A new therapeutic approach in Alzheimer disease: some novel pyrazole derivatives as dual MAO-B inhibitors and antiinflammatory analgesics

The increasing life expectancy in our population makes Alzheimer's disease (AD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that monoamine oxidase-B (MAO-B) inhibitors and antiinflammatory agents might be effective in treating AD. Therefore, a novel series of 1-thiocarbamoyl-3-substituted phenyl-5-(2-pyrrolyl)-4,5-dihydro-(1H)-pyrazole derivatives as promising MAO-B inhibitors was synthesized and investigated for the ability to inhibit selectively the activity of the A and B isoforms of monoamine oxidase (MAO). Most of the synthesized compounds showed high activity against both the MAO-A (compounds 3e-3h) and the MAO-B (compounds 3i-3l) isoforms. All the synthesized compounds were also tested for their in vivo antiinflammatory activity by two different bioassays namely, carrageenan-induced oedema and acetic acid-induced increase in capillary permeability in mice. In addition, analgesic and ulcerogenic activities were determined. The combined antiinflammatory data from in vivo animal models showed that compound 3k exhibited anti-inflammatory activity comparable to that of indomethacin with no ulcerogenic effects. Since compound 3k exhibits both antiinflammatory-analgesic activity and MAO-B inhibition, it needs further detailed studies.     

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.     

Design and synthesis of 3-pyrazolyl-thiophene, thieno[2,3-d]pyrimidines as new bioactive and pharmacological activities

Two series of 5-ethyl-2-amino-3-pyrazolyl-4-methylthiophenecarboxylate and 2-thioxo-N(3)-aminothieno[2,3-d]pyrimidines were prepared from 3,5-diethyl-2-amino-4-methylthio-phenecaboxylate and evaluated as anti-inflammatory, analgesic and ulcerogenic activities. Among the compounds studied, compounds which containing the substituted hydrazide at C-3 position 7, 16, and 17a showed more potent anti-inflammatory and analgesic activities than the standard drug (Indomethacin and Aspirin), along without ulcerogenity. While compounds 2, 5, 9, 10, and 11c showed moderate activities. Some of the newly synthesized compounds have good to excellent antimicrobial activity.     

In vitro and molecular docking studies of an anti-inflammatory scaffold with human peroxiredoxin 5 and tyrosine kinase receptor

A new series of 4-(3-(2-amino-3,5-dibromophenyl)-1-(4-substitutedbenzoyl)-4,5-dihydro-1H-pyrazol-5-yl)benzonitrile (4a-h) compounds were synthesized and evaluated for in-vitro anti-inflammatory activities. The spectral (IR, NMR) and elemental analyses data of the product indicated the formation of new pyrazoles 4a-h. Compound 4e exhibited potent anti-inflammatory property with 85.45 % inhibitions. This value was compared with standard diclofenac sodium. This data is explained using molecular docking analysis of receptor- ligand binding. These results demonstrated that pyrazole derivatives are potential inhibitors of Human Peroxiredoxin 5 and Tyrosine kinase receptor in the treatment of inflammation related illness.     

Design and synthesis of 3-(4-ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones as a novel class of analgesic and anti-inflammatory agents

A new series of 3-(4-ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-ethylphenyl)-3H-quinazolin-4-one from 4-ethyl aniline with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. The compound 2-(N'-3-pentylidene-hydrazino)-3-(4-ethylphenyl)-3H-quinazolin-4-one (AS2) emerged as the most active compound of the series and was moderately more potent than the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to aspirin.     

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 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, anti-inflammatory, analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(alpha-Carbomethoxy-beta-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 microg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC(50) value 31.59 microg/mL.     

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.     

Synthesis, biological evaluation, and docking studies of 3-(substituted)-aryl-5-(9-methyl-3-carbazole)-1H-2-pyrazolines as potent anti-inflammatory and antioxidant agents

A novel series of 3-(substituted)-aryl-5-(9-methyl-3-carbazole)-1H-2-pyrazolines (5a-o) has been synthesized and the structures of newly synthesized compounds were characterized by IR, (1)H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their in vitro and in vivo anti-inflammatory activity, and also for their antioxidant activity. Compounds 5b, 5c, 5d and 5n were found to be selective COX-2 inhibitors. Compound 5c was found to potent inhibitor of the carrageenin induced paw edema in rats. Most of the compounds exhibited good DPPH and superoxide radical scavenging activity, while compounds 5c, 5d, 5i and 5k exhibited good hydroxyl radical scavenging activity. Molecular docking result, along with the biological assay data, suggested that compound 5c was a potential anti-inflammatory agent.     

