Synthesis and pharmacological evaluation of novel limonin derivatives as anti-inflammatory and analgesic agents with high water solubility

A novel series of water-soluble derivatives of limonin were synthesized by introducing various tertiary amines onto the C (7)-position of limonin. Ten target compounds were characterized and screened for their anti-inflammatory and analgesic activity in vivo. Compound 3c exhibited the strongest analgesic and anti-inflammatory activity among the limonin and its derivatives tested; its analgesic activity is more potent than that of aspirin and its anti-inflammatory activity is stronger than that of naproxen.     

Synthesis and pharmacological evaluation of pyrazoline derivatives as new anti-inflammatory and analgesic agents

A series of 3-(4-biphenyl)-5-substituted phenyl-2-pyrazolines (2a-h) and 1-benzoyl-3-(4-biphenyl)-5-substituted phenyl-2-pyrazolines (3a-h) were synthesized by condensation of chalcones with hydrazine hydrate in solvent system ethanol and DMF. The newly synthesized compounds were screened for their anti-inflammatory and analgesic activity, and were compared with standard drug. Among the compounds studied, compound 2e showed more potent anti-inflammatory and analgesic activity than the standard drug, along with minimum ulcerogenic index.     

Synthesis and pharmacological evaluation of some 3-phenyl-2-substituted-3H-quinazolin-4-one as analgesic, anti-inflammatory agents

A variety of novel 3-phenyl-2-substituted-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-phenyl-3H-quinazolin-4-one with different aldehydes and ketones. The starting material 2-hydrazino-3-phenyl-3H-quinazolin-4-one was synthesized from aniline. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. While the test compounds exhibited significant activity, compounds, 2-(N'-2-butylidene-hydrazino)-3-phenyl-3H-quinazolin-4-one (AS1), 2-(N'-3-pentylidene-hydrazino)-3-phenyl-3H-quinazolin-4-one (AS2) and 2-(N'-2-pentylidene-hydrazino)-3-phenyl-3H-quinazolin-4-one (AS3), exhibited moderate analgesic activity. The compound 2-(N'-2-pentylidene-hydrazino)-3-phenyl-3H-quinazolin-4-one (AS3) showed more potent anti-inflammatory activity when compared to the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic side effect when compared to aspirin.     

Design,synthesis, and evaluation of anti-inflammatory,analgesic, ulcerogenicity,and nitric oxide releasing studies of novel indomethacin analogs as non-ulcerogenic derivatives

Most non-steroidal anti-inflammatory drugs (NSAIDs) suffer from the deadlier gastrointestinal (GI) toxicities. The free -COOH group is responsible for the GI toxicity associated with all traditional NSAIDs. In the present research work, the main objective was to develop new chemical entities as potential anti-inflammatory agents with no GI toxicities. The results of synthesis and pharmacological screening of a series of hybrid molecules having general formula 2-(5-(5-(substituted phenyl)-2-oxo-ethylthio)-1,3,4-oxadiazole-2-yl)-2-phenyl-1H-indol-1-yl)-2-oxoethyl nitrate are described. These compounds were tested in vivo for their anti-inflammatory, analgesic, and ulcerogenic properties, and subjected to histopathological studies. Compound 7c, 2-(5-(5-(3-hydroxyphenyl)-2-oxo-ethylthio)-1,3,4-oxadiazole-2-yl)-2-phenyl-1H-indol-1-yl)-2-oxoethyl nitrate, was the most potent in this series. The compounds that showed significantly reduced GI ulcerogenicity also showed promising results in histopathological studies, and they were found to cause no mucosal injury. All the synthesized compounds were found to exhibit significant nitric oxide releasing activity in an in vitro method. In conclusion, the designed hybrid molecules were found to be significantly promising.     

Synthesis and biological evaluation of nitric oxide releasing derivatives of 6-amino-3-n-butylphthalide as potential antiplatelet agents

A series of novel nitric oxide releasing derivatives of 6-amino-3-n-butylphthalide were designed, synthesized and evaluated as potential antiplatelet agents. Compound 10b significantly inhibited the adenosine diphosphate (ADP)-induced platelet aggregation in vitro, superior to 6-amino-3-n-butylphthalide, 3-n-butylphthalide (NBP) and ticlopidine. Meanwhile 10b released moderate levels of NO, which could be beneficial for improving cardiovascular and cerebral circulation. Furthermore, 10b had an enhanced aqueous solubility relative to NBP. These findings may provide new insights into the development of novel antiplatelet agents for the treatment of thrombosis-related ischemic stroke.     

Synthesis and biological evaluation of novel heterocyclic ionone-like derivatives as anti-inflammatory agents

Five- and six-membered heterocyclic ionone-like derivatives 4-6 have been synthesised in one step and with good yield from the key intermediate 3a and appropriate bifunctional reagents. Four were active as inhibitors of the respiratory burst of human neutrophils without affecting cell viability. The two most active compounds (5a,d) tested in neutrophil migration assays, were also found to be potent inhibitors of neutrophil chemotactic responsiveness. These two molecules could be considered as lead compounds of new drugs which can be an effective tool to treat psoriasis and related neutrophilic dermatoses.     

