Investigations of new pyridazinone derivatives for the synthesis of potent analgesic and anti-inflammatory compounds with cyclooxygenase inhibitory activity

In this study we describe the synthesis of two novel 4-phenyl-and 4-(2-chlorophenyl)-6-(5-chloro-2-oxo-3H-benzoxazol-7-yl)-3(2H)-pyridazinone derivatives (compounds 8a and b) and their testing as inhibitors of cyclooxygenases (COX-1 and COX-2). Both compounds inhibited COX-1 (by 59 % and 61 % for compounds 8a and 8b respectively and COX-2 (by 37 % and 28 % for compounds 8a and 8b respectively) at a concentration of 10 microM. Furthermore, we tested the analgesic and anti-inflammatory activities of the synthesized compounds in vivo by using the p-benzoquinone-induced writhing test and the carrageenan-induced hind paw edema model, respectively. Compounds 8a and 8b showed potent analgesic and anti-inflammatory activities without causing gastric lesions in the tested animals.     

Synthesis and antimicrobial study of fluoroquinolone-based 4-thiazolidinones

The title compounds 2-substituted phenyl-3-{1-cyclopropyl-6-fluoro-7-[4-(4-methoxyphenylpiperazin-1-yl]-4-oxo-1,4-dihydroquinoline} carboxamido-1,3-thiazolidin-4-ones 6a–j have been synthesized from lead molecule 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1; this reacted with thionyl chloride to give acid chloride 2 and with hydrazine hydrate to afford hydrazide 3. The hydrazide 3 on condensation with substituted aromatic aldehydes a–j gave Schiff base; these on reaction with N-(4-methoxyphenyl) piperazine and thioglycolic acid furnished title compounds 6a–j. All of the synthesized compounds have been established by elemental analysis. IR and NMR spectral data and have been screened for antifungal and antibacterial activities.     

Newer substituted beta-aminonaphthalenes as potent anti-inflammatory agents

beta-[2-(3'-Chloro-2'-oxo-4'-substituted aryl-1'-azetidinyl)-thiazol-4- yl]aminonaphthalenes 13-17 and beta-[2-(1',3'-disubstitutedphenyl-formazan-4'-yl)-thiazol-4-yl] aminonaphthalenes 8-12 were synthesized from beta-(2-arylideneamino-thiazol-4-yl)aminonaphthalenes 3-7 by diazotisation and by cycloaddition with monochloroacetyl chloride, respectively, on the azomethine group of the compounds 3-7. The newly synthesized compounds showed potent anti-inflammatory and analgesic activities and were less ulcerogenic than phenylbutazone.     

Synthesis of novel 1-pyrazolylpyridin-2-ones as potential anti-inflammatory and analgesic agents

A new series of 4-alkyl/aryl-2-oxo-1-pyrazolyl-1,2-dihydropyridine-3-carbonitriles, pyrazolo[3,4-b]pyridine-5-carbonitriles and pyrido[2,3-d]pyrimidine-6-carbonitriles have been synthesized and tested for their anti-inflammatory and analgesic activities. Among the tested compounds, 3e and 8b exhibited comparable anti-inflammatory activity to the standard (indomethacin). Compounds 5, 7a, and 8b displayed potent analgesic activity. Detailed syntheses, spectroscopic and biological data are reported.     

New 4-thiazolidinones of nicotinic acid with 2-Amino-6-methylbenzothiazole and their biological activity

The title compounds 6aaj, 2-[(6-methyl-1,3-benzothiazol-2-yl)amino]-N-[2-(substituted phenyl/furan-2-yl)-4-oxo-1,3-thiazolidin-3-yl]nicotinamides, were prepared from 2-chloropyridine-3-carboxylic acid (1) and 2-amino-6-methyl-benzothiazole (2) by known methods. All the compounds have been established by IR, (1)H NMR, (13)C NMR and elemental analyses. The in vitro antimicrobial screening of the compounds were carried out against two Gram positive (S. aureus, S. pyogenes), two Gram negative (E. coli, P. aeruginosa) bacteria and three fungal species (C. albicans, A. niger, A. clavatus) using the broth microdilution method. Some of the compounds are comparable with standard drugs.     

