-2. Preliminary biological studies and docking gave an interesting insight, into the validity of employing benzofuran analogues as good anti-inflammatory agent.     

Semantics, Inflammation, Cytokines and Common Sense

Semantic evaluation of some of the terms we regularly employ—inflammation, anti-inflammatory, pro-inflammatory, anti-inflammatory drugs, cytokines, homeostasis and stress—raises concerns about their precise meanings and about their mechanistic implications. Semantic imprecision may have undesirable conceptual consequences.     

The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents

Most anti-inflammatory drugs have been associated with an increased risk of serious upper gastrointestinal complications. Epidemiological studies have estimated the magnitude of the risk for specific anti-inflammatory drugs. The risk of upper gastrointestinal tract bleeding or perforation increases around twofold with use of oral steroids or low dose aspirin, and increases around fourfold with use of nonaspirin nonsteroidal anti-inflammatory drugs. Acetaminophen at daily doses of 2000 mg and higher has also been associated with an increased risk. Overall, the risk is dose dependent and is greater with more than one anti-inflammatory drug taken simultaneously. Hence, whenever possible, anti-inflammatory drugs should be given in monotherapy and at the lowest effective dose in order to reduce the risk of serious upper gastrointestinal complications.     

Synthesis of novel of 2, 5-disubstituted 1, 3, 4- oxadiazole derivatives and their in vitro anti-inflammatory,anti-oxidant evaluation,and molecular docking study

A series of novel 2, 5-disubstituted 1, 3, 4-Oxadiazole derivatives as a potential anti-inflammatory, and anti-oxidant agent were synthesized via cyclisation. Hydrazide molecule treated with substituted acids in the presence of phosphorus oxychloride (POCl₃) as an efficient reagent as well as solvent by conventional method with shorter reaction time and excellent yield. The newly synthesized 1, 3, 4- oxadiazole derivatives exhibited excellent to good anti-inflammatory and anti-oxidant activities compaired to the standard drugs. Molecular docking study on the crucial anti-inflammatory target–cyclooxygenase-2 (COX-2) revealed the ability of the scaffold to correctly recognize the active site and achieve significant bonded and non-bonded interactions with key residues therein. This study could identify potential compounds which can be pertinent starting points for structure-based drug design to obtain newer anti-inflammatory agents.     

Design,synthesis, biological evaluation,and molecular docking of chalcone derivatives as anti-inflammatory agents

In this study, two series of 35 new chalcone derivatives containing aryl-piperazine or aryl-sulfonyl-piperazine fragment were synthesized and their structures were characterized by ¹H, ¹³C and ESI-MS. The in vivo and in vitro anti-inflammatory activities of target compounds were evaluated by using classical para-xylene-induced mice ear-swelling model and ELISA assays. Furthermore, docking studies were performed in COX-2 (4PH9). The in vivo anti-inflammatory assays indicated that most of the target compounds showed significant anti-inflammatory activities. Docking results revealed that the anti-inflammatory activities of compounds correlated with their docking results. Especially, compound 6o exhibited the most potent anti-inflammatory activity in vivo with the lowest docking score of ?17.4 kcal/mol and could significantly inhibit the release of LPS-induced IL-6 and TNF-α in a dose-dependent manner in vitro.     

New cannabidiol (CBD) derivatives: Synthesis,anti-inflammatory activity,and molecular docking

A series of new cannabidiol (CBD) derivatives were synthesized by employing hydrogenation reaction and click chemistry. Then, the cytotoxicity and anti-inflammatory activities of cannabinoid derivatives were determined. Compound 14 was found to have low cytotoxicity and high anti-inflammatory activity, and the anti-inflammatory mechanism of compound 14 was preliminarily explored, which inhibited the synthesis and release of the pro-inflammatory cytokine TNF-α. The experimental results were confirmed by docking analysis. The water solubility of compound 14 was determined. Based on the results, the structure-activity relationships (SARs) of the CBD derivatives were discussed for exploring novel anti-inflammatory drugs.     

