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.     

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 of novel substituted 7-(benzylideneamino)-4-methyl-2H-chromen-2-one derivatives as anti-inflammatory and analgesic agents

A series of novel Schiff' base-containing a 7-amino-4-methylcoumarin moiety have been synthesized III a-l, characterized by spectroscopic data and studied for their anti-inflammatory and analgesic activity. The results of the anti-inflammatory and analgesic activity evaluation of 7-(substituted benzylideneamino)-4-methyl-2H-chromen-2-one derivatives III a-l proved to be comparable or more potent with respect to the reference drugs. In particular, compounds 7-(4-chlorobenzylideneamino)-4-methyl-2H-chromen-2-one III f, 7-(2,4-dichlorobenzylideneamino)-4-methyl-2H-chromen-2-one III g and 7-(4-bromobenzylideneamino)-4-methyl-2H-chromen-2-one III h exhibited potent anti-inflammatory and analgesic activity.     

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, 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 of some floctafenine derivatives of expected anti-inflammatory/analgesic activity

New derivatives related to floctafenine were synthesized and representative examples were screened for their anti-inflammatory and analgesic activities. All compounds tested were found to exhibit anti-inflammatory and analgesic activities and some were more potent than the references, floctafenine and indomethacin, in carragenan-induced rat's paw edema. None of the tested compounds showed an ulcerogenic effect on the p-benzoquinone-induced writhing test in mice.     

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.     

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.     

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.     

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 of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives of potential anti-inflammatory activity

A series of 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid derivatives 4-10 were synthesized by rearrangement of 4-(3-pyridyl)-hydrazono-2-phenyl-2-oxazolin-5-one 3 in the presence of different nucleophiles to afford derivatives 4, 7, and 8, while hydroxamic acid derivative 6 was prepared from reaction of methyl ester 4 with hydroxylamine hydrochloride. Semicarbazide 9 and thiosemicarbazide 10, derivatives of the 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic acid, were synthesized via hydrazide 8 with potassium cyanate and appropriate isothiocyanate, respectively. The structures of the synthesized compounds were confirmed by elemental analyses, IR, (1)H-NMR, and mass spectra. The results of the anti-inflammatory activity of the synthesized derivatives showed that most of the tested compounds 4-10 showed significant inhibition against carrageenan-induced rat paw edema in albino rats. Derivatives 4 and 8 showed promising results and were found to be equipotent or more potent than Indomethacin and Celecoxib as reference drugs at two dose levels, 5 and 10 mg/kg, and they have no ulcerogenic activity.     

吡酮酸类抗菌药物的研究——Ⅹ.1,7-双取代-6-氟-1,4-二氢-4-氧代喹啉-3-羧酸类化合物的合成与构效关系

本文合成了一系列1-位含有呋喃环系,异噁唑环系及取代苯基,7-位为不同取代氨基的吡酮酸类化合物,测定了这些化合物对大肠杆菌ATCC-25922,金黄色葡萄球菌ATCC-6538 p的MIC值,并与双氟哌酸进行对照,探讨了这些化合物的构效关系。     

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 and biological evaluation of some hydroxypyrazole derivatives as anti-inflammatory-antimicrobial agents

Some hydroxypyrazole derivatives 2-7 were synthesized by cyclocondensation of the keto-ester 1 with hydrazines hydrate or substituted hydrazines followed by reduction and acylation with acetic anhydride or trifluoroacetic anhydride. The newly synthesized compounds were evaluated for their anti-inflammatory, antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compounds N-(4-(5-hydroxy-1-trifluoroacetyl-1H-pyrazol-3-yl)phenyl) trifluoroacetamide 4b, 3-(4-nitrophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-ol 5b, and N-(4-(5-hydroxy-1-methyl-1H-pyrazol-3-yl)phenyl)trifluoroacetamide 7b were proved to be the most active anti-inflammatory, antimicrobial agents in the present study with a good safety margin and minimal or no ulcerogenic effect.     

Studies on 1,2,4-triazole derivatives as potential anti-inflammatory agents

The reaction of acetic or propionic acid hydrazides with various aryl/alkyl isothiocyanates gave thiosemicarbazides which furnished the 1,2,4-triazoles by alkali cyclization. The 4-aryl/alkyl-5-(1-phenoxyethyl)-3-[N-(substituted)acetamido]thio-4H-1,2,4-triazole derivatives were synthesized by reacting the triazoles with 2-chloro-N-(substituted)acetamide. The chemical structures of the compounds were elucidated by IR, (1)H-NMR, FAB(+)-MS spectral data and elemental analysis. In the pharmacological studies, anti-inflammatory activities of these compounds have been screened and significant activities were observed.     

Synthesis and anti-inflammatory and analgesic activities of phenoxyalkanoic acid derivatives

The synthesis of phenoxyalkanoic acid derivatives and their anti-inflammatory and analgesic activities are described. Analysis of structure-activity relationships shows that in trichlorophenoxy derivatives anti-edematous potency is associated with the presence of 1-thiopropyl moiety and 2 or 4-aminopyridyl moiety at R′ position contributes to the analgesic activity.     

Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents

In an attempt to develop potent anti-HIV drugs, 20 andrographolide derivatives were designed, synthesized, and evaluated for their in vitro anti-HIV activity. The screening results revealed that five compounds showed potent anti-HIV activities with therapeutic indices (TI) above 10. The most promising compound 6f shows a significant TI close to 34.07, with the potency to be a new lead.     

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 and analgesic and anti-inflammatory activity of some new (6-acyl-2-benzoxazolinone and 6-acyl-2-benzothiazolinone derivatives with acetic acid and propanoic acid residues

In this study for developing potent analgesic and anti-inflammatory compounds, we synthesized 6-acyl-2-benzoxazolinone and 6-acyl-2-benzothiazolinone derivatives with acetic acid and propanoic acid side chain, and performed preliminary screening of their in vivo analgesic and anti-inflammatory activities at a single dose of 100 mg/kg inmice by a p-benzoquinone-induced writhing test and a Carrageenaninduced hind paw edema model, respectively. We also determined their gastric ulceration effects in the tested animals. Propanoic acid derivatives were generally found to have higher analgesic and anti-inflammatory activities, and among them, 3-(6-benzoyl-2-benzothiazolinon-3-yl)propanoic acid (Compound 4 a) exhibited the highest analgesic and anti-inflammatory activity. However, all compounds showed lower anti-inflammatory effects than we observed for indomethacin at 10 mg/kg dose. Consequently, 6-acyl-2-benzoxazolinone/2-benzothiazolinones having propanoic acid side chain might lead to further studies for developing better candidates with potent analgesic and anti-inflammatory effects while acetic acid derivatives do not exhibit comparable satisfactory features.     

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.