Synthesis of some triazolophthalazine derivatives for their anti-inflammatory and antimicrobial activities

Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3-carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2″,3″-1',5']imidazo[3',4'-1,5]-1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non-acidic anti-inflammatory/antimicrobial agents.     

Synthesis and pharmacological evaluation of novel quinoxalines as potential nonulcerogenic anti-inflammatory and analgesic agents

Some new substituted quinoxaline and furo[2,3-b]quinoxaline derivatives have been synthesized and tested for their anti-inflammatory and analgesic activities and for their ulcerogenic potential. The pharmacological evaluation of selected synthesized compounds revealed that 5a was equipotent and compounds 3, 4b, 4e and 5b possessed strong anti-inflammatory activity in chronic inflammatory models compared with indometacin (CAS 53-86-1) as reference drug. In addition, compound 4a was the safest one and the others showed little ulcerogenic activity. All the tested compounds showed moderate analgesic activity compared to the reference drug.     

Novel pirfenidone analogues: synthesis of pyridin-2-ones for the treatment of pulmonary fibrosis

A new series of polysubstituted 1-aryl-2-oxo-1,2-dihydropyridine-3-carbonitriles and pyrazolo[3,4-b]pyridine-5-carbonitriles and pyrido[2,3-d]pyrimidine-6-carbonitriles have been synthesized and tested for their antifibrotic activity. Among the tested compounds, compounds IIc and IVb exhibited higher antifibrotic activity than the standard pirfenidone PD with a reduction of the hydroxyproline level to 50 and 140 micromol/lung, respectively. However, bicyclic pyridone VIIIb displayed a high mortality rate. Detailed syntheses, spectroscopic and biological data are reported.     

Synthesis and potential biological activity of some novel 3-[(N-substituted indol-3-yl)methyleneamino]-6-amino-4-aryl-pyrano(2,3-c)pyrazole-5-carbonitriles and 3,6-diamino-4-(N-substituted indol-3-yl)pyrano(2,3-c)pyrazole-5-carbonitriles

Starting from N-substituted indole-3-carboxaldehydes (1a-g) a series of new 3-[(N-substituted indol-3-yl)methyleneamino]-6-amino-4-aryl-pyrano(2,3-c)pyrazole-5-carbonitriles (3a-g and 4a-g) have been synthesized via the acid catalyzed condensation reaction of 1a-g with 3-amino-5-pyrazolone, followed by the reaction with arylidene malononitriles. A series of new 3,6-diamino-4-(N-substituted indol-3-yl)pyrano(2,3-c)pyrazole-5-carbonitriles (7a-g) have been prepared either via the base catalyzed condensation reaction of 1a-g with 3-amino-5-pyrazolone to give 6a-g, followed by the reaction with malononitrile or by the reaction of N-substituted-3-indolylidene malononitriles (5a-g) with 3-amino-5-pyrazolone. According to the obtained results, the newly synthesized compounds possess significant anti-inflammatory, analgesic and anticonvulsant activities. The anticonvulsant potency of certain tested compounds was more pronounced than both anti-inflammatory and analgesic activities. Moreover, most of the newly synthesized compounds possess potential antimicrobial activity against Escherichia coli and Pseudomonas aeruginosa.     

Amide derivatives of [6-(5-methyl-3-phenylpyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acids as potential analgesic and anti-inflammatory compounds

In this study, amide derivatives of [6-(5-methyl-3-phenyl-pyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid were synthesized and tested for their in vivo analgesic and anti-inflammatory activity by using the p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. The analgesic and anti-inflammatory activity of the compounds 6a, 6d, 6e, 6g, 6h and 6m were more potent than that of aspirin as an analgesic and indomethacin as an anti-inflammatory drug, respectively. The other derivatives generally resulted in comparable activity to reference compounds. Inhibitor activity of the active compounds on cyclooxygenase isoforms was also investigated by using in vitro human whole blood assay and found that these derivatives did not exert their analgesic and anti-inflammatory activities through COX inhibition and other mechanisms might be involved.     