Synthesis, analgesic, anti-inflammatory and antibacterial activities of some novel 2-butyl-3-substituted quinazolin-4-(3H)-ones

A variety of novel 2-butyl-3-substituted quinazolin-4-(3H)-ones have been synthesized by reacting (2-butyl-4-oxo-3H-quinazolin-3-yl)dithiocarbamic acid methyl ester with a variety of amines; the starting material dithiocarbamate was synthesized from anthranilic acid. The title compounds were investigated for analgesic, anti-inflammatory and antibacterial activities. While the test compounds exhibited significant activity, compounds A1, A2, A3 and A4 showed more potent analgesic activity and compound A4 showed more potent anti-inflammatory activity than the reference diclofenac sodium.     

Synthesis, analgesic, anti-inflammatory and antibacterial activities of some novel 2-methyl-3-substituted quinazolin-4-(3H)-ones

A series of novel 2-methyl-3-substituted quinazolin-4-(3H)-ones have been synthesized by treating (2-methyl-4-oxo-3H-quinazolin-3-yl)dithiocarbamic acid methyl ester with different amines, the starting material dithiocarbamate was synthesized from anthranilic acid. The compounds synthesized were investigated for analgesic, anti-inflammatory and antibacterial activities. All the test compounds exhibited significant activity, the compounds VA2, VA3 and VA4 shown more potent analgesic activity, and the compounds VA3 and VA4 shown more potent anti-inflammatory activity than the reference compound diclofinac sodium.     

Synthesis, analgesic, anti-inflammatory and antibacterial activities of some novel 2-methylthio-3-substituted quinazolin-4-(3H)-ones

A variety of novel 2-methylthio-3-substituted quinazolin-4-(3H)-ones have been synthesized by reacting (2-methylthio-4-oxo-3H-quinazolin-3-yl)dithiocarbamic acid methyl ester with a variety of amines, the starting material dithiocarbamate was synthesized from methylanthranilate. The title compounds were investigated for analgesic, anti-inflammatory and antibacterial activities. While the test compounds exhibited significant activity, the compounds A1, A2, A3 and A4 shown more potent analgesic activity, and the compound A4 shown more potent anti-inflammatory activity than the reference diclofenac sodium.     

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.     

Anti-inflammatory activity of some novel alpha-amino naphthalene derivatives

alpha-Acetylamino naphthalene (1) was reacted with different aromatic aldehydes and with primary or secondary amines to give alpha-aminonaphthylsubstitutedaryl chalkones (2-5) and alpha-(substituted aminoethyl)-amidonaphthalenes (14-25), respectively. These substituted chalkones were treated with hydrazinehydrate and hydroxylamine hydrochloride to give 1-acetyl-5-substitutedaryl-3-(alpha-aminonaphthyl)-2-pyrazolines (6-9) and alpha-(2-substitutedaryl-isoxazolin-4-yl)-aminonaphthalenes (10-13), respectively. Their chemical structures were confirmed by IR and 1H-NMR spectral data and elemental analysis. Studies of the anti-inflammatory and ulcerogenic activities and acute toxicity of these newly synthesized compounds were performed in vivo and compared with the standard drug, phenylbutazone (CAS 50-33-9). Some of these compounds showed potent anti-inflammatory activity and less ulcerogenic effects than phenylbutazone.     

Synthesis, anti-inflammatory and analgesic activity of some new 4(3H)-quinazolinone derivatives

4(3H)-quinazolinone and pyrazole derivatives have been shown to have analgesic and anti-inflammatory properties. In this study, 14 new 3-methyl-4(3H)quinazolinone derivatives bearing 2-[1'-phenyl-3'-(substituted-phenyl)-2'-propenylidene]hydrazino or 2[5'-(substituted phenyl)-3'-phenyl-2'-pyrazolin-1'-yl] groups have been synthesized with the aim of obtaining new analgesic and anti-inflammatory leads. The structures were elucidated by means of UV, IR, 1H-NMR, 13C-NMR, mass spectroscopy, and elemental analysis data. The anti-inflammatory activities of the synthesized compounds were determined by carrageenan-induced hind paw edema test in mice. All the compounds showed statistically significant effects. For analgesic activity assessment, p-benzoquinone-induced writhing test was applied in mice. The results obtained were in accordance with the anti-inflammatory activity tests.     

