Design and synthesis of thiourea derivatives containing a benzo[5,6]cyclohepta[1,2-b]pyridine moiety as potential antitumor and anti-inflammatory agents

Thiourea derivatives (6a-e) were developed and screened for antitumor and anti-inflammatory activity. Most of the compounds exhibited growth inhibitory effects comparable to 5-fluorouracil in vitro against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. They also showed stronger anti-inflammatory activity than ibuprofen in vivo in the xylene-induced ear swelling assay in mice.     

Synthesis and evaluation of anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation properties of new 2-(4-isobutylphenyl)propanoic acid derivatives

Synthesis and pharmacological evaluation of various 2-(4-isobutylphenyl)propanoic acid derivatives containing 1,3,4-thiadiazole and thiadiazolo[3,2-a][1,3,5]triazine-5-thione nucleus is reported here. The structures of new compounds are supported by IR, (1)H & (13)C NMR data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic and lipid peroxidation activities. The compounds, which showed less ulcerogenic action, also showed reduced malondialdehyde production (MDA). Compound 4i and 5f showed 89.50 and 88.88% of inhibition in paw edema, 69.80 and 66.25% protection against acetic acid-induced writhings and 0.7 and 0.65 of severity index, respectively, compared to 90.12, 72.50 and 1.95 values of ibuprofen.     

Synthesis and biological evaluation of cyanoguanidine derivatives of loratadine

Cyanoguanidine derivatives of loratadine (3a–i) were synthesized and screened for antitumor and anti-inflammatory activity. The most promising compound 3c (R = n-C₈H₁₇) possessed at least twofold higher in vitro cytotoxicity than 5-fluorouracil against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. The mode of action, however, is so far unclear. The participation of the COX-1/2 enzymes on the cytotoxicity, however, is very unlikely. Nevertheless all compounds showed stronger in vivo anti-inflammatory activity than ibuprofen in the xylene-induced ear swelling assay in mice.     

Synthesis and biological evaluation of some new pyridazinone derivatives

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.     

Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs.     

Synthesis and biological evaluation of some new pyridazinone derivatives

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.     

Design and study of some novel ibuprofen derivatives with potential nootropic and neuroprotective properties

Six novel ibuprofen derivatives and related structures, incorporating a proline moiety and designed for neurodegenerative disorders, are studied. They possess anti-inflammatory properties and three of them inhibited lipoxygenase. One compound was found to inhibit cyclooxygenase (COX)-2 production in spleenocytes from arthritic rats. The HS-containing compounds are potent antioxidants and one of them protected against glutathione loss after cerebral ischemia/reperfusion. They demonstrated lipid-lowering ability and seem to acquire low gastrointestinal toxicity. Acetylcholinesterase inhibitory activity, found in two of these compounds, may be an asset to their actions.     

Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis,docking studies and investigation of anti-inflammatory,ulcerogenic liability and analgesic activities

A novel group of 1,3,4-oxadaiazoles, a group known for their anti-inflammatory activity, is hybridized with nitric oxide (NO) releasing group, oxime, for its gastro-protective action and potential synergistic effect. The synthesized hybrids were evaluated for their anti-inflammatory, analgesic, antioxidant and ulcerogenic activities. Most of the tested compounds showed excellent anti-inflammatory activity with compound 8e being more active than indomethacin. They also showed moderate analgesic activity but no antioxidant one. The ability of the synthesized compounds to inhibit COX-1 and COX-2 is studied and the prepared compounds were able to inhibit both COXs non-selectively with IC₅₀s of 0.75–70.50 μM. Docking studies revealed the mode of interaction of the tested compounds into the empty pocket of the isozymes. All of the synthesized compounds interact with COXs active site with energy scores comparable to that of ibuprofen. All compounds showed a safer profile on the stomach tissue integrity compared to conventional NSAIDs. The designed strategy was applied to ibuprofen to introduce ibuprofen/oxadiazole/NO hybrid. The synthesized ibuprofen hybrid is a promising alternative to ibuprofen having similar anti-inflammatory activity but with safer GIT profile.     