Novel bis(1-acyl-2-pyrazolines) of potential anti-inflammatory and molluscicidal properties

A variety of bis[3-aryl-4,5-dihydro-1H-pyrazol-1-carboxaldehydes] 4a-h were obtained via reaction of bis[1-aryl-2-propen-1-ones] 3a-h with hydrazine hydrate in refluxing formic acid. In addition, the corresponding bis[1-acetyl-3-aryl-4,5-dihydro-1H-pyrazoles] 4i-m were formed through conducting the reaction of 3 with hydrazine hydrate in refluxing acetic acid. The starting bis(2-propen-1-ones) 3a-h were prepared stereoselectively as E,E'-geometric isomer via condensation of bisbenzaldehydes 1a,b with (un)substituted acetophenones 2 in ethanolic KOH solution. Anti-inflammatory as well as ulcerogenic activities of the prepared pyrazolines were evaluated in vivo and compared with that of a standard drug (indomethacin). Many of the tested compounds show remarkable anti-inflammatory properties with an ulcerogenic liability (especially 4f, g, j, and k) lower than that of the standard used drug. Compound 4f was established to be the best effectively prepared anti-inflammatory active pyrazoline derivative and safer than indomethacin with respect to its ulcerogenic liability. Molluscicidal activity of the prepared compounds against Biomphalaria alexandrina snails (the intermediate host of Schistosoma mansoni) was screened. Where, some of the prepared compounds show considerable activities.     

Design, synthesis, biological evaluation, and comparative Cox1 and Cox2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with gastric mucosal and renal adverse reactions, related to inhibition of cyclooxygenase1 (Cox1) in tissues where prostaglandins exert physiological effects. This led us to develop a set of ibuprofenic acid and mefenamic acid esters, namely: 4-((4-substituted benzylidene)amino)phenyl 2-(4-isobutylphenyl)propanoate and 4-((4-substituted benzylidene)amino)phenyl 2-((2,4-dimethylphenyl)amino)benzoate analogs, which were synthesized by condensation of the corresponding acids with Schiff's bases [4-(4-substituted benzylideneamino)phenols] involving dicyclohexyl carbodiimmide (DCC) as mild dehydrating agent. The main objective is to reduce the GIT toxicity associated with acute and chronic NSAIDs use. Anti-inflammatory, analgesic as well as ulcerogenic activities of the prepared esters were evaluated in vivo and compared with that of ibuprofen as reference standard in all screenings, involving the carrageenan induced paw oedema model and hot plate method. Most of the synthesized esters showed remarkable analgesic and anti-inflammatory activities. Interestingly, all of the compounds were found to be non-ulcerogenic under the tested conditions. This evidence have suggested that modification of the carboxyl function of representative NSAIDs results in retained or enhanced anti-inflammatory and analgesic activities with reduced ulcerogenic potential. Additionally, a comparative AutoDock study into Cox 1 and Cox2 has been done involving both of rigid and flexible docking for potential selectivity of our compounds within different Cox enzymes and to find out the binding orientation of these novel esters into their binding site. Some of the newly prepared aforementioned compounds showed considerable more Cox2 over Cox1 binding affinities by flexible docking better than rigid one.     

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.     

