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Benzoxazine and quinazoline are nitrogen-containing heterocyclic scaffolds found in various biologically active compounds. Due to their diverse biological actions, these heterocyclic rings serve as crucial frameworks for designing medicinal compounds. This study aimed to synthesize and assess in vivo anti-inflammatory, analgesic, and low ulcerogenic potential of a few novel benz[d][1,3]-oxazine-4-one and quinazolinone derivatives. Benzoxazinones (3a-e) were synthesized by cyclizing the carboxylic group (-COOH) of five nonsteroidal anti-inflammatory drugs viz., aceclofenac, ibuprofen, diclofenac, mefenamic acid and ketoprofen (2a-e) with anthranilic acid (1) using dry phosphorus oxychloride (POCl3 ) in pyridine. The corresponding quinazolinone derivatives (5a-e) were obtained by reacting 3a-e with isonicotinic acid hydrazide (4). Both sets of compounds were evaluated for their anti-inflammatory, analgesic effects, and ulcerogenicity in animal models. Structural characterization was performed using spectral analysis. Among the benzoxazinone derivatives, compound 2-(2-((2,6-dichlorophenyl) amino) benzyl)-4H-benzo[d][1,3]oxazin-4-one (3d) exhibited significant anti-inflammatory activity (62.61% inhibition of rat paw edema) and analgesic activity (62.36% protection in acetic acid-induced writhings) with tolerable gastrointestinal toxicity (2.67 ulcerogenicity index) compared to quinazolinone derivatives. The results of antiinflammatory and analgesic activities of both the series are comparable with the respective, positive control. Compound 3d, a benzoxazinone-diclofenac hybrid, emerged as a lead molecule with potent anti-inflammatory, analgesic activities and moderate gastric toxicity showcasing the promising potential for further development. [ABSTRACT FROM AUTHOR]

A series of 3-[2-chloroquinolin-3-yl)methylene]-5-aryl-furan-2(3H)-ones {3(a-p)} were synthesized. The required 3-(substitutedbenzoyl) propionic acids {2(a-d)} were prepared under Friedal Craft acylation reaction conditions. The substituted 2-chloroquinoline-3-carbaldehydes {1(a-d)} were synthesized by reaction of substitutedphenylethanone-oxime with phosphorus oxychloride in presence of dimethyl formamide using the Vilsmeir Haack reaction method. These compounds were screened for their anti-inflammatory and antibacterial activities along with their ulcerogenic and lipid peroxidation potentials. The compounds that showed significant anti-inflammatory activity were further screened for their analgesic activity. The compounds were less toxic in terms of ulcerogenicity as compared to a standard, which was also supported by lipid peroxidation studies. The antibacterial activities were performed against Staphylococcus aureus and Escherichia coli. Compounds 3f, 3n and 3o showed significant activity against both S. aureus and E. coli having an MIC value of 6.25μg mL-1.

3-Arylidene-5-(4-methylphenyl)-2(3H)-furanones 2a-m were prepared from 3-(4-methyl-benzoyl)propanoic acid 1 and several aromatic aldehydes. Some of the selected furanones were reacted with ammonia gas and benzylamine to give corresponding 3-arylidene-1,3-dihydro-5-(4-methylphenyl)-2H-pyrrol- 2-ones 3a-h and 3-arylidene-1-benzyl-1,3-dihydro-5-(4-methylphenyl)-2H- -pyrrol-2-ones 4a-f, respectively, which were characterized on the basis of IR, 1H-NMR, mass spectral data and elemental analysis results. These compounds were tested for their anti-inflammatory and antibacterial activities. The compounds, which showed significant anti-inflammatory activity, were further screened for their analgesic and ulcerogenic activities. Three new compounds (2e, 2h and 4d), out of twenty-seven showed very good anti-inflammatory activity in the carrageenan induced rat paw edema test, with significant analgesic activity in the acetic acid induced writhing test together with negligible ulcerogenic action. The antibacterial activity is expressed as the corresponding MIC values.

A novel series of 1-(4-phenoxyphenyl)-3-[5-(substituted aryl)-1,3,4-oxa- diazol-2-yl]propan-1-one was synthesized by reaction of 3-(4-phenoxybenzoyl)propionic acid with several aryl acid hydrazides in phosphorus oxychloride. The structures of the compounds were supported by IR, 1H- and 13C-NMR, MS data and elemental analysis results. These compounds were tested for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. A few compounds were found to have very good anti-inflammatory activity in the carrageenan-induced rat paw edema test, while a fair number of the compounds showed significant analgesic activity in the acetic acid-induced writhing test. These new compounds showed very low ulcerogenic action with reduced malondialdehyde content (MDA), which is one of the by-products of lipid peroxidation.