Synthesis and biological evaluation of 2,5-disubstituted 1,3,4-oxadiazole derivatives with both COX and LOX inhibitory activity

Dual cyclooxygenase/lipoxygenase (COX/LOX) inhibitors constitute a valuable alternative to classical nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors for the treatment of inflammatory diseases. A series of 3-(5-phenyl/phenylamino-[1,3,4]oxadiazol-2-yl)-chromen-2-one and N-[5-(2-oxo-2H-chromen-3-yl)-[1,3,4]oxadiazol-2-yl]-benzamide derivatives were synthesized and screened for anti-inflammatory, analgesic activity. All the derivatives prepared are active in inhibiting oedema induced by carrageenan. Compound 4e was found more potent with 89% of inhibition followed by compound 4b (86%). Compounds with >70% of anti-inflammatory activity were tested for analgesic, ulcerogenic, and lipid peroxidation profile. Selected compounds were also evaluated for inhibition of COXs (COX-1 and COX-2) and LOXs (LOX-5, LOX-12, and LOX-15). Compound 4e was comparatively selective for COX-2, LOX-5, and LOX-15. Study revealed that these derivatives were more effective than ibuprofen with reduced side effects. It can be suggested that these derivatives could be used to develop more potent and safer NSAIDs.     

Synthesis, docking studies and anti-inflammatory activity of 4,5,6,7-tetrahydro-2H-indazole derivatives

A regioselective synthesis of 2,3-disubstituted tetrahydro-2H-indazols, mediated by alpha-zirconium sulfophenylphosphonate-methanephosphonate, was reported. Docking studies into the catalytic site of COX-2 were used to identify potential anti-inflammatory lead compounds. Two lead derivatives were chosen endowed with good binding energies and good ADME profiling. The biological in vivo evaluation of these compounds in two different experimental models (Freund's adjuvant-induced arthritis and carrageenan-induced oedema) proved the presence of anti-inflammatory activity. Noteworthy, both compounds evidenced the lack of any gastric injury even at high doses in gastric ulcerogenic assays.     

Macrolactonolides: A novel class of anti-inflammatory compounds

A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17β-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.     

Synthesis,biological evaluation and molecular modeling study of pyrazole derivatives as selective COX-2 inhibitors and anti-inflammatory agents

A novel series of pyrazole derivatives were synthesized and evaluated in vivo for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Among all compounds, 5a, and 5b showed comparable anti-inflammatory activity to Nimesulide, the standard drug taken for the studies. In silico (docking) studies were carried out to investigate the theoretical binding mode of the compounds to target the cyclooxygenase (COX-2) using Autodock 4.2.     

Novel anti-inflammatory agents based on pyridazinone scaffold; design, synthesis and in vivo activity

Herein, we report the design, synthesis, and pharmacological properties of a series of arylethenylpyridazinones 3a-h and arylethylpyridazinone derivatives 3k-i from the corresponding aryloxohexenoic 1a-e and aryloxohexanoic acids 2a,d, respectively. The synthesized compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Compound 3j demonstrated the greatest in vivo activity with ED(50) equal to 17mumol compared with celecoxib with no ulceration on the gastric mucosa. Docking study of the synthesized compounds into the active site of COX-2 revealed a similar binding mode to RS-57067, a COX-2 inhibitor.     

Design,synthesis, evaluation,and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents

Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by ¹H NMR, ¹³C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100?mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC₅₀ >100?μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.     

