New thiazolidinyl analogs containing pyridine ring: synthesis, biological evaluation and QSAR studies

A series of pyridine derivatives of thiazolidin-4-ones (4a–4o) has been synthesized. Structures of these compounds were established on the basis of elemental analysis, IR, ¹H NMR, ¹³C NMR, and Mass spectral data. All the synthesized compounds have been evaluated for their anti-inflammatory and analgesic effects. The results showed that compound 2-[4-methylphenylimino]-5-(1H-pyridin-2-ylmethylidene)-1,3-thiazolidin-4-one (4d), 2-(2,4-dinitro-phenylhydrazinylidine)-5-(1H-pyridin-2-yl-methylidene)-1,3-thiazolidin-4-one (4h), and 2-[3-nitro-phenylimino]-5-(1H-pyridin-2-yl-methylidene)-1,3-thiazolidin-4-one (4j) exhibited good anti-inflammatory and analgesic activity. Compound 4h was found to be the most active compound of the series with an interesting dual anti-inflammatory and analgesic activity. Docking simulation was performed to position synthesized compounds into the active site of COX-2. The relationships of energy-based docking score with analgesic and anti-inflammatory activities were also investigated by linear regression method. The QSAR models with R ² of 0.621 and 0.740 were developed for analgesic and anti-inflammatory activities, respectively.     

Design, synthesis and evaluation of novel indomethacin�Cflavonoid mutual prodrugs as safer NSAIDs

Indomethacin suffers from the general side effects of NSAIDs. The study aimed to retard the adverse effects of gastrointestinal (GI) origin. Two conjugates of indomethacin were synthesized by esterification with flavonoids namely, naringenin and hespertin. Purified synthesized mutual prodrugs were characterized by m.p., TLC, elemental analyzes, FTIR, NMR and MS. Synthesized conjugates were subjected for antiinflammatory, analgesic and antiulcer activity. These conjugates showed retention of antiinflammatory activity with reduced ulcerogenic side effects. These results indicated that indomethacin–flavonoid conjugates have the potential to be developed as safer NSAIDs.     

酮洛芬丹皮酚酯及其类似物的合成及抗炎活性研究

目的 合成5种酮洛芬酯类化合物,并研究其抗炎活性和胃肠道不良反应。方法 以丹皮酚及结构类似物和酮洛芬为原料,通过碳二亚胺法合成5种化合物;采用二甲苯致小鼠耳廓肿胀模型和角叉菜胶致大鼠足趾肿胀试验对化合物抗炎活性做了初步的药理学筛选;同时考察化合物对胃肠道不良反应的影响。结果 化合物的结构经¹H-NMR及MS得到确证;5个目标化合物均能显著地减轻小鼠的耳肿胀和大鼠的足趾肿胀程度,与其相应的阳性和阴性对照组相比,都具有良好的抗炎效果;同时,5个目标化合物对胃肠损伤面积明显小于阳性组和阴性组,能够明显地减轻胃肠道的不良反应。结论 合成了5种酮洛芬酯类化合物;抗炎活性均明显强于酮洛芬;且对胃肠道的不良反应明显地减轻。     

Synthesis, characterization, in vitro hydrolysis and pharmacodynamic profiles of potential novel mutual prodrugs of N-(2,3-xylyl anthranilic acid)

In present research work, we report the synthesis, in vitro hydrolysis study and pharmacological evaluation of new mutual prodrugs of mefenamic acid (MA) and 1,2 dihydro-1,5-dimethyl-4-(1-methylethyl)-2-phenylpyrazol-3-one with the aim of improving the therapeutic potency and retard the adverse effects of gastrointestinal origin. The structure of the synthesized mutual ester prodrugs (MP1 and MP2) were confirmed by IR, ¹H NMR, ¹³C NMR, mass spectroscopy and their formation was confirmed by TLC. The purity of the synthesized compounds was established by elemental analysis. The title compounds were tested for analgesic activity by acetic acid-induced writhing method; anti-inflammatory activity was tested by carrageenan-induced rat paw edema method and ulcerogenicity. The study of the analgesic activity revealed that both prodrugs (MP1 and MP2) have shown significant reduction (81.67, 63.90 %) in writhing response produced by acetic acid as compared to parent drug MA (61.10 %). Both mutual prodrugs showed better maximum anti-inflammatory effects (71.43, 85.71 %) and for longer time as compared to parent drug MA (53.14 %). The synthesized prodrugs were also found to be very less irritating to gastric mucosal membrane than parent drugs. The kinetics of ester hydrolysis was studied in simulated gastric fluid (SGF) at pH 1.2 and simulated intestinal fluid (SIF) at pH 7.4. The release of free MA from prodrugs showed negligible hydrolysis in SGF as compared to SIF. This indicated that prodrugs were sufficiently stable at pH 1.2 and do not break in the stomach, but release MA in SIF.     