In this study, a series of novel chromene based 2,6-disubstituted-thiazolo[3,2-b] [1,2,4] triazole derivatives (7a-g) were synthesized by condensing 5-substituted-1,2,4-traizole-thione (6a-g) using poly phosphoric acid through one pot reaction. The structure of new compounds was supported by 1H NMR, 13C NMR and MS data. The synthesized compounds were evaluated using writhing assays for analgesic and carrageenan-induced rat paw edema method for anti-inflammatory activities respectively. Some of the newly synthesized compounds 7c, 7f and 7g showed very good anti-inflammatory activity with 90.83%, 85.81% and 88.40% protection respectively along with low GI toxicity as compared to standard drug ibuprofen while compounds 7a, 7b, 7d and 7f showed highest analgesic activity with 52.54%, 54.02%, 56.76% and 52.45% protection among them compound 7d showed better protection than standard drug ibuprofen. [ABSTRACT FROM AUTHOR]

A small library of twenty-four quinoline based butenolides also known as furanones and their nitrogen analogues was prepared by using two different aroylpropionic acids, viz. 3-(2-naphthoyl)propionic acid ( 3 ) and 3-(biphenyl-4-yl)propionic acid ( 4 ), as starting materials. The 3-aroylpropionic acids were reacted with different 6-substituted-2-chloroquinolin-3-carbaldehydes ( 2a–d ) to obtain the corresponding furan-2(3 H )-ones ( 5a–h ). The purified and characterized furanones were then converted into their corresponding 2(3 H )-pyrrolones ( 6a–h ) and N -benzyl-pyrrol-2(3 H )-ones ( 7a–h ). The antimicrobial activities of the title compounds were evaluated against two strains of each Gram +ve ( Staphylococcus aureus and Bacillus subtilis ), Gram −ve bacteria ( Escherichia coli and Pseudomonas aeruginosa ) and against fungal strains of Aspergillus niger and Aspergillus flavus . In vivo anti-inflammatory potential of the title compounds was investigated by standard method. Majority of the compounds showed significant antibacterial activity against both the Gram +ve strains. Eight most potent anti-inflammatory compounds ( 5b, 5d, 5h, 6b, 7b, 7d, 7f, 7h) which exhibited >53% inhibition in edema, were also screened for their in vivo analgesic activity. All the tested compounds were found to have significant reduction in ulcerogenic action but only three compounds ( 5d, 5h and 7h ) showed comparable analgesic activity to standard drug, diclofenac. The results were also validated using in silico approach and maximum mol doc score was obtained for compounds 7a–h . On comparing the in vivo and in silico anti-inflammatory results of synthesized compounds, N -benzyl pyrrolones ( 7a–h ) emerged as the potent anti-inflammatory agents. It was also observed that compounds that possess electron withdrawing group such as Cl or NO 2 are more biologically active. [ABSTRACT FROM AUTHOR]

The aim of this study was to design and synthesize pharmaceutical agents containing imidazolidine heterocyclic ring in the hope of developing potent, safe and orally active anti-inflammatory agents. A number of substituted-imidazolidine derivatives ( 3a–k ) were synthesized starting from ethylene diamine and aromatic aldehydes. The imidazolidine derivatives ( 3a–k ) were investigated for their anticipated anti-inflammatory, and analgesic activity in Wistar albino rats and Swiss albino mice, respectively. Bioactivity score, molecular and pharmacokinetic properties of the imidazolidine derivatives were calculated by online computer software programs viz. Molinspiration and Osiris property explorer. The results of biological testing indicated that among the synthesized compounds only three imidazolidine derivatives namely 4-[1,3-Bis(2,6-dichlorobenzyl)-2-imidazolidinyl]phenyl-diethylamine ( 3g ), 4-[1,3-Bis(3-hydroxy-4-methoxybenzyl)-2-imidazolidinyl]phenyl-diethylamine ( 3i ) and 4-(1,3-Bis(4-methoxybenzyl)-4-methylimidazolidin-2-yl)-phenyl-diethylamine ( 3j ) possess promising anti-inflammatory and analgesic actions. Additionally these derivatives displayed superior GI safety profile (low severity index) with respect to the positive control, Indomethacin. All synthesized compounds showed promising bioactivity score for drug targets by Molinspiration software. Almost all the compounds were predicted to have very low toxicity risk by Osiris online software. Compound number ( 3i) emerged as a potential candidate for further research as it obeyed Lipinski’s rule of five for drug likeness, exhibited promising biological activity in-vivo and showed no risk of toxicity in computer aided screening. [ABSTRACT FROM AUTHOR]

