Synthesis of modified steroids as a novel class of non-ulcerogenic, anti-inflammatory and anti-nociceptive agents

The identification of compounds able to treat both pain and inflammation with limited side effects is one of the prominent goals in biomedical research. This study aimed at the synthesis of new modified steroids with structures justifying non-ulcerogenic, anti-inflammatory and anti-nociceptive activities. The steroid derivatives were synthesized via straightforward and efficient methods and their structures were established based on the analytical and spectral data. The in vivo anti-inflammatory, anti-nociceptive and anti-ulcerogenic activities of some of these compounds were studied. The newly synthesized compounds 8b, 19b, 24 and 31a showed anti-inflammatory, anti-nociceptive and anti-ulcerogenic activity with various intensities. Oedema was significantly reduced by either dose 25 or 50 mg/kg of all tested compounds at 3 and 4 h post-carrageenan. Compound 19b was the most effective in alleviating thermal pain. The analgesic activity of either dose of the compounds 8b, 24, 31a as well as the high dose 19b was significantly higher than that for indomethacin (IND). Gastric mucosal lesions caused in the rats by the administration of 96% EtOH and IND were inhibited by all tested compounds administered at (50 mg/kg) dose in the study.     

Prospects for cannabinoids as anti-inflammatory agents

The marijuana plant (Cannabis sativa) and preparations derived from it have been used for medicinal purposes for thousands of years. It is likely that the therapeutic benefits of smoked marijuana are due to some combination of its more than 60 cannabinoids and 200-250 non-cannabinoid constituents. Several marijuana constituents, the carboxylic acid metabolites of tetrahydrocannabinol, and synthetic analogs are free of cannabimimetic central nervous system activity, do not produce behavioral changes in humans, and are effective antiinflammatory and analgesic agents. One cannabinoid acid in particular, ajulemic acid, has been studied extensively in in vitro systems and animal models of inflammation and immune responses. This commentary reviews a portion of the work done by investigators interested in separating the medicinal properties of marijuana from its psychoactive effects. Understanding the mechanisms of the therapeutic effects of nonpsychoactive cannabinoids should lead to development of safe effective treatment for several diseases, and may render moot the debate about "medical marijuana".     

Development of triarylsulfonamides as novel anti-inflammatory agents

Triaylsulfonamides were identified as novel anti-inflammatory agents, acting by inhibition of RANKL and TNFα signaling. Structure-activity studies led to the identification of compounds with in vitro potencies of <100 nM against J774 macrophages and osteoclasts, but with little activity against osteoblasts or hepatocytes (IC₅₀ >50 μM). A representative compound (4k, ABD455) was able to completely prevent inflammation in vivo in a prevention model and was highly effective at controlling inflammation in a treatment model.     

Chloropyrimidines as a new class of antimicrobial agents

In the course of our investigations of pyrimidines as antimycotic agents, we have identified a sub-class, with significant in vitro activity against mycobacteria. The salient feature of these pyrimidine derivatives (3a-o and 7a,b) is their appended aryl, heteroaryl and alkylthio substituent at position 6 and also alkylthio substituent at position 2. The rational design, synthesis, and evaluation of the in vitro antibacterial activity against six pathogenic bacteria including virulent and non-virulent strains of Mycobacterium tuberculosis is described. Some of the synthesized compounds (3c, 3h, 3i, 3o) have displayed only potent in vitro antimycobacterial activity with MIC of 0.75 microg/mL except 3i which also demonstrated activity against Escherichia coli at 12.5 microg/mL concentration. Only two compounds, 3a and 3b, demonstrated antibacterial activity against Pseudomonas aeruginosa and E. coli with MIC 12.5 microg/mL. All the synthesized compounds were also evaluated for their antimycotic activity against five pathogenic fungi but only some of them 3j-n and 7a,b were found most potent against Aspergillus fumigatus and Trichophyton mentagrophytes.     

Synthesis,pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents

A novel series of 5-[2-(2,6-dichlorophenylamino)benzyl]-3-(substituted)-1,3,4-oxadiazol-2(3H)-thione (4a–k) derivatives have been synthesized by the Mannich reaction of 5-[2-(2,6-dichlorophenylamino)benzyl]-1,3,4-oxadiazol-2(3H)-thione (3) with an appropriately substituted primary/secondary amines, in the presence of formaldehyde and absolute ethanol. Structures of these novel compounds were characterized on the basis of physicochemical, spectral and elemental analysis. The title compounds (4a–k) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 10 mg/kg b.w. Compound 4k exhibited the most promising and significant anti-inflammatory profile while compounds 4a, 4d, 4e, 4i, and 4j showed moderate to good inhibitory activity at 2nd and 4th h, respectively. These compounds were also found to have considerable analgesic activity (acetic acid induced writhing model) and antipyretic activity (yeast induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. Compounds that displayed promising anti-inflammatory profile were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 4a, 4e, 4g and 4k exhibited effective inhibition against COX-2. In an attempt to understand the ligand–protein interactions in terms of the binding affinity, docking studies were performed using Molegro Virtual Docker (MVD-2013, 6.0) for those compounds, which showed good anti-inflammatory activity. It was observed that the binding affinities calculated were in agreement with the IC₅₀ values.     