NSAI Activity Study of 4-Phenyl-2-thioxo-benzo[4,5]thieno [2,3-d]pyrimidine Derivatives

A series of 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3-d]pyrimidine derivatives endowed with anti-inflammatory and related pharmacological properties were submitted to a more extensive study to know their exact pharmacological profile and their possible side effects. The studied compounds possess a remarkable analgesic activity, devoid of central effects. They also show an interesting anti-inflammatory profile evidenced by their effectiveness in different experimental models of inflammation. In addition, these compounds exhibit none or very little activity on CNS, scarce toxicity and low gastrointestinal agressivity.     

Evaluation of mefenamic acid mutual prodrugs

Mutual prodrugs consisting of mefenamic acid with menthol and thymol have been synthesized as a gastrosparing NSAIDs, devoid of ulcerogenic side effects. The structures of synthesized esters were confirmed by IR, ¹H NMR, and mass spectroscopy. The kinetics of ester hydrolysis was studied in nonenzymatic buffer solutions, at pH 2 and 7.4 as well as in human plasma by HPLC. Its anti-inflammatory, analgesic, and ulcerogenic activities were evaluated. Then biochemical parameters (GWM and Hexosamine), oxidative parameters (LPO, GSH, CAT, and SOD), and protein estimation was also done. The results indicated that synthesized prodrugs are chemically stable, biolabile, and posses optimum lipophilicity. The synthesized prodrugs are characterized by better ulcer index than the parent drug.     

Design,synthesis of new chiral fluorine-containing β-hydroxysulfonamides from natural amino acids and study of their anti-inflammatory and analgesic activities

A series of new chiral fluorine-containing β-hydroxysulfonamides were conveniently synthesized in three steps, starting from natural L-amino acids, and evaluated for their anti-inflammatory and analgesic activities. The structures of these compounds were supported by FT-IR, ¹H, ¹³C and ¹⁹F NMR, elemental analysis and HRMS. Among the tested compounds, 4c, 4g and 4h exhibited promising anti-inflammatory activity. Moreover, compound 4h showed a significant analgesic activity. The structure–activity relationships of selected compounds were discussed.     

Synthesis,pharmacological and biological screening of some novel pyrimidine derivatives

In the present study a new series of 4-substituted phenyl-6-(pyridin-2-yl)pyrimidin-2-ol (1–9) and 4-substituted phenyl-6-(pyridin-2-yl)pyrimidin-2-thiol (10–18) have been synthesized by cyclizing 3-substituted phenyl-1-(pyridin-2-yl)prop-2-en-1-one with urea/thiourea in the presence of NaOH as base (1a–18a). 3-Substituted phenyl-1-(pyridin-2-yl)prop-2-en-1-one was prepared by condensing 2-acetylpyridine with substituted benzaldehyde in the presence of 20 % NaOH as base. The structures of the newly synthesized compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectroscopic studies. Newly synthesized compounds were screened for their anti-inflammatory, analgesic, cytotoxic, and antitubercular activities studies. Few of the compounds exhibited excellent anti-inflammatory activities compared to standard drug diclofenac sodium. Some compounds have shown moderate analgesic activities compared to standard drug pentazocine. Also, some compounds have exhibited moderate cytotoxic and antitubercular activities.     

Synthesis,analgesic and anti-inflammatory activities of new methyl-imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles

Background

Long-term clinical employment of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with significant side effects including gastrointestinal (GI) lesions and kidney toxicity. In this paper we designed and synthesized new imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles by molecular hybridization of previously described anti-inflammatory compounds in the hope of obtaining new safer analgesic and anti-inflammatory agents.

Methods

The target structures were synthesized by preparation of 5-methyl-1H-imidazole-4-carboxylic acid ethyl ester 5. The reaction of hydrazine hydrate with this ester afforded the 5-methyl-1H-imidazole-4-carboxylic acid hydrazide 6 which was converted to target compounds 7-15 according to the known procedures. In silico toxicity risk assessment and drug likeness predictions were done, in order to consider the privileges of the synthesized structures as drug candidates.