New racemosol derivatives as potent cyclooxygenase (COX) inhibitors

Racemosol (1) and 10-O-demethylracemosol (2), natural products from Bauhinia malabarica Roxb., exhibit potent in vitro anti-inflammatory activities against cyclooxygenase-1 and -2 (COX-1 and -2) enzymes. To investigate the structure-activity relationship (SAR) of these molecules, we prepared and fully characterized 17 derivatives by functionalizing one, two, or all three OH group(s) of 2 (Scheme). Both the size and polarity of the substituents as well as the substitution pattern in compounds 3a-q were found to be critical for anti-inflammatory activity. The orientation of the drugs and their mode of binding were studied by molecular docking based on the known 3D structure of the complex between COX-2 and the drug SC-558. Whereas the monoacetoxy derivative 3h exhibited an equally potent inhibitory activity towards both COX-1 and -2 (Table 1), its diacetoxy congener 3i was slightly more selective toward COX-2. In vivo anti-inflammatory tests showed that 3i and 2 are slightly more active than the reference compound phenylbutazone (Table 2).     

Design, synthesis and biological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agents

The synthesis of novel series of structurally related 1H-pyrazolyl derivatives is described. All the newly synthesized compounds were tested for their in vivo anti-inflammatory activity by two different bioassays namely; cotton pellet-induced granuloma and sponge implantation model of inflammation in rats. In addition, COX-1 and COX-2 inhibitory activities, ulcerogenic effects and acute toxicity were determined. The same compounds were evaluated for their in vitro antimicrobial activity against Escherichia coli, as an example of Gram negative bacteria, Staphylococcus aureus as an example of Gram positive bacteria, and Candida albicans as a representative of fungi. The combined anti-inflammatory data from local and systemic in vivo animal models showed that compounds 4, 5, 8, 9, 11 and 12a exhibited anti-inflammatory activity comparable to that of indomethacin with no or minimal ulcerogenic effects and high safety margin (LD(50)>500 mg/Kg). In addition, compounds 4, 7, 10, 12a and 12b displayed appreciable antibacterial activities when compared with ampicillin, especially against S. aureus. Compounds 4 and 12a are the most distinctive derivatives identified in the present study because of their remarkable in vivo and in vitro anti-inflammatory potency and their pronounced antibacterial activities comparable to ampicillin against Gram positive. On the other hand, compound 12a exhibited good selective inhibitory activity against COX-2 enzyme. Therefore, such compound would represent a fruitful matrix for the development of anti-inflammatory-antimicrobial candidates.     

Synthesis and biological evaluation of imidazol-2-one and 2-cyanoiminoimidazole derivatives: novel series of PDE4 inhibitors

This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.     

Design,synthesis and pharmacological evaluation of novel azole derivatives of aryl acetic acid as anti-inflammatory and analgesic agents

A series of substituted azole derivatives (3a–e, 4a–e and 5a–e) were synthesised by the cyclisation of N¹(diphenylethanoyl)-N⁴-substituted phenyl thiosemicarbazides under various reaction conditions. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen, were screened for their analgesic, ulcerogenic and lipid peroxidation activities. The compounds 5-(diphenylmethyl)-N-(4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3b) and 5-(diphenylmethyl)-N-(3-chloro-4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3c) emerged as the most active compounds of the series, and were moderately more potent than the standard drug, ibuprofen. (This abstract was published in Inflammation Research, Supplement 2, Volume 56, page A101, 2008.)     

Synthesis, anti-inflammatory, analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(alpha-Carbomethoxy-beta-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 microg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC(50) value 31.59 microg/mL.     

Synthesis and pharmacological evaluation of 2,5-cycloamino-5H-[1]benzopyrano[4,3-d]pyrimidines endowed with in vitro antiplatelet activity

A series of new 2,5-cycloamino-5H-[1]benzopyrano[4,3-d]pyrimidines 3a-i have been synthesized and tested in vivo for the anti-inflammatory/analgesic/antipyretic effects and in vitro to evaluate the antiplatelet activity on guinea-pig platelet-rich plasma aggregated by collagen, adenosine-5'-diphosphate (ADP) and arachidonic acid (AA). Title compounds were ineffective in vivo; however, the pyrrolidino derivatives 3a and 3c exhibited an antiplatelet activity against all the aggregants differing from that of acetylsalicylic acid (ASA) while the 5-morpholino derivatives 3g-i showed the most potent ASA-like antiplatelet activity.