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.     

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 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 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.     

Synthesis and analgesic and antiinflammatory activity of methyl 6-substituted-3(2h)-pyridazinone-2-ylacetate derivatives

A series of methyl 6-substituted-3(2H)-pyridazinone-2-ylacetates 9 were synthesized and their analgesic and anti-inflammatory effects were evaluated in the phenylbenzoquinone-induced writhing test (PBQ test) and carrageenan-induced paw edema method, respectively. Side effects of the compounds were examined on gastric mucosa. None of the compounds showed gastric ulcerogenic effect compared with reference nonsteroidal anti-inflammatory drugs. Methyl 6-(4-(4-fluorophenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9e was found to be more active than acetylsalicylic acid (ASA). Methyl 6-(4-(2-ethoxyphenyl)piperazine)-3(2H)-pyridazinone-2-ylacetate 9c has shown an anti-inflammatory activity as compared to the standard compound indometacin at the carrageenan-induced paw edema method.A significant dependence of the anti-inflammatory effect on the substituents has been observed. The pharmacological study of these compounds confirms that modification of the chemical group at the position 6 of the 3(2H)-pyridazinone system influences analgesic and anti-inflammatory activities. The structures of these new pyridazinone derivatives were confirmed by their IR and (1)H-NMR spectra and elemental analysis.     

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 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 of new 2-[1(2H)-phthalazinon-2-yl]acetamide and 3-[1(2H)-phthalazinon-2-yl]propanamide derivatives as antinociceptive and anti-inflammatory agents

As a consequence of our ongoing studies on heterocyclic compounds for new antinociceptive and anti-inflammatory agents bearing lactam functional group, new 2-[1(2H)-phthalazinon-2-yl]acetamide and 3-[1(2H)-phthalazinon-2-yl]propanamide derivatives have been synthesized. Among the compounds synthesized, compound (4e) was found the most active derivative in terms of antinociceptive and anti-inflammatory activities, without gastric lesions and bleeding at the given dose.     

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.     

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.     

强效镇痛剂研究——Ⅴ.N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7302)酯类衍生物的合成及镇痛活性

本文报道了一系列N-[1-(β-酰氧基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺类衍生物及其化学结构与镇痛强度之间的关系,并测定了几个代表化合物的镇痛作用时间及与阿片受体亲和力。实验结果表明,7302的β-羟基酯化后,均能维持一定的镇痛强度,其镇痛作用时间与母体化合物7302相近。从受体结合试验来看,酯化后与受体亲和的能力显著下降。     

Synthesis, molecular modelling and biological evaluation of 4-amino-2(1H)-quinazolinone and 2,4(1H,3H)-quinazolidone derivatives as antitumor agents

A series of 6-benzoyl-, 6-arylthio- and 6-arylsulfonyl-4-amino-2(1H)-quinazolinones and -2,4(1H,3H)-quinazolinediones were prepared. They were evaluated in vitro for their cytotoxicity against the NCI-60 cancer cell lines.     

New 4-[(1-benzyl-1H-indol-3-yl)carbonyl]-3-hydroxyfuran-2(5H)-ones, beta-diketo acid analogs as HIV-1 integrase inhibitors

In addition to our recent report on a series of rationally designed benzylindolyldiketo acids acting as potent HIV-1 integrase strand transfer inhibitors, we disclose the results obtained with novel compounds chemically modified on the diketo acid moiety in order to investigate its influence on the biological activity and cytotoxicity. The activity of designed and synthesized 4-[(1-benzyl-1H-indol-3-yl)carbonyl]-3-hydroxyfuran-2(5H)-one derivatives lies in the micromolar range with regard to HIV IN enzymatic activity. The microwave-assisted synthesis was employed in some steps of the chemical procedures.     

Synthesis of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)semi-carbazides and their transformation into 4-chloro-2-mercapto-N-(4,5-dihydro-5-oxo-4-phenyl-1H-1,2,4-triazol-3-yl)benzenesulfonamides as potential anticancer and anti-HIV agents

Synthesis of a series of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)semicarbazides (6-16) and 4-chloro-2-mercapto-N-(4,5-dihydro-5-oxo-4-phenyl-1H-1,2,4-triazol-3-yl)benzenesulfonamides (17-22) were reported. Compounds 7-9, 17, 19-22 were tested at the US National Cancer Institute for their in vitro anticancer and anti-HIV activities. Results of anticancer screening showed moderate activity of 21 and 22, while 19 was found to have encouraging anti-HIV activity at EC(50) = 28.8 microM.     