Results and discussion

The analgesic and anti-inflammatory profile of the synthesized compounds were evaluated by writhing and carrageenan induced rat paw edema tests respectively. Compounds 8, 9 and 11-13 and 15 were active analgesic agents and compounds 8, 9 and 11-13 showed significant anti-inflammatory response in comparison with control. Compounds 11 and 13 were screened for their ulcerogenic activities and none of them showed significant ulcerogenic activity. The active Compounds 11 and 12 showed the highest drug likeness and drug score.

Conclusions

The analgesic and anti-inflammatory activities of title compounds were comparable to that of standard drug indomethacin with a safer profile of activity. The results revealed that both of oxadiazole and triazole scaffolds can be determined as pharmacophores. The in silico predictions and pharmacological evaluations showed that compounds 11 and 12 can be chosen as lead for further investigations.     

Evaluation of anti-inflammatory,analgesic activities,and side effects of some pyrazole derivatives

Background and purpose

Non-steroidal anti-inflammatory drugs are associated with several side effects, such as gastrointestinal mucosal damage, renal toxicity, and cardiovascular side effects. Aiming to find a novel analgesic/anti-inflammatory drug with minimal side effects, the present study was designed to screen and evaluate some newly synthesized pyrazole derivatives.

Method

Anti-inflammatory activity using carrageenan-induced rat paw edema and cotton-pellet-induced granuloma, COX-1/COX-2 selectivity using thin layer chromatography, and analgesic using hot plate and tail flick tests as well as ulcerogenic and renal side effects of the ten compounds were assessed.

Results and discussion

The results of the carrageenan-induced rat paw edema showed that the carboxyphenylhydrazone derivative (N9) was more potent than the chlorophenyl counterpart (N8) with a relative activity compared to celecoxib of 1.08 and ?0.13, respectively, after 1 h. Even though this is true, N9 caused significant increase in the ulcer index, creatinine, and Blood Urea Nitrogen levels. The cotton granuloma test showed that the carboxyphenylhydrazone derivative (N7) was also more potent than its chlorophenyl counterpart (N6) with a relative activity compared to celecoxib of 1.13 and 0.86, respectively. Moreover, adding an acetyl not only increased the anti-inflammatory activity from a relative activity compared to celecoxib of 0.57–1.17 for the compounds X4 and N5, respectively, in the granuloma test, but also increased the selectivity toward COX-2 from 0.197 to 47.979.

Conclusion

As a conclusion, from the ten compounds analyzed, N5 and N7 showed promising results as anti-inflammatory/analgesic agents with low ulcerogenicity and nephrotoxicity and thus should be further analyzed to determine the ED50 and other side effects.

     

苯基呋咱氮氧化物与双氯芬酸偶联化合物的合成及其抗炎镇痛活性

目的寻找能增强双氯芬酸(DC)抗炎镇痛活性,又能降低其胃肠道副作用的一氧化氮供体型DC(NO-DC)。方法以酯键将NO供体3-羟甲基-4-苯基-呋咱氮氧化物及其异构体与DC偶联,考察偶联物的抗炎镇痛活性及胃肠道毒副反应,研究偶联物体内外的NO释放作用。结果合成了15个新化合物,其中目标物(II_1～9) 9个,其结构经IR,¹HNMR,MS和元素分析确证。II₃和II₉的抗炎活性与DC相当,II₂的抗炎镇痛活性强于DC,胃肠道副作用小于DC,并小于文献报道的硝酸酯类NO-DC,体内有明显的NO释放。结论II₂值得深入研究。     

Synthesis of new 1,2,4-triazoles as anti-inflammatory and anti-nociceptive agents

A series of fifteen new substituted 1,2,4-triazoles (6a – 6o) have been synthesized in order to obtain new agents with potential anti-inflammatory and anti-nociceptive activity. The title compounds were synthesized using 4-methylbenzoic acid as a starting reactant. The synthesized compounds were characterized by spectroscopic methods (IR, ¹H NMR, ¹³ C NMR, FAB⁺ − MS) and elemental analysis (nitrogen analysis). The title compounds were evaluated for anti-inflammatory activity by the carrageenan induced paw edema method, and some compounds were evaluated for anti-nociceptive activity by the hot plate method and tail immersion method. Compounds N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-piperidin-1-ylacetamide (6f), 2-(4-benzylpiperazin-1-yl)-N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]acetamide (6i) and N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-morpholin-4-ylacetamide (6 k) showed significant anti-inflammatory activity compared to other synthesized compounds, and N-[3-mercapto-5-(4-methylphenyl)-4H-1,2,4-triazol-4-yl]-2-morpholin-4-ylacetamide (6 k) exhibited superior anti-nociceptive activity.     

