Newer substituted benzoxazepinyl-quinazolinones as potent antipsychotic and anticonvulsant agents

3-Amino-[2'-substitutedaryl-3'-substitutedarylaminomethylene-2',3'- dihydro-1',5'-benzoxazepin-4'-yl]-2-methyl-quinazolin-4(3H)-ones 11-18 and 3-amino-[2'-substituted aryl-3'-substitutedaryl-azo-2',3'- dihydro-1',5'-benzoxazepin-4'-yl]-2-methyl-quinazolin-4(3H)-ones 19-26 were synthesized from 3-amino-[2'-substitutedaryl-2',3'-dihydro-1',5'- benzoxazepin-4'-yl]-2-methyl-quinazolin-4(3H)-ones 7-10 by Mannich's reaction and by diazotisation, respectively, on the 3rd position of the benzoxazepine ring of the compounds 7-10. The newly synthesized compounds showed potent antipsychotic and anticonvulsant activities.     

Newer indolyl imidazolones as anti-inflammatory agents

Sixteen new 1,2-disubstituted-4-(indol-3'-yl)methylene imidazol-5-ones were synthesized by the condensation of oxazolone with different aryl amines and evaluated as to their anti-inflammatory and antiproteolytic activities. These derivatives showed 2-38% protection against carrageenin-induced paw oedema in albino rats at a dose of 100 mg/kg p.o. All compounds showed antiproteolytic activity. The degree of inhibition against trypsin-induced hydrolysis of casein ranged from 10 to 75% at a concentration of 4 X 10(-4) mol/l. Furthermore, active compounds of the series were also screened for their analgesic activity against aconitine-induced writhing in albino mice. The toxicity of the compounds was reflected by their approximate LD50 values.     

Tetrazoles as potent anti-inflammatory agents

Various new tetrazoles were tested for their anti-inflammatory activity against carrageenin-induced paw oedema in albino rats. Among these, two most potent derivatives were evaluated in detail using cotton pellet implantation methods in albino rats of either sex. These two active analogues were also tested for their analgesic activity in albino mice and ulcerogenic liability in albino rats. All derivatives of the present series were evaluated for their antiproteolytic activity. The toxicity of the compounds was assessed by determination of their approximate LD50 in albino mice. An attempt has also been made to establish the structure activity relationship.     

Novel thiazolidinones as potent anti-inflammatory and analgesic agents

Various new butyridenyl-2-hydroxybenzylidenyl-1,3-thiazolidinones were synthesized and characterized by elemental analyses, IR and PMR spectral data. The compounds were evaluated for their ability to afford protection against inflammation by carrageenin-induced oedema and cotton pellet implantation in albino rats of either sex. The active derivatives of the present series were also tested for their analgesic activity against aconitine-induced writhing in albino mice and ulcerogenic activity in albino rats. The toxicity of the compounds was reflected by determination of their approximate LD50 in albino mice. An attempt has also been made to correlate their structure-activity relationship.     

Synthesis of pyrazole-based 1,5-diaryl compounds as potent anti-inflammatory agents

Series of 1,5-diaryl pyrazole ester derivatives have been synthesized and found to contain potent inhibitory activity against cyclooxygenase-2 (COX-2) enzyme. The article describes synthesis of the target pyrazole analogs and biological assay using Carrageenan induced rat paw for investigation.     

Statins as anti-inflammatory agents

The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in cardiovascular disease have generally been attributed to their cholesterol-lowering property. However, an increasing number of in vitro and in vivo studies indicate that statins have direct anti-inflammatory effects that are not mediated by their hypocholesterolemic activity. In this article, the HMG-CoA-reductase-dependent and -independent mechanisms by which statins might affect leukocyte adhesion and migration to sites of inflammation are reviewed and the implications for the design of new statin-derived drugs are discussed.     