Design,syntheses, and evaluation of 2,3‐diphenylcycloprop‐2‐en‐1‐ones and oxime derivatives as potential cyclooxygenase‐2 (COX‐2) inhibitors with analgesic‐antiinflammatory activity

A group of 2,3‐diphenylcycloprop‐2‐enes having a variety of substituents at the para‐position of the C‐2 phenyl ring (H, F), and C‐3 phenyl ring (H, F, SMe, SOMe, SO₂Me), in conjunction with either a C‐1 carbonyl, oxime, oxime acetate, benzoyl hydrazone, or hydrogen substituent were synthesized for in vivo evaluation as analgesic and antiinflammatory (AI) agents, and as potential selective cyclooxygenase‐2 (COX‐2) inhibitors. This group of cycloprop‐2‐ene compounds exhibited significant analgesic activity, since 4% NaCl‐induced abdominal constriction was reduced by 43–90% at 30 min, and 41–100% at 60 min, after drug administration relative to the reference drugs aspirin and celecoxib (58% and 32% inhibition at 30 min after drug administration) for a 50 mg/kg intraperitoneal dose. AI activities, determined using the carrageenan‐induced rat paw edema assay, showed that this class of cycloprop‐2‐ene compounds exhibited AI activities in the inactive‐to‐modest activity range (0–26% inhibition) for a 50 mg/kg oral dose. The AI potency order for a group of 2,3‐diphenylcycloprop‐2‐enes with respect to the C‐1 substituent was oxime>hydrogen>carbonyl>benzoyl hydrazone. 2,3‐Diphenylcycloprop‐2‐en‐1‐one oxime ( 20 ) was the most active AI agent, inducing a 26% reduction in inflammation, relative to the reference drugs ibuprofen and celecoxib, which showed 52% and 58% reductions in inflammation, at 5 h after drug administration. In vitro COX‐1 and COX‐2 inhibition studies showed that 2,3‐diphenylcycloprop‐2‐en‐1‐one oxime ( 20 ) is a selective COX‐2 inhibitor (COX‐1 IC₅₀>100 μM; COX‐2 IC₅₀=2.94 μM; COX‐2 selectivity index>34). A molecular modeling study that docked the oxime ( 20 ) in the active site of the human COX‐2 isozyme showed that it binds in the vicinity of the mouth of the COX‐2 binding site with the O‐atom of the oxime (=N–OH) moiety separated from the NH₂ group of Arg¹²⁰ by about 3.65 Å. This orientation of the oxime compound ( 20 ) in the COX‐2 binding site could be due to a potentially strong ionic interaction between the =NOH oxime moiety and the guanidinium moiety of Arg¹²⁰. Drug Dev. Res. 57:6–17, 2002. © 2002 Wiley‐Liss, Inc.     

Design and synthesis of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives as antibacterial agents based on cajaninstilbene acid scaffold hopping

The prevalence of multidrug resistance among clinically significant bacterial pathogens underlines a critical need for the development of new classes of antibacterial agents with novel structural scaffolds. Cajaninstilbene acid (CSA), which is isolated from pigeonpea leaves, has shown potent antibacterial activity. In this study, a series of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives derived from CSA were designed and synthesized, and their antibacterial activities were evaluated. Several synthesized compounds exhibit better antibacterial activity than CSA against Staphylococcus aureus, Staphylococcus epidermidis, and two strains of methicillin-resistant S. aureus. Meanwhile, the results of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assays illustrate the good selectivity between bacteria and normal cells of the most active compounds 6u and 6v . Furthermore, well combinations with bacterial RNA polymerase of 6u arising from docking study imply the possible mechanism of antibacterial activity of these synthetic compounds.     

Synthesis and pharmacological properties of 1-[2-hydroxy-3-(4-o,m,p-halogenophenyl)- and 3-(4-m-chlorophenyl)-1-piperazinyl]propyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d]pyrimidine-5-carboxylic acid with analgesic and sedative activities

Synthesis of 1-[2-hydroxy-3-(4-o,m,p-halogenophenyl)- and 3-(4-m-chlorophenyl)-1-piperazinyl]propyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (18, 20-23, 25, 27-30 and 19, 24, 26) is described. All substances were active as analgesic agents in "writhing syndrome" test and except of 18 and 23 they acted stronger than acetylsalicylic acid. All final derivatives tested significantly suppressed the spontaneous locomotor activity of mice.     

Synthesis of enantiopure non‐natural α‐amino acids using tert‐butyl (2S)‐2‐[bis‐(tert‐butoxycarbonyl)amino]‐5‐oxopentanoate as key‐intermediate:the first synthesis of(S)‐2‐amino‐oleic acid

Abstract: A general method for the synthesis of enantiopure non‐natural α‐amino acids is described. The key intermediate tert‐butyl (2S)‐2‐[bis(tert‐butoxycarbonyl)amino]‐5‐oxopentanoate was obtained from l ‐glutamic acid after suitable protection and selective reduction of the γ‐methyl ester group by DIBALH. Wittig reaction of this chiral aldehyde with various ylides led to a variety of δ,ε‐unsaturated α‐amino acids. This methodology was applied to the synthesis of (S)‐2‐amino‐oleic acid.