Synthesis,characterization, and anti-rheumatic potential of phthalazine-1,4-dione and its Cu(II) and Zn(II) complexes

Two new metal complexes derived from the reaction of 2-[(2-hydroxybenzoyl) 2,3,4a,5,10,10a-hexahydro-5,10[1′,2′]-benzenobenzo[g]phthalazine-1,4-dione] (HBPD) with Cu(II) and Zn(II) have been synthesized and characterized by using elemental analysis, spectral analysis (UV–Vis, IR, ¹H NMR, ¹³C NMR), conductance, thermal analysis, and magnetic moments. The in vivo collagen-adjuvant arthritis model in rats revealed a significant antioxidant, analgesic, and anti-rheumatic effects for HBPD and its copper and zinc complexes in comparison with standard piroxicam. The results showed that, the investigated Cu and Zn complexes have higher anti-inflammatory activity than the free ligand.     

Synthesis, characterization and in vitro hydrolysis studies of ester and amide prodrugs of dexibuprofen

Ten prodrugs of dexibuprofen having ester and amide moieties instead of free carboxylic acid which involves in gastrointestinal side effects have been synthesized. Dexibuprofen acid chloride was condensed with different amino acid methyl ester hydrochlorides and five alcohols to afford the amide and ester prodrugs. All of the synthesized prodrugs were characterized by their mp, R _f, elemental analysis, FTIR, ¹H NMR, and ¹³C NMR spectroscopy. The in vitro hydrolysis studies in plasma reflect prodrugs have been varied in terms of reactivity toward hydrolysis, owing to the different chemical structures. In alkyl substitution the branched chain alkyl substituents or aromatic substituents resulted in enhanced lipophilicity but diminished dissolution and hydrolysis rate. The amide prodrugs with branched and aromatic substitution can also be considered for sustained release. Prodrugs are less irritating to gastric mucosa than dexibuprofen.     

2-Amino-5-sulfanyl-1,3,4-thiadiazoles: a novel series of anti-inflammatory and analgesic agents

2-Amino-5-sulfanyl-1,3,4-thiadiazole derivatives were synthesized via the interaction of 2-amino-5-sulfanyl-1,3,4-thiadiazole, Ar-Cl, and benzene sulfonamide/benzene sulfonyl chloride. Twelve compounds were synthesized, out of which six compounds show significant anti-inflammatory and analgesic activity and were devoid of gastrointestinal side effects (ulcerogenic effect), which zre the most frequent adverse reactions associated with orally ingested anti-inflammatory or antiarthritic agents.     

Dextran successful carrier molecule for the delivery of NSAIDs with reduced gastrointestinal effect

The dextran ester polymeric prodrug of aceclofenac and mefenamic acid was synthesized through carbonyldiimidazole coupling agent. The prepared polymeric prodrug was characterized by UV, IR, X-RD and ¹H NMR. The in vitro hydrolysis study was performed by HPLC and polymeric conjugate subjected for in vitro hydrolysis showed negligible hydrolysis in simulated gastric fluid pH 1.2 for 3 h. The half-life of the aceclofenac dextran conjugate in simulated intestinal fluid (SIF) pH 7.4 and phosphate buffer solution (PBS) pH 9.0 was found to be 8.51 h and 33.72 min, respectively. The half-life 4.66 h and 25.4 min was found in SIF pH 7.4 and PBS pH 9.0, respectively for mefenamic acid conjugates. The conjugates were screened for biological activity such as anti-inflammatory, analgesic and ulcerogenic activity. The statistical data obtained from the biological experiment suggested that the value was found to be significant with respect to normal control.     

