Novel thiazolyl,thiazolinyl and benzothiazolyl Schiff bases as possible lipoxygenase's inhibitors and anti-inflammatory agents

In continuation of our previous research, several new thiazolyl/thiazolinyl/benzothiazolyl Schiff bases have been designed, synthesized and identified. The referred compounds are reported to act as lipoxygenase inhibitors affecting inflammation and/or psoriasis. The compounds were screened for their reducing activity (with the stable free radical 1,1-diphenyl-2-picryl-hydrazyl, DPPH) and for inhibition of soybean lipoxygenase (LOX). Anti-inflammatory activity was examined in vivo using the carrageenin induced mice paw edema (32.6-75%). The results are discussed in terms of structural and physicochemical characteristics of the compounds. Compound 2d possessed the highest inhibition 75%.     

Synthesis,analgesic and anti-inflammatory activities of new methyl-imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles

Background

Long-term clinical employment of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with significant side effects including gastrointestinal (GI) lesions and kidney toxicity. In this paper we designed and synthesized new imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles by molecular hybridization of previously described anti-inflammatory compounds in the hope of obtaining new safer analgesic and anti-inflammatory agents.

Methods

The target structures were synthesized by preparation of 5-methyl-1H-imidazole-4-carboxylic acid ethyl ester 5. The reaction of hydrazine hydrate with this ester afforded the 5-methyl-1H-imidazole-4-carboxylic acid hydrazide 6 which was converted to target compounds 7-15 according to the known procedures. In silico toxicity risk assessment and drug likeness predictions were done, in order to consider the privileges of the synthesized structures as drug candidates.

Results and discussion

The analgesic and anti-inflammatory profile of the synthesized compounds were evaluated by writhing and carrageenan induced rat paw edema tests respectively. Compounds 8, 9 and 11-13 and 15 were active analgesic agents and compounds 8, 9 and 11-13 showed significant anti-inflammatory response in comparison with control. Compounds 11 and 13 were screened for their ulcerogenic activities and none of them showed significant ulcerogenic activity. The active Compounds 11 and 12 showed the highest drug likeness and drug score.

Conclusions

The analgesic and anti-inflammatory activities of title compounds were comparable to that of standard drug indomethacin with a safer profile of activity. The results revealed that both of oxadiazole and triazole scaffolds can be determined as pharmacophores. The in silico predictions and pharmacological evaluations showed that compounds 11 and 12 can be chosen as lead for further investigations.     

Synthesis, anticonvulsant, and anti-inflammatory activities of some new benzofuran-based heterocycles

Treatment of 2-bromoacetylbenzofuran (2) with pyridine afforded its corresponding pyridinium bromide 3. The latter salt reacted with some activated alkenes and acetylenes to give the corresponding indolizine derivatives. Treatment of the salt 3 with benzylidenemalononitriles 9 afforded polysubstituted aniline derivatives, however with arylidenecyanothioacetamides 15 it gave the corresponding 4,5-dihydrothiophenes. Bromide 3 also coupled with p-chlorobenzenediazonium salt followed by ammonium acetate to give the corresponding 1,2,4,5-tetrazine derivative. The biological activity of the newly synthesized compounds was examined and some of them were found to possess anticonvulsant and anti-inflammatory activities.     

Synthesis and anti-inflammatory activities of new cyanopyrane derivatives fused with steroidal nuclei

Thirteen new heterocyclic derivatives containing a cyanopyrane ring fused to a steroidal moiety were conveniently synthesized and screened for their anti-inflammatory potencies comparable to that of the glucocorticoid prednisolone. Four compounds 5a, 5b, 6b, and 8 exhibited superior anti-inflammatory indices (in rats, protection against carrageenan induced edema and inhibition of plasma PGE). All the candidates were less toxic than the reference drug concerning LD(50) values. Synthetic steroidal structures fused to a substituted cyanopyrane ring seem to be a promising approach in search for novel leads for potent anti-inflammatory agents.     

