Synthesis and biological evaluation of novel pyrazoline derivatives as anti-inflammatory and antioxidant agents

A series of novel 5-aryl-3-cyclopropyl-4,5-dihydropyrazole derivatives 2a-p were synthesized via cyclization of chalcones 1a-h with thiosemicarbazide or semicarbazide HCl and evaluated as anti-inflammatory/antioxidant agents. The structures were confirmed by elemental analyses and spectral data. The free radical scavenging activity toward superoxide was determined. Their effect on hepatocytes viability and nitric oxide (NO) production in LPS-stimulated macrophages was also determined. The results showed that compounds 2e and 2n demonstrated the highest free-radical scavenging and anti-inflammatory activities, thus can be useful in the prevention of oxidative stress and inflammation-related disorders.     

Synthesis of novel pyrazole and dihydropyrazoles derivatives as potential anti-inflammatory and analgesic agents

Novel dihydropyrazole 5-8, 10 and pyrazole derivatives 12, 14, 15, 17 were synthesized. The structures of the newly synthesized compounds were elucidated by spectral and elemental analyses. The anti-inflammatory activity of all new compounds was evaluated using the carrageenan-induced rat paw edema test using indomethacin and celecoxib as reference drugs. The most active derivatives as anti-inflammatory agents were accordingly tested for their analgesic activity using the p-benzoquinone-induced writhing method in mice and results revealed that these compounds had also good analgesic activity. The ulcerogenic liability of the selected compounds was also evaluated. Results showed that the selected derivatives had anti-inflammatory activity comparable to or slightly lower than the reference drugs, reaching about 82% inhibition with a considerable gastric safety profile.     

Synthesis and biological evaluation studies of novel quinazolinone derivatives as antibacterial and anti-inflammatory agents

Some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones bearing sulfonamide derivatives (4–11) were synthesized in good yields and evaluated for their possible antibacterial, anti-inflammatory activities and acute toxicity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their antibacterial activities were evaluated by the agar well diffusion method while their anti-inflammatory activities were evaluated by the carrageenan-induced hind paw edema test. All the tested compounds showed considerable antibacterial activities and high to moderate anti-inflammatory activities that last for 12 h compared to ibuprofen. All the tested compounds showed no toxic symptoms or mortality rates 24 h post-administration at tested anti-inflammatory doses. In addition, LD₅₀ for all tested compounds was higher than that for ibuprofen implying their good safety margin. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.     

Synthesis of baicalein derivatives as potential anti-aggregatory and anti-inflammatory agents

The direct acylation of trimethoxyphenol (1) with substituted cinnamoyl chlorides followed by Fries rearrangement and cyclization afforded a practical route for the synthesis of novel baicalein derivatives 4 functionalized on the B-ring in good overall yields. In the methylthiazoletetrazolium bromide (MTT) assay, none of the synthetic polyhydroxyflavonoids were cytotoxic at concentrations up to 200 microM on lipopolysaccharide (LPS)-activated murine RAW 264.7 macrophages over 24 h, while in the same cells they significantly inhibited NO production. Among the derivatives, 4d (IC50=46.1 +/- 0.3 microM) was found to exhibit the most potent activity compared with N-nitro-(L)-arginine methyl ester (L-NAME, IC50 >300 microM). Compounds 4b, 4e, 4f, 4h and 4i remarkably inhibited platelet aggregation induced by arachidonic acid and collagen in rabbit washed platelets compared with aspirin. Analysis of their structure-activity relationships indicated that, in the structural modification on the B-ring of baicalein (4a), introduction of appropriate electro-withdrawing substituents such as 2-Cl (4b), 4-Cl (4d), and 4-phenyl (4i) notably increased the potency on the inhibition of LPS-activated NO production and arachidonic acid- and collagen-induced aggregation. Baicalein itself was equally effective in the inhibition of LPS-activated NO production and collagen-induced aggregation but less active against arachidonic acid-induced aggregation. Our in-vitro results suggested that by appropriate structural modification of baicalein it may be possible to develop novel therapeutic agents against platelet-aggregation and inflammation.     

Evaluation and discovery of novel synthetic chalcone derivatives as anti-inflammatory agents

Major anti-inflammatory agents, steroids and cyclooxygenase, were proved to have serious side effects. Here, a series of chalcone derivatives were synthesized and screened for anti-inflammatory activities. QSAR study revealed that the presence of electron-withdrawing groups in B-ring and electron-donating groups in A-ring of chalcones was important for inhibition of LPS-induced IL-6 expression. Further, compounds 22, 23, 26, 40, and 47 inhibited TNF-α and IL-6 release in a dose-dependent manner and decreased LPS-induced TNF-α, IL-1β, IL-6, IL-12, and COX-2 mRNA production. Mechanistically, compounds 23 and 26 interfered with JNK/NF-κB signaling and dose-dependently prevented ERK and p38 activation. In addition, 23 and 26 exhibited a significant protection against LPS-induced death and were able to block high glucose-activated cytokine profiles in macrophages. Together, these data show a series of anti-inflammatory chalcones with potential therapeutic effects in inflammatory diseases.     

