ABSTRACT
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.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Isoindoles/chemical synthesis , Analgesics/analysis , Analgesics/chemistry , Anti-Inflammatory Agents/analysis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents, Non-Steroidal/analysis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Drug Design , Drug Discovery , Isoindoles/analysis , Isoindoles/chemistry , Isoindoles/pharmacology , Morpholinos/chemistry , Structure-Activity RelationshipABSTRACT
Treatment of 6-aminothiouracil (1) with 2,3-dichloroquinoxaline (2) in ethanol/TEA afforded 6-amino-2-(3-chloroquinoxalin-2-ylthio)pyrimidin-4(3H)-one (3), which was refluxed in DMF to give 2-aminopyrimido[2',1':2,3]thiazolo[4,5-b]quinoxaline-4-one (4). Compound 4 was utilized as a key intermediate for the synthesis of a new pyrimido[2',1':2,3]thiazolo[4,5-b]quinoxaline derivatives 5-14via the reaction with 2-chlorobenzaldehyde, 2-chlorocyclohex-1-enecarbaldehyde, 2-chlorobenzoic acid, 2,4-dichlorobenzoic acid, 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde, 2-chloro-4,6-dimethylnicotinonitrile, alpha,beta-unsaturated ketones and isonicotinaldehyde, respectively. The chemical structures of the newly synthesized compounds were characterized by IR, NMR and mass spectral analysis. These compounds were also screened for their analgesic and anti-inflammatory activities. Some of these compounds (3, 4, 9, 10 and 12-14) exhibited promising activities.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Pyrimidines/pharmacology , Quinoxalines/pharmacology , Thiazoles/pharmacology , Acetic Acid , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Carrageenan , Drug Evaluation, Preclinical , Edema/chemically induced , Edema/drug therapy , Female , Male , Mice , Molecular Structure , Pain/drug therapy , Pain Measurement , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Rats , Rats, Sprague-Dawley , Stereoisomerism , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
A series of fused and non fused 1,2,4-triazoles with (2,4-dichlorophenoxy) moiety are prepared utilizing 3-((2,4-dichlorophenoxy)methyl)-4-amino-4H-1,2,4-triazole-5-thiol (3). The latter on reaction with carboxylic acids, ethylchloroformate, ethylcyanoacetate and sodium nitrite gives five membered fused triazole derivatives 4a-d, 5, 6, 7 and 10, respectively. The six membered heterocycles 11, 12 and 14 are prepared by cyclization of compound 3 with phenacyl bromide, chloroacetic acid and alpha-bromoketone respectively. Most of the newly synthesized compounds were screened for their anti-inflammatory and molluscicidal activities. The compounds 4b, 4d, 11 and 14 showed potent anti-inflammatory activities in dose dependent manner while compounds 3, 4b, 8 and 10 exhibited promising molluscicidal activities.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Biomphalaria/drug effects , Edema/drug therapy , Molluscacides/chemical synthesis , Thiadiazines/chemical synthesis , Thiadiazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Carrageenan , Drug Evaluation, Preclinical , Edema/chemically induced , Molecular Structure , Molluscacides/chemistry , Molluscacides/pharmacology , Rats , Thiadiazines/chemistry , Thiadiazines/pharmacology , Thiadiazoles/chemistry , Thiadiazoles/pharmacologyABSTRACT
The 5,10-dihydro-2-thioxo-pyrimido[4,5-b]quinolines (2a-c) and its oxidized form 3 were prepared and used as key intermediates for the synthesis of thiazolo[3',2':1,2]pyrimido[4,5-b]-quinolines (5a-c), isoxazolo[5'',4'':4',5']thiazolo[3',2':1,2]pyrimido[4,5-b]quinolines (6a-c), 4-chloro-2-methylthio-pyrimido[4,5-b]quinoline, its amino derivatives (19-21) and 10,11,12,13-tetrahydro-5H-quino[2',3':4,5]pyrimido[6,1-b]quinazoline (22). The newly synthesized compounds were characterized by IR, NMR (1H, 13C) and mass spectral studies. Representative of the synthesized compounds was tested and evaluated for anti-oxidant, anti-inflammatory and analgesic activities. Compounds 2a-c showed the highest inhibitory anti-oxidant activity either using erythrocyte hemolysis or ABTS methods. Compounds 2a, 10b, 16, and 17a manifested the best protective effect against DNA damage induced by bleomycin. Compounds 2c, 5a, 20a, 2a, and 2b exhibited a potent anti-inflammatory activity using carrageenan-induced paw edema test in rats.