Prenyloxyphenylpropanoids as a novel class of anticonvulsive agents

In this study, we synthesized some natural and semi-synthetic prenyloxyphenylpropanoids (e.g., acetophenones, benzoic and cinnamic acids, chalcones, and coumarins), and we assessed their in vivo neuroprotective activity, using the mouse maximal electroshock-induced seizure model (MES test). 7-Isopentenyloxycoumarin and (2E)-3-{4-[(3-methylbut-2-enyl)oxy]phenyl}prop-2-enoic acid, administered ip at a dose of 300 mg/kg, suppressed MES-induced seizures in mice in a time- and dose-dependent manner.     

New jasmonate analogues as potential anti-inflammatory agents

In an effort to develop new anti-inflammatory agents, methyl jasmonate analogues (2-20) were synthesized and evaluated for their inhibitory effects on the production of pro-inflammatory mediators (NO, IL-6, and TNF-alpha) in lipopolysaccharide (LPS)-activated RAW264.7 murine macrophage cells. The introduction of an enone functionality to the structure of a plant hormone (1) rendered the product (2) a significant anti-inflammatory activity. Analogues further derived from 2 (7, 9, 13, and 15) exhibited even more enhanced activity, and these compounds were much more potent than natural anti-inflammatory prostaglandins (PGA(1), PGA(2), and 15-deoxy-Delta(12,14)-PGJ(2)). Among them, compounds 9 and 15 showed the highest potency, while compounds 7 and 13 would be more desirable with respect to safety. This is the first study demonstrating the anti-inflammatory potential of jasmonate derivatives, and the present results suggest that alpha-haloenone jasmonates (7, 9, 13, and 15) may serve as potential anti-inflammatory leads.     

Discovery of talmapimod analogues as polypharmacological anti-inflammatory agents

Abstract

Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC₅₀=1.95?µM) and COX-2 (IC₅₀=0.036?µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.     

Bacteriophage endolysins as a novel class of antibacterial agents

Endolysins are double-stranded DNA bacteriophage-encoded peptidoglycan hydrolases produced in phage-infected bacterial cells toward the end of the lytic cycle. They reach the peptidoglycan through membrane lesions formed by holins and cleave it, thus, inducing lysis of the bacterial cell and enabling progeny virions to be released. Endolysins are also capable of degrading peptidoglycan when applied externally (as purified recombinant proteins) to the bacterial cell wall, which also results in a rapid lysis of the bacterial cell. The unique ability of endolysins to rapidly cleave peptidoglycan in a generally species-specific manner renders them promising potential antibacterial agents. Originally developed with a view to killing bacteria colonizing mucous membranes (with the first report published in 2001), endolysins also hold promise for the treatment of systemic infections. As potential antibacterials, endolysins possess several important features, for instance, a novel mode of action, a narrow antibacterial spectrum, activity against bacteria regardless of their antibiotic sensitivity, and a low probability of developing resistance. However, there is only one report directly comparing the activity of an endolysin with that of an antibiotic, and no general conclusions can be drawn regarding whether lysins are more effective than traditional antibiotics. The results of the first preclinical studies indicate that the most apparent potential problems associated with endolysin therapy (e.g., their immunogenicity, the release of proinflammatory components during bacteriolysis, or the development of resistance), in fact, may not seriously hinder their use. However, all data regarding the safety and therapeutic effectiveness of endolysins obtained from preclinical studies must be ultimately verified by clinical trials. This review discusses the prophylactic and therapeutic applications of endolysins, especially with respect to their potential use in human medicine. Additionally, we outline current knowledge regarding the structure and natural function of the enzymes in phage biology, including the most recent findings.     

Antibacterials as anti-inflammatory agents: Dual action agents for oral health

Background Inflammatory processes with a range of specialized cells and biochemical mediators form a complex network of inter-related signal transducing pathways that relay information to preserve normal functions. Advances in molecular analyses of the information relay pathways for their constituents and principal ligands along with mechanisms utilized by the host for microbial recognition have stimulated interest in therapeutic agents with dual functionalities i.e. antibacterial and anti-inflammatory effects. Aim This review examines clinically tested agents for oral health applications with both antimicrobial and anti-inflammatory effects to include antibiotics, antimicrobials and phenolics. Results Bis-phenols such as triclosan, representing a unique dual functional therapeutic for routine oral hygiene, with its demonstrated clinical effects on inhibiting the dental plaque biofilm, reducing inflammation (gingivitis) and subsequent periodontitis is described. Cyclines, comprising another class of approved anti-inflammatory agents used at the patient level for oral health is discussed. Dual active agents in current clinical practice for systemic conditions are highlighted to summarize the clinical validity of dual function agents as an emerging therapeutic strategy. Conclusions Clinical studies demonstrate therapeutic benefits of agents with dual functionality with their effects on microorganisms and the concomitant host inflammatory response. Advances in microbial pathogenesis and resultant inflammation will facilitate progress in this emerging area poised to be a significant milestone for dental therapeutics     

Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents.