Studies on Synthesis and Pharmacological Activities of 1,2,4‐Triazolo[3,4‐b]1,3,4‐thiadiazoles and their Dihydro Analogues

4‐Amino‐5‐substituted aryl‐3‐mercapto‐1,2,4‐triazoles are versatile synthons for constructing various biologically active heterocycles. Starting from 4‐amino‐5‐substituted aryl‐3‐mercapto‐1,2,4‐triazole 3a – c , a series of new 3,5‐disubstituted‐1,2,4‐triazolo‐[3,4‐b]1,3,4‐thiadiazoles and their 5,6‐dihydrotriazolothiadiazoles were prepared. The structures of all the newly synthesized compounds have been confirmed by elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR, and mass spectra. The antimicrobial effects of the synthesized compounds were investigated using the paper disc method. Anti‐inflammatory and analgesic activities of the synthesized compounds were assessed by carrageenan‐induced rat paw oedema method and by Eddy's hot plate method, respectively. Some of the compounds exhibited promising antimicrobial activities as well as moderate to good anti‐inflammatory activity and analgesic activity.     

Synthesis of 2-(aryl)-5-(arylidene)-4-thiazolidinone derivatives with potential analgesic and anti-inflammatory activity

A series of novel N-[5-(arylidene)-2-(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide derivatives was synthesized and evaluated for analgesic and anti-inflammatory activity. In this study, biphenyl-4-carboxylic acid hydrazide was converted to the corresponding aryl hydrazones using aryl aldehydes in the presence of catalytic amount of glacial acetic acid. The aryl hydrazones on reaction with thioglycolic acid in the presence of anhydrous zinc chloride yielded N-[2-(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide which further on reaction with aromatic aldehydes in the presence of anhydrous sodium acetate and glacial acetic acid furnished the title compounds. All compound exhibited anti-inflammatory activity at the dose 10?mg/kg. The structures of all these newly synthesized compounds were confirmed by their elemental analyses (C, H, N) and spectral data (IR and ¹H NMR).     

Anti-inflammatory effects of DA-9601, an extract of Artemisia asiatica,on aceclofenac-induced acute enteritis

DA-9601 is an extract obtained from Artemisia asiatica, which has been reported to have anti-inflammatory effects on gastrointestinal lesions; however, its possible anti-inflammatory effects on the small intestine have not been studied yet. Therefore, in this study, we investigated the protective effects of DA-9601 against the ACF-induced small intestinal inflammation. Inflammation of the small intestine was confirmed by histological studies and the changes in the CD4⁺ T cell fraction induced by the inflammation-related cytokines, and the inflammatory reactions were analyzed. Multifocal discrete small necrotic ulcers with intervening normal mucosa were frequently observed after treatment with ACF. The expression of IL-6, IL-17, and TNF-α genes was increased in the ACF group; however, it was found to have been significantly decreased in the DA-9601 treated group. In addition, DA-9601 significantly decreased the levels of proinflammatory mediators such as IL-1β, GM-CSF, IFN-γ, and TNF-α; the anti-inflammatory cytokine IL-10, on the other hand, was observed to have increased. It is known that inflammatory mediators related to T cell imbalance and dysfunction continuously activate the inflammatory response, causing chronic tissue damage. The fractions of IFN-γ⁺ Th1 cells, IL-4⁺ Th2 cells, IL-9⁺ Th9 cells, IL-17⁺ Th17 cells, and Foxp3⁺ Treg cells were significantly decreased upon DA-9601 treatment. These data suggest that the inflammatory response induced by ACF is reduced by DA-9601 via lowering of the expression of genes encoding the inflammatory cytokines and the concentration of inflammatory mediators. Furthermore, DA-9601 inhibited the acute inflammatory response mediated by T cells, resulting in an improvement in ACF-induced enteritis.     

Ketorolac-dextran conjugates: synthesis, in vitro and in vivo evaluation

Ketorolac is a non-steroidal anti-inflammatory drug. Dextran conjugates of ketorolac (KD) were synthesized and characterized to improve ketorolac aqueous solubility and reduce gastrointestinal side effects. An N-acylimidazole derivative of ketorolac (KAI) was condensed with a model carrier polymer, dextran of different molecular masses (40000, 60000, 110000 and 200000). IR spectral data confirmed formation of ester bonding. Ketorolac contents were evaluated by UV-spectrophotometric analysis. The molecular mass was determined by measuring viscosity using the Mark-Howink-Sakurada equation. In vitro hydrolysis studies were performed in aqueous buffers (pH 1.2, 7.4, 9) and in 80% (V/V) human plasma (pH 7.4). At pH 9, a higher rate of ketorolac release from KD was observed as compared to aqueous buffer of pH 7.4 and 80% human plasma (pH 7.4), following first-order kinetics. In vivo biological screening in mice and rats indicated that conjugates retained analgesic and anti-inflammatory activities with significantly reduced ulcerogenicity compared to the parent drug.