Synthesis and Antimicrobial Activities of Some New Azetidin-2-ones and Thiazolidin-4-ones

Various (4-substituted) phenyl-3-β-[(N-benzenesulphonyl/tosyl)-4-(un)substituted anilino]propionylamido-1,3-thiazolidine-4-ones (3a-x) and 1-β-[(N-benzenesulphonyl/tosyl)-4-(un)substituted anilino]-propionylamido-3-chloro-4-(4-substituted)phenyl-azetidin-2-ones (4a-x) have been synthesised by the cyclocondensation of Schiff bases (2a-x) with thioglycolic acid and chloroacetyl chloride, respectively. The structures of the newly synthesised compounds have been established on the basis of their spectral data and elemental analysis. All compounds were evaluated for antimicrobial activities against Escherichia coli, Bacillus cirroflagellosus, Aspergillus niger and Colletotrichum capsici. Most compounds investigated exhibited significant antifungal activity against Colletotrichum capsici, comparable to that of fluconazole, the standard used.     

1-烷基-1-苄基-4-(3-氯-2-羟基)丙基哌嗪季铵盐的合成及生物活性

设计合成了7个1-烷基-1-苄基-4-(3-氯-2-羟基)丙基哌嗪季铵盐(Ia～g)。生物活性试验结果表明,苄基苯环上连有强吸电子取代基时,可使抗炎和镇痛活性明显增强;季铵盐中的负离子对生物活性有一定的影响。在20mg·kg^-1的剂量下,Id和Ie的抗炎活性和Ie的镇痛活性明显。     

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.     

Novel 3,3a,4,5,6,7-hexahydroindazole and arylthiazolylpyrazoline derivatives as anti-inflammatory agents

A novel series of 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole substituted at the 2-position were synthesized. The reaction of 2, 6-bis-benzylidenecyclohexanone (1) with thiosemicarbazide in the presence of NaOH afforded a mixture of the 3-H, 3a-H trans 2 and cis 2a diastereoisomers which have been separated by fractional recrystallization. Interaction of the first intermediate 2 with substituted phenacyl bromides, aromatic aldehydes and chloroacetic acid in presence of a mixture of acetic acid and acetic anhydride, and 2, 3-dichloroquinoxaline yielded the corresponding 7-benzylidene-3, 3a, 4, 5, 6, 7-hexahydro-3-phenyl-2H-indazole derivatives substituted at the 2-position with 4-aryl-2-thiazolyl 3a, b, 5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl 4a, b and thiazolo[4, 5-b]quinoxalin-2-yl 5, respectively. Moreover, the other intermediates 3, 5-diaryl-1-thiocarbamoyl-2-pyrazolines 7a-d were reacted with the previously-mentioned reagents and gave the corresponding 3, 5-diaryl-1-(4-aryl-2-thiazolyl)-2-pyrazolines 8a-h, 3, 5-diaryl-1-(5-arylidene-4, 5-dihydro-4-oxo-2-thiazolyl)-2-pyrazolines 9a-d and 3, 5-diaryl-1-(thiazolo[4, 5-b]quinoxalin-2-yl)-2-pyrazoline derivatives 10a, b, respectively. Some of the newly prepared compounds were subjected to evaluation for their anti-inflammatory activity. The structures of the new compounds were confirmed by elemental analyses as well as (1)H-NMR, IR, and MS data.     

Synthesis of novel bioactive pyrazolothiazoles

The synthesis of 3-{substituted 1,3-thiazol-5-yl}-1-substituted 1H-pyrazole-4-carboxylates (4a–n) has been achieved in facile manner by the reaction between 2-aminothiazoles, dimethylformamide dimethyl acetal and hydrazine. All the synthesized compounds were characterized by spectral and elemental analyses. These compounds were also evaluated against anti-inflammatory activity and showing promising activities.     

