Antifungal and anthelmintic activity of novel benzofuran derivatives containing thiazolo benzimidazole nucleus: an in vitro evaluation

A novel series of thiazolo[3,2-a]benzimidazole derivatives containing benzofuran nucleus (5a–l) have been synthesized. The key intermediate, substituted benzimidazol-sulfanyl benzofuran ethanone (3a–d) was prepared by refluxing the mixture of substituted 2-acetyl benzofuran and substituted 2-mercaptobenzimidazole in acetic acid. The cyclisation of compounds (3a–d) using polyphosphoric acid furnished the corresponding 6-substituted benzofuran thiazolo[3,2-a]benzimidazoles (4a–d). Further, the cyclized compounds (4a–d) were subjected for Mannich reaction to give corresponding Mannich bases (5a–l). All newly synthesized compounds were screened for antifungal and anthelmintic activity. Amongst the tested compounds, 4b and 4d exhibited potential antifungal activity. From the anthelmintic activity data, it was found that the compounds 3a, 3b and 5i were found to be more effective against the tested earthworm Pheretima posthuma. In correlation to anthelmintic activity, the selected compounds were subjected for molecular docking studies and the compounds 3a and 5i have emerged as active anthelmintic agents with maximum binding affinity (?3.7 and ?5.4 kcal/mol).     

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.     

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 hybrid molecules combining benzothiophene or benzofuran with rhodanine as dual COX-1/2 and 5-LOX inhibitors: Synthesis,biological evaluation and docking study

New molecular hybrids combining benzothiophene or its bioisostere benzofuran with rhodanine were synthesized as potential dual COX-2/5-LOX inhibitors. The benzothiophene or benzofuran scaffold was linked at position -2 with rhodanine which was further linked to various anti-inflammatory pharmacophores so as to investigate the effect of such molecular variation on the anti-inflammatory activity. The target compounds were evaluated for their in vitro COX/LOX inhibitory activity. The results revealed that, compound 5h exhibited significant COX-2 inhibition higher than celecoxib. Furthermore, compounds 5a, 5f and 5i showed COX-2 inhibitory activity comparable to celecoxib. Compound 5h showed selectivity index SI = 5.1 which was near to that of celecoxib (SI = 6.7). Compound 5h displayed LOX inhibitory activity twice than that of meclofenamate sodium. Moreover, compounds 5a, 5e and 5f showed significant LOX inhibitory activity higher than that of meclofenamate sodium. Compound 5h was screened for its in vivo anti-inflammatory activity using formalin-induced paw edema and gastric ulcerogenic activity tests. The results revealed that, it showed in vivo decrease in formalin-induced paw edema volume higher than celecoxib. It also displayed gastrointestinal safety profile as celecoxib. The biological results were also consistent with the docking studies at the active sites of the target enzymes COX-2 and 5-LOX. Also, compound 5h showed physicochemical, ADMET, and drug-like properties within those considered adequate for a drug candidate.     

Synthesis and biological evaluation of novel angularly fused polycyclic coumarins

In a three-step sequence, an array of angularly fused polycyclic heterocycles with coumarin, benzofuran and pyridine rings were synthesized from 4-bromomethylcoumarins and salicylonitrile. All the final compounds were fully characterized and screened for anti-microbial, anti-inflammatory and analgesic activities. Several compounds exhibited promising inflammation inhibiting and anti-microbial properties.     

Synthesis,discovery and preliminary SAR study of benzofuran derivatives as angiogenesis inhibitors

A series of benzofuran derivatives were synthesized and evaluated against HUVEC proliferation. Among these compounds, compound 32 exhibited good inhibitory activity and remarkable selectivity to HUVEC. Our current data suggested that array order of methyl, acrylate and carboxylate groups in benzofuran scaffold is the basic requirement for inhibitory activity against HUVEC proliferation. These results demonstrated that benzofuran scaffold represents a promising structural core to discover a new class of active and selective angiogenesis inhibitors.     

Synthesis, hydrolysis studies and phamacodynamic profiles of amide prodrugs of dexibuprofen with amino acids

The present investigation deals with the synthesis of novel prodrugs of dexibuprofen with amino acids with an aim to achieve potent anti-inflammatory activity and less gastrointestinal toxicity. Structures of synthesized compounds were confirmed by spectral and elemental analyses. In vitro hydrolytic studies in simulated intestinal fluid, 80% plasma and rat faecal matter showed satisfactory release of dexibuprofen due to enzymatic cleavage. The synthesized prodrugs were evaluated for anti-inflammatory activity, analgesia, ulcerogenicity and histopathology. The anti-inflammatory activity of dexibuprofen was 43.3% whereas an improved value of 73.4, 77.3, 72.8 and 64.5% was observed for the synthesized prodrugs. The percentage analgesia of the prodrugs increased, whereas a decrease in the mean ulcer index values than dexibuprofen was observed. The histopathological studies revealed less ulceration in the gastric region when treated with prodrugs. Thus, the prodrugs were proved to be better in action as compared with the parent drug.     

