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 anti-inflammatory activity of some 3-(4,6-disubtituted-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl) propanoic acid derivatives

A series of 3-(4,6-disubtituted-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl) propanoic acid derivatives has been synthesized by condensation of thiourea, 5-(4-subtituted phenyl)-5-oxopentanoic acid and substituted aldehyde. The synthesized compounds were screened for their anti-inflammatory activity using rat paw edema method. Most of the compounds from the series showed significant (p <0.05) anti-inflammatory activity.     

Synthesis of some pyrazolyl benzenesulfonamide derivatives as dual anti-inflammatory antimicrobial agents

Four series of pyrazolylbenzenesulfonamide derivatives were synthesized and evaluated for their anti-inflammatory activity using cotton pellet induced granuloma and carrageenan-induced rat paw edema bioassays. Moreover, COX-1 and COX-2 inhibitory activity, ulcerogenic effect and acute toxicity were also determined. Furthermore, the target compounds were screened for their in-vitro antimicrobial activity against Eischerichia coli, Staphylococcus aureus and Candida albicans. Compounds 4-(3-Phenyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9a and 4-(3-Tolyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9b were not only found to be the most active dual anti-inflammatory antimicrobial agents in the present study with good safety margin and minimal ulcerogenic effect but also exhibited good selective inhibitory activity towards COX-2. A docking pose for 9a and 9b separately in the active site of the human COX-2 enzyme was also obtained. Therefore, these compounds would represent a fruitful matrix for the development of dual anti-inflammatory antimicrobial candidates with remarkable COX-2 selectivity.     

Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs.     

Synthesis and anti-inflammatory activity of 2-aryloxy methyl oxazolines

A series of potential biologically active 2-aryloxy methyl oxazolines 3a-n have been synthesized from substituted hydroxybenzenes 1a-n with good chemical yield. The compounds 3a-n were screened for their anti-inflammatory, ulcerogenic, cyclooxygenase activities and also for their acute toxicity. The potency of the compounds was compared with that of the standard drugs, aspirin and phenyl butazone. The outcome indicates that compounds 3b (48.2%), 3h (48.5%) and 3l (46.5%) offered significant anti-inflammatory activity with low ulcerogenic activity than the standard drugs.     

Synthesis of some newer derivatives of 2-amino benzoic acid as potent anti-inflammatory and analgesic agents

Diazotization of N-benzylidene anthranilic acids 1a-1n at pH 9 yielded N-[alpha-(phenylazo) benzylidene] anthranilic acids 2a-2n and at pH 3 yielded N-benzylidene-5-(phenylazo) anthranilic acids 3a-3n. When compounds 3a-3n were treated with thioglycolic/thiolactic acid in the presence of anhydrous ZnCl(2), 2-(4-oxo-2-phenylthiazolidin-3-yl)-5-(phenylazo) benzoic acids 4a-4n were afforded. The newly synthesized compounds were screened for their anti-inflammatory and analgesic activities and were compared with standard drugs, aspirin and phenylbutazone. Out of the compounds studied, the most active compound 4n showed more potent activity than the standard drugs at all doses tested.     

Synthesis, anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activity evaluation of benzimidazole/benzoxazole derivatives and some Schiff's bases

A series of N-(acridin-9-yl)-4-(benzo[d]imidazol/oxazol-2-yl) benzamides has been synthesized by the condensation of 9-aminoacridine derivatives with benzimidazole or benzoxazole derivatives. Condensation of 2-hydroxy naphthaldehyde with functionalized diamines leads to the formation of Schiff's bases and not imidazole derivatives. All these compounds were characterized by correct FT-IR, (1)H NMR, MS and elemental analyses. These compounds were screened for anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activities. Compounds 11 and 7e(f) showed good anti-inflammatory (35.8% at 50 mg/kg po) activity and good analgesic activity (60% at 50 mg/kg po), respectively. Compound 3b showed significant in vitro activity against CDK-5 (IC(50)=4.6 microM) and CDK-1(IC(50)=7.4 microM) and compound 3a showed moderate CDK-5 inhibitory activity (IC(50)=7.5 microM). The other compounds showed moderate anti-inflammatory and analgesic activities.     