Butenolide-based eighteen new amide derivatives ( 1-18) have been synthesized and evaluated for anti-inflammatory activity. The compounds 9, 17 and 4 exhibited significant in vivo inhibition of 84.69, 76.52 and 76.22 % inflammation, respectively, after 5 h without causing any damage to stomach and liver in comparison with the standard drug indomethacin which showed 79.04 % inhibition. The compounds showing potent anti-inflammatory activity were further evaluated for ex vivo TNF-α suppression. Compounds 9, 17 and 4 significantly suppressed TNF-α concentration to 74.83, 71.74 and 67.11 % as compared to indomethacin which exhibited a suppression of 69.01 %. Compounds 9 and 17 were also found to suppress the expression of COX-2 and NF-κB in the paw tissue. Moreover, compound 9 showed significant analgesic activity (57.03 %) which was comparable to indomethacin (61.03 %). [ABSTRACT FROM AUTHOR]

A focused library of novel benzyl pyrrolones has been synthesized and their in silico molecular docking studies carried out against TNF- α target. Among all the docked molecules, compound 3f showed best glide score of −6.89. All the synthesized compounds were evaluated for in vivo anti-inflammatory activity by carrageenan-induced paw edema model. Compounds showing significant anti-inflammatory activity were further tested for their in vitro TNF α expression. Compounds 3b and 2b were found to show significant inhibition of 76.22% and 71.47%, respectively after 5 h in comparison with standard drug indomethacin, which showed 80.98% inhibition of inflammation. Compounds 3b and 2b also suppressed TNF α level by 65.03% and 60.90% as compared indomethacin, which showed 68.84% of inhibition. Compound 3b showed significant analgesic activity of 60.04%, and its activity was comparable with indomethacin (64.04%). Compounds 3b and 2b were also tested for their effect on protein expression of COX-2 and NF- κB in the liver tissues. Compounds 3b and 2b were further evaluated for their gastric risk and lipid peroxidation action and showed superior GI safety along with reduction of LPO as compared to indomethacin. Hepatotoxicity study showed that these two compounds did not cause any damage to liver. [ABSTRACT FROM AUTHOR]

[Display omitted] The study aimed to synthesize and evaluate the potential anti-inflammatory and analgesic activities of rationally designed hybrid molecules of imidazolone and indole nuclei linked through a methylene bridge. Indolyl-imidazolone hybrids were synthesized in three simple steps starting from 2-phenyl-1 H -indole (1). In the first step, compound 1 was converted to 2-phenyl-1 H -indole-3-carbaldehyde (2) using standard conditions of the Vilsmeier Haack reaction. Benzoyl glycine was reacted with 2 (step 2) followed by treatment with aromatic/aliphatic amines (step 3) to furnish the indolyl-imidazolone hybrids. In vivo anti-inflammatory and analgesic activity along with ulcerogenicity of the prepared hybrids were evaluated in experimental animals. Molecular properties and pharmacokinetic profile were also predicted using online computational software. Cyclooxygenase-2 (COX-2) enzyme (PDB: 3pgh) was used for molecular docking studies. Indomethacin and aspirin were used as reference compounds for the comparison purpose. The percentage inhibition in edema in rats and reduction in frequency of acetic acid induced writhes in mice indicated that two compounds namely 3-(3-Hydroxpropyl)-2-phenyl-5-[(2-phenyl-1 H -indol-3-yl)methylene]-4 H -imidazol-4-one (4g) and 3-(2,4-Dinitrophenyl)-2-phenyl-5-[(2-phenyl-1 H -indol-3-yl) methylene]- 4 H -imidazol-4-one (4b) could be useful in treating pain and inflammatory conditions. Both the hybrid molecules exhibited better biological spectrum than the standard drug indomethacin. Additionally, both the potent compounds were noted to be less ulcerogenic than indomethacin. Pharmacokinetic profile predicted using ADMETsar and SwissADME cheminformatic software indicated compound 4g to be orally bioavailable with high blood brain barrier permeability. However, molecular docking studies revealed that compound 4b binds to COX-2 enzyme more strongly than 4g as indicated by a lower binding energy and formation of hydrogen bond interactions with amino acid residues in the binding pocket. It could be concluded that hybrid compounds 4b and 4g are promising lead candidates and should be further studied to develop compounds for the treatment of inflammatory conditions. [ABSTRACT FROM AUTHOR]