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 pharmacological investigation of 3-subsituted-amino-2-methylsulfanyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-ones as analgesic and anti-inflammatory agents

In the present work, design, synthesis, and pharmacological evaluation of the analgesic, anti-inflammatory, and ulcerogenic-index activities of new 3-subsituted-amino-2-methylsulfanyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-ones, structurally planed by exploiting a clear concept of bio-isosterism, are reported. All compounds exhibited significant analgesic and anti-inflammatory activity. Compounds A1, A3 showed higher analgesic activity and more potent anti-inflammatory activity than that of the reference compound diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared to that of acetylsalicylic acid.     

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 molluscicidal activity of new cinnoline and pyrano [2,3-c]pyrazole derivatives

2-(3-Hydroxy-5,5-dimethylcyclohexylidene)malononitrile 5 undergoes an azo coupling reaction with aryldiazonium salts to afford 3-amino-2-aryl-6,6-dimethyl-8-oxo-2,6,7,8-tetrahydrocinnoline-4-carbonitriles 7. Upon reflux in acetic acid, these compounds were acetylated to give the cinnoline derivatives 9. The pyrazolones 10a, b react with 3-furfurylidene- and 3-thienylidene-malononitrile derivatives 11a, b to afford the pyrano[2,3-c]pyrazole derivatives 13a-d. These newly synthesized compounds show generally a moderate molluscicidal activity to Biomphalaria alexandrina snails.     

Synthesis and evaluation of the analgesic and anti-inflammatory activity of new 3(2H)-pyridazinone derivatives

A series of 6-substituted-3(2H)-pyridazinone derivatives were synthesized and evaluated for analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H-NMR spectra and elementary analysis. Analgesic and anti-inflammatory activities of the title compounds have been evaluated. Four of the ten tested compounds possessed significant analgesic effects in the phenylbenzoquinone-induced writhing test (PBQ test). The most active derivatives 8a, 8b, 8d, 8e were void of gastric ulcerogenic effect or acute toxicity at the maximal dose (200 mg/kg p.o.). In the carrageenan-induced paw edema model, compound 8d (6- [4- (2-fluorophenyl) piperazin-1-yl]-3(2H)-pyridazinone) showed anti-inflammatory activity similar to that of the standard drug indometacin (CAS 53-86-1). A significant dependence of the anti-inflammatory effect on the substituents was observed; The pharmacological study of these compounds confirms that modification of the chemical group at position 6 of the 3(2H)-pyridazinone ring influences analgesic and anti-inflammatory activities.     

Selenium-containing heterocycles: synthesis and pharmacological activities of some new 4-methylquinoline-2(1H) selenone derivatives

Several selenolo[2,3-b]quinolines and pyrimido[4',5':4,5]selenolo[2,3-b]quinolines were prepared by annulations via reaction of NaSeH with 2-chloro-3-cyano-4-methylquinoline 1 followed by reactions with aromatic aldehydes, cycloalkanones, and acetic anhydride. Spectroscopic (IR, 1H-NMR, and MS) properties of the synthesized compounds are reported. Some selected compounds 5a, 7b, 7c, 8b-d, 9a, 11b, and 11d were investigated for their anti-inflammatory and analgesic activities; in addition, the most active compounds were tested for their ulcerogenicity and acute toxicity. Moreover, some of the test compounds 7c, 9a, 11b, and 11d were screened for their antibacterial and antifungal activities.     

Synthesis and evaluation of analgesic, anti-inflammatory and antioxidant activities of new 6-acyl-3-alkyl-5-methyl-2(3H)-benzoxazolones

A new series of 6-acyl-3-alkyl-5-methyl-2(3H)-benzoxazolones have been obtained starting from 5-methyl-2(3H)-benzoxazolone. All the compounds have been characterized by IR, 1H-NMR and mass spectroscopy. The new compounds were screened for analgesic and anti-inflammatory activities and ulcerogenic effect. The in vitro antioxidant capacity of the synthesized compounds were tested by the nitric oxide radical scavenging assay. Most of the compounds showed antiinflammatory activity. Among them, 3-[4-(4-fluorophenyl)piperazinomethyl] -6-(3-chlorobenzoyl)-5-methyl-2(3H)-benzoxazolone (3j) was found more potent than the reference drug indometacin (CAS 53-86-1) with 41.66% decrease in edema. Compared with the control, some of the compounds exhibited analgesic effects. Similar to the anti-inflammatory activity results, compound 3j showed the highest analgesic profile with 48.56% inhibition. No active hemorragic focus was observed in the microscopic evaluation in the ulcerogenic effect studies of the tested compounds. 6-(3-Chlorobenzoyl)-5-methyl-2(3H)-benzoxazolone (2b) and 3-[4-(4-fluorophenyl-piperazino)methyl]-6-(3-chlorobenzoyl)-5-methyl-2(3H)-benzoxazolone (3j) showed nearly maximum antioxidant activity compared to ascorbic acid (CAS 50-81-7) with IC50 values of 27.6 and 30.1 microg/mL, respectively.     