Synthesis of new pyrroles of potential anti-inflammatory activity

We herein disclose a series of novel pyrrole derivatives 1-4 and pyrrolo[2,3-d]pyrimidine derivatives 6-11 as novel potent anti-inflammatory compounds. The structures were confirmed by IR, (1) H-NMR, and MS. Some newly synthesized compounds were examined for their in-vivo anti-inflammatory activity. Several derivatives showed a promising anti-inflammatory activity compared to ibuprofen. In this paper, we examine and discuss the structure-activity relationships and anti-inflammatory activities of these compounds.     

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 anti-inflammatory activity evaluation of novel 7-alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinolines

In this study, a novel series of 7-alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinolines were synthesized by using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material. These compounds were evaluated for anti-inflammatory activity through monitoring their ability to inhibit xylene-induced ear edema in mice. Some of the tested compounds exhibited significant activity, and the compounds 5f (7-(benzyloxy)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-1-amine) and 5i (7-(p-chlorobenzyloxy)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-1-amine) showed the highest anti-inflammatory activity (52% and 58% inhibition, respectively, at 2 h pre-administration) which were comparable to or even slightly more potent than the reference drug ibuprofen (55%). Furthermore, the structure-activity relationship of these 1,2,4-triazole quinolines was demonstrated.     

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.     

Anti-angiogenic,anti-inflammatory and anti-nociceptive activities of vanillyl alcohol

Vanillyl alcohol displayed a significant inhibition in the chick chorioallantoic membrane (CAM) angiogenesis. Vanillyl alcohol was also shown to contain anti-inflammatory activity using acetic acid-induced permeability and carrageenan-induced air pouch models in mice. Anti-nociceptive activity of vanillyl alcohol was also assessed using acetic acid-induced writhing test in mice. Taken together, vanillyl alcohol possesses anti-angiogenic, anti-inflammatory, and anti-nociceptive activities, which may be partly responsible for pharmacological efficacies of several folkloric medicines containing vanillyl alcohol.     

Synthesis, analgesic and anti-inflammatory activity of 4-(2-phenoxyphenyl)semicarbazones

A series of 4-(2-phenoxyphenyl)semicarbazones was synthesized and evaluated for their analgesic and anti-inflammatory activities. Several compounds (e. g. 10h, 10i, and 11i) were found to be more potent than the reference drug mefenamic acid in the formalin test. Based on the results of an anti-inflammatory study, 1-(1-(2,5-dimethoxyphenyl)ethylidene)-4-(2-phenoxyphenyl)semicarbazide 11i was the most active compound.     

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 some chalcones and pyrazolines carrying morpholinophenyl moiety as potential anti-inflammatory agents

Chalcones of 2a–f and their corresponding products, pyrazolines 3a–f , were synthesized and evaluated for their anti‐inflammatory activity against carrageenan edema in albino rats at a dose of 10 mg/kg. All the compounds of this series showed promising anti‐inflammatory activity. The most active compounds of this series, 2a , 2b , and 2d , were found to be most potent. They showed higher percentage of inhibition of edema than the standard drug indomethacin.     

Anti-inflammatory and analgesic activities of newly synthesized chiral peptide derivatives using (3-benzoyl- 4,5-dioxo-2-phenyl-pyrrolidin-1-yl)acetic acid ethyl ester as starting material

A series of heterocyclic derivatives was synthesized using (3-benzoyl-4,5-dioxo-2-phenyl-pyrrolidin-1-yl)acetic acid ethyl ester 1 as starting material. Treatment of 1 with 1 N NaOH or hydrazine hydrate afford the corresponding acid 2 and acid hydrazides 4 and 5, which were reacted with several reagents to produce some new peptido hetero-organic derivatives 6-12. The pharmacological screening showed that many of these newly synthesized compounds have good anti-inflammatory and analgesic activities comparable to diclofenac potassium and valdecoxib as reference drugs.     