Synthesis and pharmacochemical evaluation of novel aryl-acetic acid inhibitors of lipoxygenase, antioxidants, and anti-inflammatory agents

Lipoxygenase catalyzes the first two steps of the transformation of arachidonic acid into leukotrienes which are implicated in host defense reactions. It is well known that many acids possess potent anti-inflammatory activity. Taking into account that compounds bearing a thienyl, naphthyl, pyrollyl, and 2,4-di-tert-butyl-phenol moieties possess anti-inflammatory activity which is related to their capacity to transfer electrons and to scavenge reactive oxygen species, we synthesized some new aryl-acetic acids and we explored their ability to inhibit soybean lipoxygenase, to present antioxidant and anti-inflammatory activities, and to interact with glutathione. The compounds have shown important antioxidant activity, medium anti-inflammatory activity, and very good inhibition of soybean lipoxygenase. Compound 3-(3,5-di-tert-butyl-2-hydroxy-phenyl)-2-phenyl-acrylic acid (1i) showed significant in vitro LO inhibition (IC(50) 65 microM). The results are discussed in terms of structural and physicochemical characteristics of the compounds. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity are experimentally determined by RPTLC method.     

Design,synthesis, and pharmacological evaluation of novel oxadiazole and oxadiazoline analogs as anti-inflammatory agents

Two novel series of oxadiazole and oxadiazoline analogs possessing an indole nucleus were synthesized for their potential anti-inflammatory activity. The structures of the compounds were elucidated by elemental and spectral (IR, ¹H-NMR, ¹³C-NMR, and MS) analysis. Most of the test compounds demonstrated appreciable anti-inflammatory activities. The anti-inflammatory activity of oxadiazoles at doses of 100?mg/kg was shown by their ability to provide 27–66%, 14–32%, and 20-51%. protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. On the other hand, the anti-inflammatory properties of oxadiazolines at doses of 100?mg/kg were reflected by their ability to provide 20-56%, 11–26%, and 25–47% protection against carrageenan-induced rat paw edema, moist cotton pellet-induced, and dry cotton pellet-induced granuloma, respectively. The ulcerogenic potential of the compounds was determined. Structure–activity relationships among synthesized compounds were also established.     

New triterpenes, myrrhanol A and myrrhanone A, from guggul-gum resins, and their potent anti-inflammatory effect on adjuvant-induced air-pouch granuloma of mice

Myrrhanol A, a new triterpene isolated from guggul (Balsamodendron or Commiphora mukul Hook.)-gum resin, displays a potent anti-inflammatory effect on exudative pouch fluid, angiogenesis, and granuloma weights in adjuvant-induced air-pouch granuloma of mice. Its effects were more marked than those of hydrocortisone and the 50% aqueous methanolic extract of the crude drug. Myrrhanol A is a plausible candidate for a potent anti-inflammatory agent.     

Design, synthesis, biological evaluation and molecular docking of curcumin analogues as antioxidant, cyclooxygenase inhibitory and anti-inflammatory agents

Curcuminoids were isolated from Curcuma longa and their pyrazole and isoxazole analogues were synthesized and evaluated for antioxidant, COX-1/COX-2 inhibitory and anti-inflammatory activities. The designed analogues significantly enhance COX-2/COX-1 selectivity and possess significant anti-inflammatory activity in carrageenan induced rat paw edema assay. Pyrazole, isoxazole analogues of curcumin (4 and 7) exhibited higher antioxidant activity than trolox. Molecular docking study revealed the binding orientations of curcumin analogues in the active sites of COX and thereby helps to design novel potent inhibitors.     

Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs,aspirin, and corticosteroids.