Synthesis of amide derivatives of [6-(3,5-dimethylpyrazol-1-yl)-3(2H)-pyridazinone-2-yl] acetic acid and their analgesic and anti-inflammatory properties

A series of structurally different amide derivatives of [6-(3,5-dimethylpyrazol-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid were prepared and tested for their analgesic and anti-inflammatory activity in vivo by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. The analgesic and anti-inflammatory activity of the compounds 6a and 6b were equipotent, and 6m was more potent than acetyl salicylic acid (CAS 50-78-2) as an analgesic and indometacin (CAS 53-86-1) as an anti-inflammatory drug, respectively. The other amide derivatives and parent carboxylic acid molecule generally resulted in lower activity to reference compounds. Inhibitor activity of the active compounds on cyclooxygenase isoforms was also investigated by using in vitro COX inhibitor screening assay and found that these derivatives did not exert their analgesic and anti-inflammatory activities through COX inhibition and that other mechanisms might be involved.     

Chemical and pharmacological investigations on 2H-pyridazino[4,5-b] [1,4]benzothiazin-1(10H)-one derivatives

The methylation of 2H-pyridazino [4,5-b][1,4]benzothiazin-1(10H)-one-5,5-dioxide 2 and the oxidation of 2-methyl-2H-pyridazino[4,5-b][1,4]benzothiazin-1(10H)-one 3 produced the same compound 4. On the contrary, in the 2-dialkylaminoalkylic series, the dialkylamino-alkylation and the oxidation reactions, carried out on compounds 2 and 8 respectively, afforded derivatives 7 and 9. In addition, the behaviour to the oxidation of the corresponding 10-methyl and 10-dialkylaminoalkyl analogues is also described. The synthesized compounds were tested for their analgesic, antiexudative and anti-inflammatory activities. The pharmacological results showed that in general dialkylaminoalkyl derivatives are more active than methyl derivatives. In particular, compounds 7 b, 9 b and 11 c exhibited an analgesic activity comparable to that of phenylbutazone; moreover 10-substituted compounds 11 a, 11 b and 11 c, screened p.o. as anti-inflammatory agents in rats, resulted equipotent to phenylbutazone and more active than 2-substituted isomers. These activities are coupled with a high LD50 and a very low ulcerogenic potential.     

Synthesis and analgesic-anti-inflammatory activities of some 1,2,4-triazine derivatives

A variety of novel N-arylidene-N'-[5-(4-isobutylphenyl)-[1,2,4]-triazin-3-yl] hydrazines 4, carboxylic acid N'-[5-(4-isobutylphenyl)-[1,2,4]-triazin-3-yl] hydrazides 5, triazolotriazines 6 and other related triazine derivatives were synthesized. Several synthetic routes were employed to access the desired compounds from 5-(4-isobutylphenyl)-[1,2,4]-triazin-3-yl hydrazine 3 as a parent compound. The analgesic and anti-inflammatory activities of the synthesized compounds were studied. The results showed that compound 4 g exhibited pronounced analgesic activity, while compound 4f displayed the highest anti-inflammatory activity. Meanwhile, compound 6d evoked dual analgesic-anti-inflammatory effect without any ulcerogenicity.     