Synthesis of some new amide-linked bipyrazoles and their evaluation as anti-inflammatory and analgesic agents

Four series of new bipyrazoles comprising the N-phenylpyrazole scaffold linked to polysubstituted pyrazoles or to antipyrine moiety through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory and analgesic activities. In vitro COX-1/COX-2 inhibition study revealed that compound 16b possessed the lowest IC₅₀ value against both COX-1 and COX-2. Moreover, the effect of the most promising compounds on inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) protein expression in lipopolysaccharide (LPS)-activated rat monocytes was also investigated. The results revealed that some of the synthesized compounds showed anti-inflammatory and/or analgesic activity with less ulcerogenic potential than the reference drug diclofenac sodium and are well tolerated by experimental animals. Moreover, they significantly inhibited iNOS and COX-2 protein expression induced by LPS stimulation. Compounds 16b and 18 were proved to display anti-inflammatory activity superior to diclofenac sodium and analgesic activity equivalent to it with minimal ulcerogenic potential.     

Synthesis and biological evaluation of new 3-substituted indole derivatives as potential anti-inflammatory and analgesic agents

Treatment of 3-cyanoacetyl indole 1 with the diazonium salts of 3-phenyl-5-aminopyrazole and 2-aminobenzimidazole afforded the corresponding hydrazones 4 and 5. 3-Cyanoacetyl indole reacted with phenylisothiocyanate to give the corresponding thioacetanilide derivative 7. Treatment of 7 with hydrazonoyl chlorides afforded the corresponding 1,3,4-thiadiazole derivatives 8a-f and 9. Also, the thioacetanilide reacted with alpha-haloketones to afford thiophene derivatives 10a,b (tenidap analogues), or thiazolidin-4-one derivative 11. The newly synthesized compounds were found to possess potential anti-inflammatory and analgesic activities.     

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.     

Synthesis and pharmacological evaluation of pyrazine N-acylhydrazone derivatives designed as novel analgesic and anti-inflammatory drug candidates

In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a–s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a–s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N′-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development.     

Synthesis and biological evaluation of novel benzofuroxan-based pyrrolidine hydroxamates as matrix metalloproteinase inhibitors with nitric oxide releasing activity

On the basis of the strategy of “multifunctional drugs”, a series of novel matrix metalloproteinase inhibitors (MMPIs) containing benzofuroxan scaffold as a nitric oxide donor were designed, synthesized and evaluated. All synthesized compounds, especially 16a, exhibited potent MMP-2,9 inhibitory activities, anti-proliferative activities and could produce high levels of NO in Hela cells. They were also evaluated for both of their anti-invasion and anti-angiogenesis effects. Furthermore, compared with LY52, 16a demonstrated competitive antitumor activity in vivo. These hybrid NO-MMPIs might offer suitable scaffolds to develop valuable MMP inhibitors for the further discovery of novel anti-cancer drugs.     

Discovery of novel 2-substituted-4-phenoxypyridine derivatives as potential antitumor agents

A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β, c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC₅₀ values of 2.18/2.61?nM. Structure-activity relationship studies indicated that n-Pr served as R¹ group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R²?=?4-F) was benefited to the potency.     

Synthesis and biological evaluation of piperlongumine derivatives as potent anti-inflammatory agents

Piperlongumine (PL) and its derivatives were synthesized by the direct reaction between acid chloride of 3,4,5-trimethoxycinnamic acid and various amides/lactams. Later their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-induced RAW-264.7 macrophages. Of the piperlogs prepared in this study, the maximum (91%) inhibitory activity was observed with PL (IC₅₀ = 3 μM) but showed cytotoxicity whereas compound 3 (IC₅₀ = 6 μM) which possess α,β-unsaturated γ-butyrolactam moiety offered good level (65%) of activity with no cytotoxicity. This study revealed that amide/lactam moiety connected to cinnamoyl group with minimum 3 carbon chain length and α,β-unsaturation is fruitful to show potent anti-inflammatory activity.     

Design,synthesis and biological evaluation of nitric oxide releasing derivatives of dapagliflozin as potential anti-diabetic and anti-thrombotic agents

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Therefore, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of NO donor and SGLT2 inhibitor were design to achieve dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the preferred hybrid 2 exhibited moderate SGLT2 inhibitory effects and anti-platelet aggregation activities, and its anti-platelet effect mediated by NO was also confirmed in the presence of NO scavenger. Moreover, compound 2 revealed significantly hypoglycemic effects and excretion of urinary glucose during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 2, is expected as a potential candidate for the intervention of cardiovascular complications in T2DM.     

Design,synthesis and pharmacological evaluation of novel azole derivatives of aryl acetic acid as anti-inflammatory and analgesic agents

A series of substituted azole derivatives (3a–e, 4a–e and 5a–e) were synthesised by the cyclisation of N¹(diphenylethanoyl)-N⁴-substituted phenyl thiosemicarbazides under various reaction conditions. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen, were screened for their analgesic, ulcerogenic and lipid peroxidation activities. The compounds 5-(diphenylmethyl)-N-(4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3b) and 5-(diphenylmethyl)-N-(3-chloro-4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3c) emerged as the most active compounds of the series, and were moderately more potent than the standard drug, ibuprofen. (This abstract was published in Inflammation Research, Supplement 2, Volume 56, page A101, 2008.)     