Design, synthesis, and evaluation of anti-inflammatory and ulcerogenicity of novel pyridazinone derivatives

A series of pyridazinone-containing compounds were designed and synthesized as congeners for diclofenac, the most potent and widely used NSAID. The target compounds were evaluated for their anti-inflammatory activity on rat paw edema inflammation model against diclofenac as a reference compound. Seven of the tested compounds demonstrated more than 50% inhibition of carrageenan-induced rat paw edema at a dose 10?mg/kg. The compounds, 6-(2-bromophenylamino)pyridazin-3(2H)-one 2a and 6-(2,6-dimethylphenylamino)pyridazin-3(2H)-one 2e, displayed 74 and 73.5% inflammation-inhibitory activity, respectively, which is comparable to diclofenac (78.3%) at the same dose level after 4?h. The most active compounds as anti-inflammatory agents, 2a, 2e, and 6a, displayed fewer number of ulcers and milder ulcer score than indomethacin in ulcerogenicity screening.     

Synthesis, evaluation, and molecular docking studies of cycloalkyl/aryl-3,4,5-trimethylgallates as potent non-ulcerogenic and gastroprotective anti-inflammatory agents

In our effort to identify the effective gastric sparing and protective anti-inflammatory agents, a series of cycloalkyl/aryl-3,4,5-trimethylgallates were synthesized and characterized. The physicochemical properties were studied to assess the lipophilicity and chemical stability. Subsequently, the compounds were evaluated for their anti-inflammatory activity and effect on gastric mucosa by most active compounds. All the compounds exhibited promising anti-inflammatory activity. In particular, 4a, 4b, 4g, and 4h emerged as the most active compounds in the series. The results of gastric mucosal studies and biochemical estimations suggested that these compounds are non-ulcerogenic and gastroprotective. The molecular docking analysis was performed to understand the binding interactions of these compounds to cyclooxygenase isoenzyme (COX-1 and COX-2). The results from this investigation suggests cycloalkyl/aryl-3,4,5-trimethylgallates as potent safer gastrosparing and protective anti-inflammatory agents.     

Synthesis of new pyridazinone derivatives as platelet aggregation inhibitors

This paper describes the synthesis and the antiplatelet activity of a series of 6-(4-(substituted-amino)phenyl)-4,5-dihydro-3(2H)-pyridazinones. Antiplatelet activity was determined by using the tail transaction bleeding test. All of the newly synthesized pyridazinone derivatives exhibited significant platelet aggregation inhibitory activity. The compounds IIIc and IIIh displayed two times more platelet aggregation inhibitory effect compared with standard drug aspirin.     

哒嗪酮类新衍生物的合成及其对血小板聚集的抑制作用

目的研究引入取代仲胺类基团对6-(4-取代乙酰氨基苯基)-5-甲基-4,5-二氢-3(2H)-哒嗪酮类化合物抗血小板凝集活性的影响。方法设计合成未见报道的目标化合物10个,所有化合物均经过1H-NMR谱等确证;参考文献方法进行体外药理实验。结果所有化合物都具有抗血小板凝集的活性,其中化合物9c,9f和9j的抗血小板凝集活性明显优于对照药MCI-154和CCI-17910。结论取代仲胺基团的空间位阻和亲水性对化合物抗血小板凝集的活性有影响。     

New celecoxib derivatives as anti-inflammatory agents

A series of 1,5-diarylpyrazoles with a substituted benzenesulfonamide moiety was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Some compounds, for example, (+/-)-2-[4-(5- p-tolyl-3-trifluoromethyl-pyrazole-1-yl)-benzenesulfonylaminooxy]-propionic acid 16 and its disodium salt 21, had a higher in vivo anti-inflammatory activity compared to celecoxib, despite having no in vitro COX-1 or COX-2 inhibitory activity. Their gastrointestinal side effect profile is essentially more favorable than that of celecoxib.     

新型哒嗪酮衍生物的合成及其对血小板聚集的抑制作用

目的 合成新的含有胺基的哒嗪酮类化合物,并研究其对此类化合物抗血小板聚集活性的影响.方法 设计合成未见报道的目标化合物9个,所有化合物均经过1H-NMR谱等确证;参考文献方法进行体外药理实验.结果 发现所有化合物都具有抗血小板凝集的活性,其中化合物9c,9e和9i的抗血小板凝集活性明显优于对照化合物MCI-154和CCI-17910.结论 引入不同的取代胺基,对化合物抑制血小板聚集的活性有影响.     