Preclinical and clinical studies of phosphodiesterase 4 inhibitors have shown that these agents may find utility in a wide range of inflammatory disorders, including asthma, chronic obstructive pulmonary disease, atopic dermatitis, rheumatoid arthritis, multiple sclerosis and various neurological disorders. The future of this class of drugs will depend upon the ability to demonstrate a reasonable safety margin against emesis and other typical phosphodieserase (PDE4) side effects, as well as in identification of the inflammatory disorder(s) most relevant to PDE4 inhibition.     

Discovery of novel FMS kinase inhibitors as anti-inflammatory agents

The optimization of the arylamide lead 2 resulted in identification of a highly potent series of 2,4-disubstituted arylamides. Compound 8 (FMS kinase IC(50)=0.0008 microM) served as a proof-of-concept candidate in a collagen-induced model of arthritis in mice.     

Novel dihydropyrimidines as a potential new class of antitubercular agents

A small library of 30 dihydropyrimidines was synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇Rv. Two compounds, ethyl 4-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylate 4a and ethyl 4-[3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 4d were found to be the most active compounds in vitro with MIC of 0.02 μg/mL against MTB and were more potent than isoniazid.     

Synthesis of a novel family of diterpenes and their evaluation as anti-inflammatory agents

The synthesis and biological evaluation of a new family of diterpenes, represented by structures 2 and 3, is presented. These compounds constitute isomeric analogues of acanthoic acid (1) and were examined as potent anti-inflammatory agents. Among them, methyl ester 12 exhibited a low non-specific cytotoxicity, inhibited TNF-alpha synthesis and displayed good specificity in suppressing cytokine expression.     

Substituted 4-methylquinolines as a new class of anti-tuberculosis agents

We report synthesis and anti-tuberculosis activities of a series of novel ring-substituted quinolines. The most effective compound of the series 3d (MIC=6.25 microg/mL, Mycobacterium tuberculosis H37Rv strain) was synthesized in one step; thus is an attractive lead molecule for anti-tuberculosis drug development. The results of this study represent the discovery of ring-substituted 4-methylquinolines as new class of potential anti-tuberculosis agents.     

New anti-inflammatory agents

The pyrrole derivatives la, b and 2a, b were used as precursors for the preparation of N-substituted pyrrole derivatives 3a, b-9a, b and pyrrolo[2,3-d]pyrimidines 13-16. Also, all the newly prepared products were tested for anti-inflammatory activity as analogues to fenamates, and some of them revealed moderate anti-inflammatory activity compared to the standard drug indomethacin.     

Coumarin Schiff-bases: as antioxidant and possibly anti-inflammatory agents

Coumarin Schiff-bases (CSB) possessing different substituents on the 4-methyl-2-substituted phenyl imino-2H-chromene-7-ol molecule were evaluated for their in-vitro antioxidant and plausible anti-inflammatory potential. The antioxidant studies of selected CSB were carried out by determining their reducing power, OH* radical scavenging activity, scavenging of stable 2,2-diphenyl-l-picrylhydrazine (DPPH*) radical and inhibition of the polyphenol oxidase (PPO) enzyme. The assessment of possible anti-inflammatory potential was performed by trypsin inhibition assay and inhibition of beta-glucuronidase. All the CSBs under study showed significant reducing effects. The majority of the tested CSB were found to be effective scavengers of DPPH* radical with moderate to low OH* scavenging ability and significantly inhibited the activity of PPO. With few exceptions, results from the inhibition assay of trypsin and beta-glucuronidase were not encouraging, however they may be helpful in defining structure-activity relationships in further optimization of the lead molecules.     

Plasma-induced dimerization of phloridzin as a new class of anti-adipogenic agents

Phloridzin is a natural phloretin glucoside found in several parts of apple trees and is an attractive target for structural modification as novel pharmaceutical agent. Nonthermal dielectric barrier discharge (DBD) plasma-induced structural changes in dihydrochalcone phloridzin (1) resulted in the isolation of three new methylene-bridged dihydrochalcone dimers, methylenebisphloridzin (2), deglucosylmethylenebisphloridzin (3), and methylenebisphloretin (4), along with phloretin (5). The chemical structures of these newly generated compounds were elucidated by interpretation of their spectroscopic data. The new phloretin dimer 4 connected by a methylene linkage exhibited significantly improved anti-adipogenic properties against pancreatic lipase as well as differentiation of 3T3-L1 preadipocytes compared to the parent compound phloridzin.