Synthesis,biological evaluation and docking studies of novel benzopyranone congeners for their expected activity as anti-inflammatory,analgesic and antipyretic agents

8-Acetyl-7-hydroxy-4-phenyl-2H-benzopyran-2-one as starting material a number of 8-substituted derivatives (i.e., hydrazones 2a,b, imine 2c, chalcones 3, pyrazoles 4, 3-cyano-2-oxo-dihydropyridines 5, and/or 3-cyano-2-imino-dihydropyridines 6) were synthesized and assayed for their anti-inflammatory, analgesic and antipyretic activities. Compounds 3c, 4b and 4i showed significant anti-inflammatory, analgesic and antipyretic activities. In addition, 1, 3b, 4d, 4e, 5b, 6a, 6c, 6d, 6e showed anti-inflammatory activity, 2b, 4h, 5e exhibit analgesic activity, and 2b, 4h, 5e showed antipyretic effect. In addition, molecular modeling and docking of the tested compounds into cyclooxygenase II complexed with its bound inhibitor indomethacin (4COX) using molsoft icm 3.4-8C program was performed in order to predict the affinity and orientation of the synthesized compounds at the active site. Also, it was found that the active compounds 1, 4i, 6a–e interact with both Serine 530, and Tyrosine 385 amino acids which are the main amino acids involved in the mechanism of cyclooxygenase II inhibition.The synthesis of the pyrazole-containing new compounds 4 proved a successful hit; also, the 2-imino derivatives of 3-cyano-dihydropyridines were more successful than the 2-oxo derivatives.According to these results, we can conclude that compounds 1, 3c, 4b, 4i, and 6c appear to be the most interesting and seem potentially attractive as anti-inflammatory, analgesic, and antipyretic agents.     

Synthesis of acridinyl-thiazolino derivatives and their evaluation for anti-inflammatory, analgesic and kinase inhibition activities

Variety of N-(4-phenyl-3-(2',3',4'(un)substituted phenyl)thiazol-2(3H)-ylidene)-2,4(un)substituted acridin-9-amine (4a-o) and 1-[(2,4-(un)substituted acridin-9-yl)-3-(4-phenyl-3-(2',3',4'(un)substituted phenyl)thiazol-2(3H)-ylidene)]isothiourea (5a-h) derivatives have been synthesized by condensation of 4-phenyl-3-(2',3',4'(un)substituted phenyl)thiazol-2(3H)-imine (3a-g) with 9-chloro-2,4-(un)substituted acridine (1a-c) and 9-isothiocyanato-2,4-(un)substituted acridine (2a-d), respectively. All these compounds were characterized by correct 1H NMR, FT-IR, MS and elemental analyses. These compounds were screened for anti-inflammatory, analgesic and kinase (CDK1, CDK5 and GSK3) inhibition activities. Some compounds exhibited good anti-inflammatory (25-32%) and potent analgesic (50-75%) activities, at 50 mg/kg p.o. A compound, 4o (R1 = H, R2 = OCH3, R3 = CH3, R4 = CH3, R5 = H) exhibited moderate CDK1 (IC50 = 8.5 microM) inhibition activity.     

Synthesis of benzamide derivatives and their evaluation as antiprion agents

A new set of 5-(2-(pyrrolidin-1-yl)acetamido)-N-butyl-2-(substituted)benzamide and 5-(2-(piperidin-1-yl)acetamido)-N-butyl-2-(substituted) benzamide derivatives were synthesized in which as structural features the 2-(1-pyrrolidinyl)- or 2-(1-piperidyl)acetylamino group or a diphenylether moiety are associated to a benzamide scaffold. Their binding affinity for human PrP(C) and inhibition of its conversion into PrP(Sc) were determined in vitro; moreover, the antiprion activity was assayed by inhibition of PrP(Sc) accumulation in scrapie-infected mouse neuroblastoma cells (ScN2a) and scrapie mouse brain (SMB) cells. The results clearly indicate the benzamide derivatives as attractive lead compounds for the development of potential therapeutic agents against prion disease.     

Synthesis,analgesic and anti-inflammatory activities of some novel pyrazolines derivatives

In search for a new analgesic and anti-inflammatory agent with improved potency, we designed and synthesized a series of 3,2-(4,5-dihydro-5-(4-morphilinophenyl)-1H-pyarazol-3-yl)phenols 6(a–g) and its N-phenylpyrazol-1-carbothioamide 7(a–g) by Claisan–Schmidt condensation followed by the reaction of hydrazine hydrate. All the synthesized compounds were assayed for their in vivo analgesic and anti-inflammatory activities. All the compounds synthesized showed the potential to demonstrate analgesic and anti-inflammatory activity, of particular interest compounds 6a, 6b, 6g, 7a, 7d and 7g were found comparable to Diclofenac.