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, antimicrobial, and anti-HIV-1 activity of certain 5-(1-adamantyl)-2-substituted thio-1,3,4-oxadiazoles and 5-(1-adamantyl)-3-substituted aminomethyl-1,3,4-oxadiazoline-2-thiones

The reaction of 5-(1-adamantyl)-1,3,4-oxadiazoline-2-thione 2 with iodoethane, 2-dimethylaminoethyl chloride hydrochloride or 2-piperidinoethyl chloride hydrochloride in ethanolic potassium hydroxide yielded the corresponding 5-(1-adamantyl)-2-ethyl or substituted ethylthio-1,3,4-oxadiazoles 3a-c. Interaction of 2 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding 5-(1-adamantyl)-3-arylaminomethyl-1,3,4-oxadiazoline-2-thiones 4a-m or 5-(1-adamantyl)-3-(4-substituted-1-piperazinylmethyl)-1,3,4-oxadiazoline-2-thiones 5a-h, respectively. All the synthesized compounds were tested for in vitro activities against certain strains of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 2, 5a, and 5e were found as the most active derivatives, particularly against the Gram-positive bacteria. In addition, the antiviral activity of compounds 2, 4a-m, and 5a-h against HIV-1 using the XTT assay was carried out. Compound 2 produced 100%, 43%, and 37% reduction of viral replication at 50, 10, and 2microg/mL concentrations, respectively.     

Design and synthesis of 3-(4-Ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones as a novel class of analgesic and anti-inflammatory agents

A new series of 3-(4-ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-ethylphenyl)-3H-quinazolin-4-one from 4-ethyl aniline with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. The compound 2-(N′-3-pentylidene-hydrazino)-3-(4-ethylphenyl)-3H-quinazolin-4-one (AS2) emerged as the most active compound of the series and was moderately more potent than the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to aspirin.     

Synthesis, analgesic, anti-inflammatory, and antimicrobial activity of some novel pyrimido[4,5-b]quinolin-4-ones

Novel series of pyrimido[4,5-b]quinolines (3a-c), triazolo[4',3':1,2]pyrimido[4,5-b]-quinolines (7a-e, 9, and 14), tetrazolo[4',3':1,2]pyrimido[4,5-b]quinolin-5-one (13), [1,3]-pyrazolo[3',2':1,2]pyrimido[4,5-b]quinolines (12a and 12b), and 2-pyrazolyl-pyrimido[4,5-b]-quinolines (15, 16a, 16b, and 19) have been synthesized. Some of the new compounds were tested against various bacteria and fungi species. In addition, the analgesic and anti-inflammatory activities are reported. Compounds 8 and 9a possess high activity toward the fungi as compared with the reference drug Nystatin. The tested compounds 5 and 8 have moderate anti-inflammatory activities. Moreover compounds 5, 8, 10, and 16a, have activities higher than the reference drug in peripheral analgesic activity testing, Compounds 5, 7a, 11a, and 16a have potencies as the reference drug in central analgesic activity testing.     

Triazole incorporated pyridazinones as a new class of antihypertensive agents: design, synthesis and in vivo screening

A number of 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were designed and synthesized by a sequence of reactions starting from respective aryl hydrocarbons. The final compounds (4a-4u) were evaluated for antihypertensive activities by non-invasive method using Tail Cuff method. The compounds 4e, 4i and 4k showed appreciable antihypertensive activity comparable with that of standard hydralazine and propranolol.     

Synthesis and analgesic/anti-inflammatory evaluation of fused heterocyclic ring systems incorporating phenylsulfonyl moiety

A series of pyrazolo[1,5-a]pyrimidine, triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazole ring systems incorporating phenylsulfonyl moiety were synthesized via the reaction of 3-(N,N-dimethylamino)-1-aryl-2-(phenylsulfonyl)prop-2-en-1-one derivatives 2a,b with appropriate nitrogen nucleophiles. The analgesic and anti-inflammatory activities of the newly synthesized compound were investigated in vivo. 3-Bromo-2-phenyl-6-(phenylsulfonyl)-7-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (5e) was found to have an excellent analgesic activity in comparison with indomethacin as a reference drug, while the highest anti-inflammatory effect was observed in the case of 2-(4-bromophenyl)-6-(phenylsulfonyl)-5-(4-methylphenyl)pyrazolo[1,5-a]pyrimidine (5d). From the structure-activity relationship (SAR) point of view, the analgesic/anti-inflammatory activity of pyrazolo[1,5-a]pyrimidine derivatives was found to be much higher than triazolo[1,5-a]pyrimidine and pyrimido[1,2-a]benzimidazole derivatives.     

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.