PURPOSE: In view of the potential pharmacophoric nature of imidazole nucleus, two series of imidazole derivatives, 2,4‑disubstituted‑1 H‑imidazoles (2a‑m) and 1,2,4‑trisubstituted‑1 H‑imidazoles (3a‑m), were synthesized with an aim of obtaining dual acting compounds i.e., anti‑inflammatory and antifungal agents. MATERIALS AND METHODS: The title compounds were synthesized from 4‑methoxyphenyl glyoxal (1) following multistep synthesis, and their structures were established on the basis of modern analytical techniques (IR, NMR and MS). The synthesized imidazoles were tested for their in vivo anti‑inflammatory activity. In addition to that, some compounds were also evaluated for their analgesic and ulcerogenic effects. The compounds were also evaluated for their in vitro antifungal activity. RESULTS: Di‑ and tri‑substituted imidazole derivatives (2a‑m and 3a‑m) were successfully synthesized. In in vivo anti‑inflammatory test, six compounds (2 h, 2 l, 3 g, 3 h, 3 l and 3 m) exhibited good anti‑inflammatory activity (49.58 to 58.02% inhibition) with minimal GI irritation (severity index; 0.17 to 0.34). These compounds were also tested for their analgesic activity and showed appreciable protection (40.53 to 49.60% protection) against saline‑induced writhing test. Indomethacin was used as standard drug for comparison. In antifungal test, two compounds (3 h and 3 l) displayed appreciable antifungal activity (MIC; 12.5 μg mL‑1) against the fungal strains tested. CONCLUSION: Two compounds, 2‑(4‑nitrophenyl)‑4‑(4‑methoxyphenyl)‑1‑phenyl‑1H‑imidazole (3 h) and 2,4‑di‑(4‑methoxyphenyl)‑1‑phenyl‑1H‑imidazole (3 l), emerged as lead compounds having dual biological activities; good anti‑inflammatory as well as antifungal effect with lesser GI irritation. [ABSTRACT FROM AUTHOR]

A series of pyridazinone derivatives ( 19-34) were synthesized with an aim to synthesize safer anti-inflammatory agents. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation (LPO) actions. The percentage inhibition in edema at different time intervals indicated that compounds 20, 26, 28 and 34 exhibited good anti-inflammatory potential, comparable with that of ibuprofen (85.77%) within a range of 67.48-77.23%. The results illustrate that 5-(4-fluoro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone ( 26) and 5-(4-chloro-benzyl)-3-(4-chloro-phenyl)-1,6-dihydro-6-pyridazinone ( 20) showed best anti-inflammatory activity. Furthermore, activity is more in case of chloro substitution as compared with methyl-substitution. The compounds synthesized were also evaluated for their ulcerogenic and LPO action and showed superior gastrointestinal safety profile along with reduction in LPO as compared with that of the ibuprofen. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of a series of 3-[5-(substituted aryl)-1,3,4-oxadiazol-2-yl]-1-(biphenyl-4-yl)propan-1-ones derived from 4-oxo-4-(biphenyl-4-yl)butanoic acid (fenbufen) is described. The structures of these compounds were supported by IR, 1H NMR, mass spectrometric data and elemental analysis. These compounds were tested for their antiinflammatory, analgesic, ulcerogenic and lipid peroxidation actions. A few compounds were found to have very good antiinflammatory activity in carrageenan induced rat paw edema test, while a fair number of compounds showed significant analgesic activity in acetic acid induced writhing test. The newly synthesized compounds showed very low ulcerogenic action with reduced malondialdehyde (MDA) content, which is one of the byproducts of lipid peroxidation. In vitro COX-1 and COX-2 isozyme inhibition studies were also performed on some of the selected compounds. Compound 4i and 4h were found to be more selective towards COX-2 as indicated by COX-2 selectivity index of 36.06 and 29.05 (COX-2 IC50 =1.5μM and 1.8μM) respectively. [Copyright &y& Elsevier]