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 anti-inflammatory activity of some new 4,5-dihydro-1,5-diaryl-1H-pyrazole-3-substituted-heteroazole derivatives

A series of 4,5-dihydro-1,5-diaryl-1H-pyrazole-3-substituted-heteroazoles were designed and synthesized in order to obtain new compounds with potential anti-inflammatory activity. The title compounds were screened for in vivo anti-inflammatory activity by using Carrageenan induced rat paw edema method. Diclofenac sodium was used as a standard drug for comparison. Out of the 30 compounds tested, compound 19a, 19b, 25a, 25b exhibited significant anti-inflammatory activity. Selected compounds were also screened for in vitro COX-2 inhibition assay and analgesic activity in the acetic acid induced writhing model.     

Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs.     

Synthesis, characterization and preliminary screening of regioisomeric 1-(3-pyridazinyl)-3-arylpyrazole and 1-(3-pyridazinyl)-5-arylpyrazole derivatives towards cyclooxygenase inhibition

In a search for novel compounds with analgesic and anti-inflammatory activity, a series of regioisomeric 1-(3-pyridazinyl)-3-arylpyrazole (5a-f, 6a-f) and 1-(3-pyridazinyl)-5-arylpyrazole (7a-f, 8a-f) derivatives were synthesized. The structure of these regioisomers was confirmed by spectral techniques. The compounds were preliminarily screened at 8 microM concentration for their inhibitory activity against cyclooxygenase enzymes, COX-1 and COX-2, using a human whole blood test. The tested derivatives showed inhibitory activity for both enzymes and are worthy of further investigation for developing better leads.     

Conventional and microwave assisted synthesis of pyrazolone Mannich bases possessing anti-inflammatory,analgesic, ulcerogenic effect and antimicrobial properties

In the present study, an efficient synthesis of some Mannich base of 5-methyl-2-[(2-oxo-2H-chromen-3-yl)carbonyl]-2,4-dihydro-3H-pyrazol-3-one (4a–j) have been described by using conventional and non-conventional (microwave) techniques. Microwave assisted reactions showed that require shorter reaction time and good yield. The newly synthesized compounds were screened for their anti-inflammatory, analgesic activity, antioxidant, and antibacterial effects were compared with standard drug. Among the compounds studied, compound (4f) showing nearly equipotent anti-inflammatory and analgesic activity than the standard drug (indomethacin), along with minimum ulcerogenic index. Compounds (4b and 4i) showing 1.06 times more active than ciprofloxacin against tested Gram-negative bacteria.     

Synthesis of some pyrazolyl benzenesulfonamide derivatives as dual anti-inflammatory antimicrobial agents

Four series of pyrazolylbenzenesulfonamide derivatives were synthesized and evaluated for their anti-inflammatory activity using cotton pellet induced granuloma and carrageenan-induced rat paw edema bioassays. Moreover, COX-1 and COX-2 inhibitory activity, ulcerogenic effect and acute toxiCIT000y were also determined. Furthermore, the target compounds were screened for their in-vitro antimicrobial activity against Eischerichia coli, Staphylococcus aureus and Candida albicans. Compounds 4-(3-Phenyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9a and 4-(3-Tolyl-4-cyano-1H-pyrazol-1-yl)benzenesulfonamide 9b were not only found to be the most active dual anti-inflammatory antimicrobial agents in the present study with good safety margin and minimal ulcerogenic effect but also exhibited good selective inhibitory activity towards COX-2. A docking pose for 9a and 9b separately in the active site of the human COX-2 enzyme was also obtained. Therefore, these compounds would represent a fruitful matrix for the development of dual anti-inflammatory antimicrobial candidates with remarkable COX-2 selectivity.     

Synthesis and biological evaluation of cyanoguanidine derivatives of loratadine

Cyanoguanidine derivatives of loratadine (3a–i) were synthesized and screened for antitumor and anti-inflammatory activity. The most promising compound 3c (R = n-C₈H₁₇) possessed at least twofold higher in vitro cytotoxicity than 5-fluorouracil against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. The mode of action, however, is so far unclear. The participation of the COX-1/2 enzymes on the cytotoxicity, however, is very unlikely. Nevertheless all compounds showed stronger in vivo anti-inflammatory activity than ibuprofen in the xylene-induced ear swelling assay in mice.     

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.     