Antibiotics as anti-inflammatory agents

Although the empirical use of some antibacterial agents in various inflammatory diseases has proved beneficial in the past, it is only recently that the therapeutic anti-inflammatory potential of cyclines and macrolides has received attention worldwide. Other drugs like fosfomycin and some quinolones are also contenders for this role. Owing to the complexity of the inflammatory process, which involves many redundant cellular effectors and soluble mediators, and the obscure etiopathogenesis of many inflammatory diseases (some of which may be secondary to persistent infections), the precise mechanisms underlying the therapeutic benefit of anti-inflammatory antibiotics remain to be elucidated. Structure-activity relationships are the key to developing new anti-inflammatory agents derived from antibacterial drugs.     

Newer inotropic agents

Impairment of myocardial contractility results in reduction of cardiac output and activation of various compensatory mechanisms which eventually work to disadvantage. Drug treatment is directed towards improving myocardial contractility with inotropic agents and relieving congestion and vasoconstriction with diuretics and vasodilators. Digitalis is a relatively modest inotropic agent with considerable toxic potential and there is a need for alternative inotropic agents which are potent, active orally, effective long term and have minimal adverse effects. A number of beta agonists have been evaluated but their application appears limited to some extent by the development of tolerance, probably due to downregulation of myocardial beta receptors. Of the non-adrenergic inotropic agents currently under evaluation, amrinone appears most promising although its mechanism of action is not known.     

Synthesis,molecular properties,toxicity and biological evaluation of some new substituted imidazolidine derivatives in search of potent anti-inflammatory agents

The aim of this study was to design and synthesize pharmaceutical agents containing imidazolidine heterocyclic ring in the hope of developing potent, safe and orally active anti-inflammatory agents. A number of substituted-imidazolidine derivatives (3a–k) were synthesized starting from ethylene diamine and aromatic aldehydes. The imidazolidine derivatives (3a–k) were investigated for their anticipated anti-inflammatory, and analgesic activity in Wistar albino rats and Swiss albino mice, respectively. Bioactivity score, molecular and pharmacokinetic properties of the imidazolidine derivatives were calculated by online computer software programs viz. Molinspiration and Osiris property explorer. The results of biological testing indicated that among the synthesized compounds only three imidazolidine derivatives namely 4-[1,3-Bis(2,6-dichlorobenzyl)-2-imidazolidinyl]phenyl-diethylamine (3g), 4-[1,3-Bis(3-hydroxy-4-methoxybenzyl)-2-imidazolidinyl]phenyl-diethylamine (3i) and 4-(1,3-Bis(4-methoxybenzyl)-4-methylimidazolidin-2-yl)-phenyl-diethylamine (3j) possess promising anti-inflammatory and analgesic actions. Additionally these derivatives displayed superior GI safety profile (low severity index) with respect to the positive control, Indomethacin. All synthesized compounds showed promising bioactivity score for drug targets by Molinspiration software. Almost all the compounds were predicted to have very low toxicity risk by Osiris online software. Compound number (3i) emerged as a potential candidate for further research as it obeyed Lipinski’s rule of five for drug likeness, exhibited promising biological activity in-vivo and showed no risk of toxicity in computer aided screening.     

Thymus hormones as prospective anti-inflammatory agents

Importance of the field: Inflammatory diseases are characterized by severe immune imbalances, leading to excessive or inappropriate release of mediators, which, in turn, result in massive damage to organs and systems. Effective means to control inappropriate immune reactions are often life-critical needs. Available data on the role of thymus-derived hormones in inflammation show their great potential.

Areas covered in this review: The review aims to systematize information for the last two decades on immune system regulation by thymic peptide hormones, with a primary focus on the role of these hormones in the systemic inflammatory response and inflammatory diseases. Anti-inflammatory potential of three thymic hormones – thymulin, thymosin-alpha, and thymopoietin – is discussed, reviewing recently published clinical and experimental studies.

What the reader will gain: Our analysis revealed the regulation of inflammatory processes via thymic hormones that could be prospective for therapeutic application. This regulation may be mediated through thymic hormone effects on peripheral immune cell activities and bidirectional coupling between thymic hormones and the hypothalamic–pituitary–adrenal axis.

Take-home message: In view of the role of thymic hormones in immune and neuroendocrine systems, they could be suitable as therapeutic agents for inflammation.     