Abstract: A series of 3-arylidene-5-(4-chloro-phenyl)-2(3H)-furanones (2–13) and their nitrogen analogues 1-benzylpyrrolones (14–18) were synthesized. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. Some of the newly synthesized compounds showed good anti-inflammatory and analgesic activities with low GI toxicity and reduced lipid peroxidation. The biological activity was found to improve upon replacement of oxygen of furanone ring with benzylamine moiety i.e. 1-benzylpyrrolones. Similarly, compounds containing halogen group(s), compounds 15 and 17, showed higher degree of anti-inflammatory activity and their activity was comparable to that of the standard. These compounds showed interesting profile of analgesic activity in acetic acid induced writhing test (peripheral effect) and in the hot-plate test (central effect). The compounds were also tested for their ulcerogenic and lipid peroxidation action and showed superior GI safety profile along with reduction in lipid peroxidation as compared to that of the standard. [Copyright &y& Elsevier]

Abstract: 2-Arylidene-4-(4-phenoxy-phenyl)but-3-en-4-olides (1–17) were prepared from 3-(4-phenoxy-benzoyl)propionic acid and aromatic aldehydes. Some of the selected butenolides were reacted with ammonia and benzylamine to give corresponding 3-arylidene-5-(4-phenoxy-phenyl)-2(3H)-pyrrolones (18–23) and 3-arylidene-5-(4-phenoxy-phenyl)-1-benzyl-2(3H)-pyrrolones (24–29) respectively, which were characterized on the basis of 1H-, 13C-NMR, Mass spectrometric data and elemental analysis results. These compounds were tested for anti-inflammatory and antimicrobial actions. The compounds, which showed significant anti-inflammatory activity, were screened for their analgesic and ulcerogenic activities. Five new compounds (5, 6, 7, 25 and 26), out of 29 showed very good anti-inflammatory activity in the carrageenan induced rat paw edema test, with significant analgesic activity in the acetic acid induced writhing test together with negligible ulcerogenic action. Antibacterial activity against Staphylococcus aureus and Escherichia coli as well as antifungal activity against Candida albicans were expressed as the corresponding minimum inhibitory concentration (MIC) values. Compound 21, 22 and 23 showed excellent activity against C. albicans with MIC-10 μg/ml. Out of the above-mentioned compounds, 22 and 23 also showed good activity against S. aureus with MIC-20 and 15 μg/ml respectively. [Copyright &y& Elsevier]

A series of 5-aryl-3-[(2-chloroquinolin-3-yl)methylene] furan-2(3H)-ones (3a-p) were synthesized. The required 3-(substituted benzoyl)propionic acids 2a-d were prepared under Friedel-Crafts acylation reaction conditions. The substituted 2-chloroquinoline-3-carboxaldehydes 1a-d were synthesized by reaction of substituted phenylethanone oxime with phosphorus oxychloride in presence of dimethylformamide using the Vilsmeier-Haack reaction method. These compounds were screened for their anti-inflammatory and antibacterial activities along with their ulcerogenic and lipid peroxidation potentials. The compounds that showed significant anti-inflammatory activity were further screened for their analgesic activity. The compounds were less toxic in terms of ulcerogenicity as compared to a standard, which was also supported by lipid peroxidation studies. The antibacterial activities were performed against Staphylococcus aureus and Escherichia coli. Compounds 3f, 3n and 3o showed significant activity against both S. aureus and E. coli having an minimum inhibitory concentration (MIC) value of 6.25 μg mL-1. [ABSTRACT FROM AUTHOR]

Abstract: A series of 6-aminomethyl-2-aryl-1-benzopyran-4-one derivatives (10–24) were synthesized. The compounds were tested for anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. Among the tested compounds, six compounds 11, 13, 16, 18, 21 and 23 showed higher degree of anti-inflammatory activity (>75% activity of standard drug ibuprofen). In addition to remarkable anti-inflammatory activity, analgesic activity was found to be comparable with that of the standard drug ibuprofen. Compounds 16 and 21 showed a significant GI protection (with respect to ulcerogenesis) and a marked decrease in lipid peroxidation values whereas compounds 11 and 16 were found to possess antimicrobial activity against Staphylococcus aureus, Escherichiacoli, Rhizopus oryza and Penicillum citrum with an MIC of 10μg/mL. [Copyright &y& Elsevier]