Although non-steroidal anti-inflammatory drugs are known to cause peptic ulcer and its complications, controversy exists about the number of deaths from ulcer which are attributable to their use. A case-control study was therefore performed to determine whether prior use of non-steroidal and other anti-inflammatory compounds was associated with an increased case fatality rate from complications of peptic ulcer. Non-steroidal anti-inflammatory drugs were used by 39% of a series of 80 patients who had died from peptic ulcer complications and by 37% of 160 controls who were survivors matched for sex, age, ulcer site, and nature of complication (odds ratio 1.1; 95% confidence interval 0.6 to 2.1). Similarly, the rates of prior use of aspirin by cases and controls were almost identical (odds ratio 1.2; 95% confidence interval 0.5 to 1.9). Thus neither nonsteroidal anti-inflammatory drugs nor aspirin were associated with increased case fatality rates from peptic ulcer complications. In contrast, corticosteroids were associated with an increased mortality (odds ratio 4.2; 95% confidence interval 0.9 to 25.6). Although this increase in the estimated relative risk was not statistically significant, a review of the case records indicated that most deaths in steroid users were due to serious sepsis, indicating that there might be a causal association between use of the drugs and the mode of death.     

Anti-inflammatory, analgesic and antipyretic activities of Physalis minima Linn

In our present investigation, the crude methanol extract and chloroform fraction of the whole plant of Physalis minima Linn (Solanaceae) was investigated for anti-inflammatory, analgesic and antipyretic activities in NMRI mice and Wistar rats of either sex at 200 and 400 mg/kg, respectively. Various established in-vivo model's were used during the study. Both crude extract and chloroform fraction showed marked anti-inflammatory and analgesic activities as compared to a control at tested doses. The antipyretic potential of the crude extract and chloroform were insignificant in the Brewer's yeast fever model. Therefore, the whole plant of Physalis minima Linn could be considered as a potential candidate for bioactivity-guided isolation of natural anti-inflammatory and analgesic agents.     

Toward the development of chemoprevention agents. Part 1: Design, synthesis, and anti-inflammatory activities of a new class of 2,5-disubstituted-dioxacycloalkanes

A new class of 2,5-disubstituted-dioxacycloalkanes were designed and synthesized via stereoselective synthetic method as cancer chemoprevention agents. The anti-inflammatory activities of these compounds were tested using the xylene-induced mouse ear edema model. Some of these compounds exhibited comparable or better anti-inflammatory activities than that of aspirin suggesting that they can be further developed as potential anti-inflammatory drug lead compounds. In addition, treatment of these anti-inflammatory agents did not prolong tail bleeding time in mice. The structure/activity relationships were also analyzed among these compounds.     

Design, synthesis and in vivo activity of 9-(S)-dihydroerythromycin derivatives as potent anti-inflammatory agents

The synthesis of a new class of 9-(S)-dihydroerythromycin derivatives and their anti-inflammatory activity on in vivo PMA assay are described. Modifying the desosamine sugar on the C-3' amino group, it was possible to differentiate between anti-biotic and anti-inflammatory action. The compounds are completely devoid of anti-microbial effects but their anti-inflammatory properties are enhanced. These results strongly suggest the potential of macrolides as a new class of anti-inflammatory agents.     

Design, synthesis, and SAR studies of some 5-aliphatic oximino esters of thiophene as potential anti-inflammatory leads: comparative biological activity profile of aliphatic oximes vs aromatic oximes

A series of novel tetra substituted thiophenes were synthesized, characterized, and evaluated for their anti-inflammatory activity in carrageenin induced rat paw edema model-an acute in vivo model. Compounds V1, V3, V11, V12, V17, and V18 showed good anti-inflammatory activity, indicating the importance of oxime moiety in modulating the activity. The structure-activity relationship studies explore "the aliphatic oxime esters" attached via a ketone bridge to fifth position of the thiophene, and indicate that this feature may enhance the anti-inflammatory activity as compared to aromatic oximes. Since free radicals are implicated in various inflammatory disorders, the free radical scavenging activity of some of the synthesized candidates was assessed using 1,1-diphenyl-2-picryl hydrazyl assay. The oxime containing analogs exhibited weak to moderate activity as free radical scavengers in DPPH assay. A plausible reasoning for its free radical scavenging ability is discussed. All the compounds were also screened in nitro blue tetrazolium model, to assess them as superoxide anion radical scavengers. A direct correlation between anti-inflammatory activity and free radical scavenging activity was not seen. The results disclose a new class of anti-inflammatory agents designed and synthesized for the first time wherein the utility of aliphatic oxime esters in modulating the anti-inflammatory activity profile is apparent. This will give us potential anti-inflammatory leads.     

Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages

Apoptotic cells are rapidly engulfed by adjacent tissue cells or macrophages before they can release pro-inflammatory/proimmunogenic intracellular contents. In addition, recognition of the apoptotic cells is actively anti-inflammatory and anti-immunogenic with generation of anti-inflammatory mediators such as transforming growth factor-beta (TGF-beta) and anti-inflammatory eicosanoids. Here, we have investigated the role played by the induction of TGF-beta in the coordinate expression of anti-inflammatory eicosanoids or peroxisome proliferator-activated receptor-gamma and in the suppression of pro-inflammatory lipid mediators and nitric oxide (NO). By use of a dominant negative TGFbetaII receptor, TGF-beta signaling was blocked, and its participation in the consequences of apoptotic cell stimulation was determined. The induction of TGF-beta itself could be attributed to exposed phosphatidylserine on the apoptotic cells, which therefore appears to drive the balanced inflammatory mediator responses. Arachidonic acid release, COX-2, and prostaglandin synthase expression were shown to be significantly dependent on the TGF-beta production. On the other hand, a requirement for TGF-beta was also shown in the inhibition of thromboxane synthase and thromboxanes, of 5-lipoxygenase and sulfidopeptide leukotrienes, as well as of inducible nitric-oxide synthase and NO. TGF-beta-dependent induction of arginase was also found and would further limit the NO generation. Finally, apoptotic cells stimulated production of 15-lipoxygenase and 15-hydroxyeicosatetraenoic acid, a potentially anti-inflammatory pathway acting through peroxisome proliferator-activated receptor-gamma, and lipoxin A(4) production, which were also up-regulated by a TGF-beta-dependent pathway in this system. These results strongly suggest that the apoptotic cell inhibition of pro-inflammatory mediator production is pleiotropic and significantly dependent on the stimulation of TGF-beta production.     

Design, synthesis, and anti-inflammatory activity both in vitro and in vivo of new betulinic acid analogues having an enone functionality in ring A

Fifteen new betulinic acid analogues were designed, synthesized, and tested for anti-inflammatory activity. Many of these analogues effectively suppress nitric oxide (NO) production in RAW cells stimulated with interferon-γ. Analogue 10 is highly and orally active in vivo for induction of the anti-inflammatory and cytoprotective enzyme, heme oxygenase-1.     

Purification and function of two analgesic and anti-inflammatory peptides from coelomic fluid of the earthworm,Eisenia foetida

The potential application of anti-inflammatory and analgesic compounds in medication and therapeutic care have become of increasing interest. We purified and characterized two novel analgesic and anti-inflammatory peptides, VQ-5 and AQ-5, from the coelomic fluid of the earthworm (Eisenia foetida). Their primary structures were determined as VSSVQ and AMADQ, respectively. Both peptides, especially AQ-5, exhibited analgesic activity in mouse models of persistent neuropathic pain and inflammation. AQ-5 also inhibited tumor necrosis factor alpha and cyclooxygenase-2 production. The mitogen-activated protein kinase signaling pathway, which is involved in analgesic and anti-inflammatory functions, was inhibited by AQ-5. Thus, the analgesic and anti-inflammatory effects of these peptides, especially AQ-5, demonstrated their potential as candidates for the development of novel analgesic medicines.     

Design,synthesis and biological evaluation of novel desloratadine derivatives with anti-inflammatory and H1 antagonize activities

To improve the anti-inflammatory activity of desloratadine, we designed and synthesized a series of novel desloratadine derivatives. All compounds were evaluated for their anti-inflammatory and H₁ antagonistic activities. Among them, compound 2c showed the strongest H₁ antagonistic and anti-inflammatory activity. It also exhibited promising pharmacokinetic profiles and low toxicity. All these results suggest that compound 2c as a novel anti-allergic agent is worthy of further investigation.     

Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis,docking studies and investigation of anti-inflammatory,ulcerogenic liability and analgesic activities

A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC₅₀s of 0.75–70.50 μM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.