Synthesis and pharmacological evaluation of some 3-(4-methylphenyl)-2-substituted amino-3H-quinazolin-4-ones as analgesic and anti-inflammatory agents

A variety of 3-(4-methyl phenyl)-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-methyl phenyl)-3H-quinazolin-4-one with a variety of aldehydes and ketones. The starting material 2-hydrazino-3-(4-methyl phenyl)-3H-quinazolin-4-one was synthesized from 4-methyl aniline. The title compounds were investigated for analgesic, anti-inflammatory, and ulcerogenic index activities. While the test compounds exhibited significant activity, compounds Al, A2, and A3 showed more potent analgesic activity and the compound A3 showed more potent anti-inflammatory activity when compared to the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared to aspirin.     

Synthesis, analgesic and anti-inflammatory evaluation of some new 3H-quinazolin-4-one derivatives

In this study, we have synthesized a series of 3H-quinazolin-4-ones in order to obtain new compounds with potential analgesic and anti-inflammatory activity. The structures of the newly synthesized compounds were confirmed by means of infrared, nuclear magnetic resonance and mass spectroscopy. Some compounds were evaluated for their analgesic and anti-inflammatory activities by writhing and carrageenan-induced rat paw edema tests, respectively. In comparison to the standard drug indomethacine, compounds 4, 6c, 12-14, 16, 18, 19, and 22 induced significant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a good dose-dependent anti-inflammatory activity. The best dual analgesic / anti-inflammatory relative activity was observed with compounds 6c, 14, 16, 18, and 22.     

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 of new (Nalpha-dipicolinoyl)-bis-L-valyl-L-phenylalanyl linear and macrocyclic bridged peptides as anti-inflammatory agents

In continuation to our search for new chiral macrocyclic peptide-based anti-inflammatories, the suggestion, synthesis, structure elucidation of some Nalpha-bis-dipicolinoyl amino acids, linear, tetra and cyclic (penta and octa)-bridged peptides 3-10, were realized herein. The newly synthesized compounds showed potent anti-inflammatory activity with low toxicity (LD50) comparable to indomethacin and diclofenac as reference anti-inflammatory drugs.     

Reactions of N(3) -substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride and biological activities of the products

A series of novel compounds were synthesized in reactions of N(3) -substituted amidrazones with cis-1,2-cyclohexanedicarboxylic anhydride: linear, isoindole, and triazole derivatives. All new structures were confirmed by H(1) NMR and IR spectrometry as well as elemental analysis. Potential biological effects of new compounds were predicted with the Prediction of Activity Spectra for Substances (PASS) program. Antiviral, antibacterial, analgesic, and anti-inflammatory activities were experimentally verified.     

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.     

Synthesis of beta-hydroxypropanoic acid derivatives as potential anti-inflammatory, analgesic and antimicrobial agents

A series of new 3-(substituted) 3-hydroxy-propanoic acid ethyl esters 1a-c, hydrazides 2a-c, thiosemicarbazides 3a-f, and semicarbazides 3g, 3h has been synthesized. Cyclization of compounds 3a-d in basic medium yielded 1,2,4-triazole-5-thiones 4a-d. On the other hand, reaction of hydrazides 2a-c with CS(2 )in basic medium afforded 1,3,4-oxadiazole-5-thiones 5a-c. All the synthesized compounds were characterized by their physical and spectral analyses data. The newly synthesized compounds were evaluated for their anti-inflammatory, analgesic, and antimicrobial activities. Compounds 1c, 3g, 4a, 4b, 4c, and 5c exhibited comparable anti-inflammatory activity to that of indomethacin and compounds 1c, 4c, and 5c were more analgesics than acetyl salicylic acid. Compounds 4b, 4c, and 5c showed superior GI safety profile (33.3%, 33.3% and 50.0% ulceration) than that of indomethacin (100% ulceration) at 100 mg/kg oral dose. Compounds 4b, 4c, and 5c were also non-toxic with a median lethal dose (LD(50)) up to 200 mg/kg. The antibacterial and antifungal screenings identified compounds 3c, 4b, 4d, 5a, and 5b as the most effective against a variety of tested microorganisms.