7-Aroyl-2,3-dihydrobenzo[b]furan-3-carboxylic acids and 7-benzoyl-2,3-dihydrobenzo[b]thiophene-3-carboxylic acids as analgesic agents

The synthesis of a series of 7-aroyl-2,3-dihydrobenzo[b]furan-3-carboxylic acids and 7-benzoyl-2,3-dihydrobenzo[b]thiophene-3-carboxylic acids is described. The isomeric 4-benzoyl-1,3-dihydrobenzo[c]furan-1-carboxylic acid was also prepared. Compounds were evaluated for analgesic activity in the mouse phenyl-p-quinone-induced writhing test. Selected compounds were tested for their ability to produce gastric damage in fasted mice and for inhibition of prostaglandin synthetase activity in vitro. Zomepirac was used as a reference. Structure-activity relationships are discussed. One of the compounds, 7-benzoyl-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylic acid (2c), combined potent analgesic activity with low gastric irritancy.     

Further evaluation of a series of anti-inflammatory N-pyrrolylcarboxylic acids: effects on the nociception in rats

The analgesic activity of nine substituted N-pyrrolylcarboxylic acids, previously reported as anti-inflammatory agents, has been evaluated. The effects on nociception were examined in male Wistar rats by the Randall-Selitto paw-pressure test. The compounds were administrated in doses 10, 20, and 40 mg/kg both i.p. and p.o. As a whole, the activities of 3-(N-pyrrolyl)propanoic acids 3e-3h and 2-[3-(ethoxycarbonyl)-2-methyl-5-phenyl-1H-1-pyrrolyl]-3-methylpentanoic acid 3i were comparable with or superior to that of metamizole used as a reference (200 mg/kg, i.p.), whereas only 3a from among the N-pyrrolyl-acetic acids 3a-3d showed analgesic activity on the inflamed paw. The compounds found most promising to increase the pain threshold significantly were the same ones with the higher anti-inflammatory activity registered in our previous study: 3-[3-(ethoxycarbonyl)-2-methyl-5-(3-nitrophenyl)-1H-1-pyrrolyl]propanoic acid 3e, together with its 5-(4-nitrophenyl)- 3f, 5-phenyl- 3g, and 5-(4-methylphenyl)- 3h analogs. Certain parallels between the analgesic activities and some physicochemical properties were observed.     

Amide derivatives of [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids as potential analgesic and anti-inflammatory compounds

In this study, we have explored the prevention of gastric side effects such as gastric lesions and bleeding while maintaining the high analgesic and anti-inflammatory activities by the derivatization of the carboxylate moiety into amides in [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids. We have tested the analgesic and anti-inflammatory activities of the synthesized compounds in vivo by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Compounds 3a, 3d, 3e, 3j and 3k potent analgesic and anti-inflammatory activities without gastric lesions in the tested animals. Therefore, conversion of the carboxylate moiety into certain amide derivatives generated potent analgesic and anti-inflammatory compounds while eliminating the gastrointestinal side effects. Cyclooxygenase (COX)-selectivity of the active compounds was also investigated by using in vitro human whole blood assay. Compounds 3a, 3e, 3h and 3k selective inhibition of COX-2 to some extent although the inhibitory activity was not very potent.     

Amide derivatives of [6-acyl-2-benzothiazolinon-3-yl] acetic acids as potential analgesic and anti-inflammatory compounds

In this study, we investigated the analgesic and anti-inflammatory activities of [6-acyl-2-benzothiazolinon-3-yl]acetic acids by the derivatization of the carboxylate moiety into amides. We have tested the analgesic and anti-inflammatory activities of the synthesized compounds in vivo by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Compounds 4h, 4i, 4n, and 4o showed comparable analgesic and anti-inflammatory activities to the references without gastric lesions in the tested animals. In addition, all compounds also tested for their inhibitory activity against cyclooxygenase (COX)-1, COX-2 and 5-lipoxygenase (LOX), but no significant inhibition was observed under assayed conditions.     

Synthesis, Analgesic, and Anti-Inflammatory Activities of [6-(3,5-Dimethyl-4-Chloropyrazole-1-yl)-3(2H)-Pyridazinon-2-yl]Acetamides

A series of structurally diverse amide derivatives of [6-(3,5-dimethyl-4-chloro-pyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid were prepared and tested for their in vivo analgesic and anti-inflammatory activity by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. The analgesic and anti-inflammatory activity of the compounds, 7c, 7d and 7k were found to be equipotent to aspirin (as an analgesic) and indometacin (as an anti-inflammatory drug), respectively. The other amide derivatives generally resulted in lower activity on comparision with reference compounds.