Synthesis and evaluation of novel benzimidazole derivatives as antimicrobial agents

Benzimidazole analogs bearing electron-withdrawing as well as electron-donating substituent were synthesized to achieve bioactive molecules with significant antimicrobial property. The desired compounds were prepared by multi-step synthesis process. The formation of intermediates and their corresponding derivatives (III _1–13 ) was confirmed by spectral characterization such as ¹H NMR, ¹³C NMR, mass spectra, IR, and elemental analysis. The compounds were screened for their antimicrobial properties against a broad panel of Gram-positive and Gram-negative bacteria as well as fungi. From the SAR study data, it was observed that the derivatives with electron-withdrawing functional groups were more bioactive than that with electron-donating functional groups.     

Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents

We report the synthesis, anti-inflammatory, and antioxidant activities of novel quinoxaline and quinoxaline 1,4-di-N-oxide derivatives. Microwave-assisted methods have been used to optimize reaction times and to improve yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase (LOX). Two of the best LOX inhibitors (compounds 7b and 8f) were evaluated as in vivo anti-inflammatory agents using the carrageenin-induced edema model. One of them (compound 7b) showed important in vivo anti-inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug.     

Synthesis of new oxadiazole derivatives as anti-inflammatory, analgesic, and antimicrobial agents

In search of pharmalogically active molecules in the class of oxadiazoles, the present article deals with the synthesis of 5-(5′-fluoro-2′-methoxybiphenyl-3-yl)-1,3,4-oxadiazol-2(3H)-one 2 from its hydrazide analog 1. The compound 2 was regioselectively N-alkylated with alkyl halides and produced the compounds 3a–f. Compound 3f was further functionalized with substituted benzenesulfonyl chlorides to give compounds 3g–j. The synthesized compounds were characterized by elemental and spectral analysis. Newly synthesized compounds were tested for their in vivo anti-inflammatory, analgesic, and in vitro antimicrobial activities. The compounds 3a–c were found to have promising anti-inflammatory and analgesic activities. Compounds 3b, 3f, and 3g showed significant antibacterial and antifungal activities.     

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.     

Design and synthesis of niflumic acid-based N-acylhydrazone derivatives as novel anti-inflammatory and analgesic agents

A new series of niflumic acid-based N-acylhydrazone derivatives 5a–p were synthesized and evaluated for their anti-inflammatory and analgesic activities. Most of the compounds have shown anti-inflammatory activity with a moderate-to-excellent activity range (20–80 % reduction in inflammation). Among them, 3-chlorophenyl 5d and 3-pyridyl derivatives 5o exhibited the most potent anti-inflammatory activity relative to niflumic acid as the reference drug (77, 76, and 70 % reduction in inflammation at 1-h postdrug administration, respectively). Also, molecular simplification of niflumic acid through replacing the N-aryl group with N-methyl group produced compounds 6a–f with anti-inflammatory activity in a quite similar manner to those of their parent derivatives. In this subgroup, 4-pyridyl derivative 6f showed the most potent anti-inflammatory activity relative to niflumic acid (80 % reduction in inflammation at 1-h postdrug administration). The compounds with highest anti-inflammatory activity were subjected to analgesic assays and showed moderate-to-excellent analgesic activities. The compound 5j, 4-methoxy derivative, exhibited the highest analgesic activity relative to niflumic acid (97 and 68 % activity, respectively).     

Synthesis,characterization, and computational studies on phthalic anhydride-based benzylidene-hydrazide derivatives as novel,potential anti-inflammatory agents

A series of phthalic anhydride-based substituted benzylidene-hydrazide derivatives (3a–i) was synthesized. The synthesized derivatives were authenticated by TLC, UV–visible, FTIR, NMR, and mass spectroscopic techniques and further screened for in vivo anti-inflammatory and analgesic activities by carrageenan-induced rat paw oedema and tail immersion methods, respectively, using diclofenac sodium as standard drug. The derivatives 3d, 3e, and 3h were found to be most active anti-inflammatory and analgesic agents among all the synthesized derivatives. The physico-chemical similarity of the derivatives with standard drugs was assessed by calculating various physicochemical properties using software programs. The percent similarity of synthesized derivatives was found to be good except 3i. The derivatives were subjected to QSAR by multilinear regression using Analyze it version 3.0 software and two statistically sound models were developed with R ² (0.933–0.960), $ R_{{adj}}^{2} $ (0.595–0.762) and Q ² (0.999) with good F (2.76–4.84) values. Molecular docking studies were performed by MVD software (version 2012.5.0.0). The derivative 3h has emerged out as most potent anti-inflammatory agent with highest dock score, i.e., ?93.64.