Substituted quinazolines,part 2. Synthesis and in-vitro anticancer evaluation of new 2-substituted mercapto-3H-quinazoline analogs

A new series of 2-substituted mercapto-3H-quinozolines bearing 6-iodo and 2-heteroarylthio functions was synthesized and screened for their in vitro antitumor activity. Eighteen compounds were identified as active anticancer agents. N'-[(3-Benzyl-4-oxo-6-iodo-3H-quinazoline-2-yl)thioacetyl]-N(3)-ethylthiosemicarbazide (10), N-benzoyl-N'-[2-(3-benzyl-4-oxo-6-iodo-3H-quinozolin-2-yl)thioacetyl]hydrazine (12), and 2-[(3, 6-dioxo-pyridazin-4-yl)thio]-3-benzyl-4-oxo-6-iodo-3H-quinazoline (20) proved to be the most active members in this study. They showed MG-MID, GI(50) values of 12.8, 11.3, and 13.8 microM, respectively. The detailed synthesis and biological screening data are reported.     

Synthesis of some new 2-(6-methoxy-2-naphthyl)- 5-aryl-1,3,4-oxadiazoles as possible non-steroidal anti-inflammatory and analgesic agents

The synthesis of some new 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k) has been described. Ethyl-6-methoxy-2-naphthoate (1) yielded on treatment with hydrazine hydrate to 6-methoxy-2-naphthoic acid hydrazide (2). Compound 2 reacted with substituted aromatic carboxylic acids (3a-k) in phosphorus oxychloride yielded 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k). Newly synthesized compounds were characterized by IR, (1)H-NMR and mass spectral data. All the compounds were screened for their anti-inflammatory and analgesic activity. Compound 4j exhibited promising anti-inflammatory and analgesic activities.     

Synthesis, anti-inflammatory and analgesic evaluation of certain new 3a,4,9,9a-tetrahydro-4,9-benzenobenz[f]isoindole-1,3-diones

In an effort to establish new candidates with improved analgesic and anti-inflammatory activities, we reported here the synthesis and in-vivo analgesic and anti-inflammatory evaluation of various series of 2-substituted-3a,4,9,9a-tetrahydro-4,9-benzeno-benz[f]isoindole-1,3-diones: [4-Bromobutoxy] 6, 5-bromopentoxy 7, [4-(4-phenylpiperazin-1-yl)butoxy] 9, [5-(4-phenylpiperazin-1-yl)pentoxy] 10, 2-(2(4)-(4-phenylpiperazin-1-yl)-2-oxoethyl/4-oxobutyl 17, 19, [2(4)-(4-methylpiperazin-1-yl]-2-oxoethyl/4-oxobutyl 20, 22, [2(4)-morpholino-2-oxoethyl/4-oxobutyl] 23, 25, and 2(4)-(piperidin-1-yl)2-oxoethyl/4-oxobutyl) 26 and 28. The newly synthesized compounds were characterized by (IR, (1)H-, (13)C-NMR, and mass spectra). The representative compounds were evaluated as analgesic and anti-inflammatory activities. Compounds 9, 19, 22, 25, and 28 exhibited activities higher than the reference drug.     

Studies on novel 7-acyl-5-chloro-2-oxo-3H-benzoxazole derivatives as potential analgesic and anti-inflammatory agents

In this study, a series of (7-acyl-5-chloro-2-oxo-3H-benzoxazol-3-yl)alkanoic acid derivatives were synthesized and evaluated for their analgesic and anti-inflammatory activities by using the p-benzoquinone-induced writhing test and the carrageenan hind paw edema model, respectively. Acetic acid-induced peritoneal capillary permeability test and serotonin-induced hind paw edema test were also employed for the most active compounds. The test results indicated that (7-acyl-2-oxo-3H-benzoxazol-3-yl)alkanoic acids (Compounds 6 a-c, 8 a-c, 10 a-c) were equally or more potent analgesic and anti-inflammatory agents than aspirin and indomethacin respectively. The compounds 8a and 8c, but not 8b have the longest carbon chain on alkanoic acid moiety did not induce gastric lesion in mice.