New celecoxib derivatives as anti-inflammatory agents

A series of 1,5-diarylpyrazoles with a substituted benzenesulfonamide moiety was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Some compounds, for example, (+/-)-2-[4-(5- p-tolyl-3-trifluoromethyl-pyrazole-1-yl)-benzenesulfonylaminooxy]-propionic acid 16 and its disodium salt 21, had a higher in vivo anti-inflammatory activity compared to celecoxib, despite having no in vitro COX-1 or COX-2 inhibitory activity. Their gastrointestinal side effect profile is essentially more favorable than that of celecoxib.     

Potassium channel modulators as anti-inflammatory agents

Destruction of self-tissue by unwanted inflammation is central to the pathology of numerous diseases and disorders. The inflammatory response consists of a series of events, involving several cell types and biological signalling molecules. Potassium (K⁺) channels are also involved in this process and may be potential therapeutic targets. Three of the most promising K⁺ channel drug targets are the K_ATP, Kv1.3 and BKCa channels and thus will be reviewed in this article. These channels affect diverse aspects of inflammation and its associated disorders. K_ATP channels protect tissue against ischaemia/reperfusion (I/R) injury, Kv1.3 channels regulate T-cell activation and BKCa channels play a role in controlling cellular activities triggered by depolarisation. K_ATP and BKCa channel openers and Kv1.3 channel blockers have all been shown experimentally to exert anti-inflammatory effects. However, their efficacy in the clinical setting remains to be determined. The most recent patents regarding the use of K⁺ channel modulators to ameliorate inflammation induced tissue damage will be discussed in light of previous work examining the role of these channels in the inflammatory response.     

Porphyrins as new endogenous anti-inflammatory agents

A series of porphyrins, tetrapyrrole natural organic compounds, are evaluated here as endogenous anti-inflammatory agents. They directly inhibit the activity of Fyn, a non-receptor Src-family tyrosine kinase, triggering anti-inflammatory events associated with down-regulation of T-cell receptor signal transduction, leading to inhibition of tumor necrosis factor alpha (TNF-α) production. This is one of the major pro-inflammatory cytokines, associated with diseases such as diabetes, tumorigenesis, rheumatoid arthritis, and inflammatory bowel disease. Porphyrins, as a chemical class, inhibited Fyn kinase activity in a non-competitive, linear-mixed fashion. In cell-based in vitro experiments on polymorphonuclear cells, porphyrins inhibited TNF-α cytokine production, T-cell proliferation, and the generation of free radicals in the oxidative burst, in a concentration-related manner. In vivo, lipopolysaccharide-induced TNF-α production in mice was inhibited by several of the porphyrins. These findings may be very important for the overall understanding of the role(s) of porphyrins in inflammation and their possible application as new anti-inflammatory agents.     

Plant phenylpropanoids as emerging anti-inflammatory agents

Plant-derived phenylpropanoids (PPPs) compose the largest group of secondary metabolites produced by higher plants, mainly, for the protection against biotic or abiotic stresses such as infections, wounding, UV irradiation, exposure to ozone, pollutants, and herbivores. PPPs are parent molecules for biosynthesis of numerous structurally and functionally diverse plant polyphenols (simple phenolic acids and esters, glycosylated derivatives of primary PPPs, flavonoids, isoflavonoids, stilbenes, coumarins, curcuminoids, lignans, etc.), which play multiple essential roles in plant physiology. During the last few decades, extensive research has been dedicated to natural and biotechnologically produced PPPs for medicinal use as antioxidants, UV screens, anticancer, antiviral, anti-inflammatory, wound healing, and antibacterial agents. In the present review, the metabolic pathways of phenylpropanoid biosynthesis in plants and their re-construction in biotechnologically engineered systems are described. Chemical physical peculiarities of PPPs defining their antioxidant, metal chelating, and UV-protecting effects as a molecular basis for their anti-inflammatory properties are discussed as well. We focused also on the discovery of PPPs-based anti-inflammatory agents since distinct PPPs were found to modulate molecular pathways underlying inflammatory responses in human cells triggered by different pro-inflammatory stimuli in vitro and to inhibit inflammation in various tissues in vivo. The problem of low bioavailability, fast metabolism, and potential toxicity/sensitization as limiting factors for the development of PPPs-based anti-inflammatory drugs is also highlighted.