One pot synthesis of pyrimidine and bispyrimidine derivatives and their evaluation for anti-inflammatory and analgesic activities

A number of pyrimidine derivatives (1-10) have been synthesized by condensation of 4-isothiocyanato-4-methylpentan-2-one with furfurylamine, histamine, 1-(3-aminopropyl)imidazole, 1-(3-aminopropyl)-2-pyrrolidinone, 2-aminobenzonitrile and 3-isothiocyanatobutanal with 1-(3-aminopropyl)-2-pyrrolidinone and 2-hydrazinopyridine under different reaction conditions. Various bispyrimidine derivatives (11-15) were obtained by condensation of 4-isothiocyanato-4-methylpentan-2-one with 2,4,8,10-tetraoxaspiro[5,5]undecane3,9-dipropamine (11'), 1,4-bis(3-aminopropyl)piperazine (13'), 3,5-diamino 1,2,4-triazole (15') and 3-isothiocyanatobutanal with 2,4,8,10-tetraoxaspiro[5,5]undecane 3,9-dipropamine, 1,4-bis(3-aminopropyl)piperazine. All these compounds were characterized by correct FT-IR, (1)H NMR, MS and elemental analysis. These compounds were screened for anti-inflammatory and analgesic activities. Anti-inflammatory activity of 3 is comparable while analgesic activity was found to be better than that of standard drug.     

Synthesis, pharmacological evaluation and docking studies of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs as COX-2 inhibitors

The existing NSAIDs having number of toxicities emphasises the need for discovery of new non-toxic anti-inflammatory agents. In this Letter, we present the simple two step chemical synthesis, in vivo pharmacological screening and docking study of few N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs. Different amino benzothiazoles were chloroacetylated and further reacted with substituted piperazines in presence of a base to get N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs (A1-C4). These compounds were evaluated for anti-inflammatory activity by carragenan induced paw oedema method. Promising compounds were screened for toxicity by evaluating the ulcerogenic potential. Molecular docking experiments were carried out against COX-2 enzyme using Surflex-Dock GeomX programme of Sybyl software on Dell T-1500 workstation to confirm the mechanism of action of active compounds among the series. In silico study reveal the binding interactions of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs with COX-2 protein and is in agreement with the in vivo anti-inflammatory activity.     

Anti-inflammatory and antimicrobial activities of novel pyrazole analogues

A new sequence of pyrazole derivatives (1–6) was synthesized from condensation technique under utilizing ultrasound irradiation. Synthesized compounds were characterized from IR, ¹H NMR, ¹³C NMR, Mass and elemental analysis. Synthesized compounds (1–6) were screened for antimicrobial activity. Among the compounds 3 (MIC: 0.25 μg/mL) was exceedingly antibacterially active against gram negative bacteria of Escherichia coli and compound 4 (MIC: 0.25 μg/mL) was highly active against gram positive bacteria of Streptococcus epidermidis compared with standard Ciprofloxacin. Compound 2 (MIC: 1 μg/mL) was highly antifungal active against Aspergillus niger proportionate to Clotrimazole. Synthesized compounds (1–6) were screened for anti-inflammatory activity and the compound 2-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(4-nitrophenyl)methyl)hydrazinecarboxamide (4) was better activity against anti-inflammatory when compared with standard drugs (Diclofenac sodium). Compounds (2, 3 and 4) are the most important molecules and hence the need to develop new drugs of antibacterial, antifungal and anti-inflammatory agents.     

Nonsteroidal anti-inflammatory drugs and their analogues as inhibitors of aldo-keto reductase AKR1C3: new lead compounds for the development of anticancer agents

Nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin, flufenamic acid, and related compounds have been recently identified as potent inhibitors of AKR1C3. We report that some other NSAIDs (diclofenac and naproxen) also inhibit AKR1C3, with the IC(50) values in the low micromolar range. In order to obtain more information about the structure-activity relationship and to identify new leads, a series of compounds designed on the basis of NSAIDs were synthesized and screened on AKR1C3. The most active compounds were 2-[(2,2-diphenylacetyl)amino]benzoic acid 4 (IC(50)=11microM) and 3-phenoxybenzoic acid 10 (IC(50)=0.68microM). These compounds represent promising starting points for the development of new anticancer agents.