Design, synthesis, and SAR studies of some 5-aliphatic oximino esters of thiophene as potential anti-inflammatory leads: comparative biological activity profile of aliphatic oximes vs aromatic oximes

A series of novel tetra substituted thiophenes were synthesized, characterized, and evaluated for their anti-inflammatory activity in carrageenin induced rat paw edema model-an acute in vivo model. Compounds V1, V3, V11, V12, V17, and V18 showed good anti-inflammatory activity, indicating the importance of oxime moiety in modulating the activity. The structure-activity relationship studies explore "the aliphatic oxime esters" attached via a ketone bridge to fifth position of the thiophene, and indicate that this feature may enhance the anti-inflammatory activity as compared to aromatic oximes. Since free radicals are implicated in various inflammatory disorders, the free radical scavenging activity of some of the synthesized candidates was assessed using 1,1-diphenyl-2-picryl hydrazyl assay. The oxime containing analogs exhibited weak to moderate activity as free radical scavengers in DPPH assay. A plausible reasoning for its free radical scavenging ability is discussed. All the compounds were also screened in nitro blue tetrazolium model, to assess them as superoxide anion radical scavengers. A direct correlation between anti-inflammatory activity and free radical scavenging activity was not seen. The results disclose a new class of anti-inflammatory agents designed and synthesized for the first time wherein the utility of aliphatic oxime esters in modulating the anti-inflammatory activity profile is apparent. This will give us potential anti-inflammatory leads.     

Synthesis,hydrolysis studies and phamacodynamic profiles of amide prodrugs of dexibuprofen with amino acids

The present investigation deals with the synthesis of novel prodrugs of dexibuprofen with amino acids with an aim to achieve potent anti-inflammatory activity and less gastrointestinal toxicity. Structures of synthesized compounds were confirmed by spectral and elemental analyses. In vitro hydrolytic studies in simulated intestinal fluid, 80% plasma and rat faecal matter showed satisfactory release of dexibuprofen due to enzymatic cleavage. The synthesized prodrugs were evaluated for anti-inflammatory activity, analgesia, ulcerogenicity and histopathology. The anti-inflammatory activity of dexibuprofen was 43.3% whereas an improved value of 73.4, 77.3, 72.8 and 64.5% was observed for the synthesized prodrugs. The percentage analgesia of the prodrugs increased, whereas a decrease in the mean ulcer index values than dexibuprofen was observed. The histopathological studies revealed less ulceration in the gastric region when treated with prodrugs. Thus, the prodrugs were proved to be better in action as compared with the parent drug.     

Design,synthesis and biological evaluation of vortioxetine derivatives as new COX-1/2 inhibitors in human monocytes

In order to identify a suitable alternative to non-steroidal anti-inflammatory drugs (NSAIDs) we aimed to develop derivatives of vortioxetine, a multimodal anti-depressive drug that has been shownpreviously to be endowed withanti-inflammatory activity in human monocytes/macrophages. Vortioxetine (1) was synthesized in good yield and different alkyl and aryl derivatives were prepared based on their structural diversity and easy availability. The compounds were tested on human monocytes isolated from healthy donors for theireffect on superoxide anion production and cytokine gene expression, and for COX-1/2 gene expression and activity modulation. Moreover, a docking study was performed to predict the interactions between the synthesized compounds and COX-1 and COX-2. Correlating experimental biological data to the molecular modelling studies, it emerged that among the novel compounds, 6 was endowed of antioxidant and anti-COX-1 activity, vortioxetine and 3 were good antioxidants and mild anti-COX-1/2 inhibitors, while 7 was a good anti-COX-1/2 inhibitor and 11 was more specific versus COX-2.     

Design, synthesis and evaluation of antiinflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives

Diclofenac sodium is being used for its anti-inflammatory actions since 28 years, but as all the NSAIDs are suffering from the deadlier GI toxicities, diclofenac sodium is also not an exception to these toxicities. The free -COOH group is thought to be responsible for the GI toxicity associated with all traditional NSAIDs. In the present research work, the main motto was to develop new chemical entities as potential anti-inflammatory agents with no GI toxicities. In this paper, the results of synthesis and pharmacological screening of a series of S-substituted phenacyl 1,3,4-oxadiazoles and Schiff bases derived from 2-[(2,6-dichloroanilino) phenyl] acetic acid (diclofenac acid) are described. The 1,3,4-oxadiazoles and diclofenac moieties are important because of their versatile biological actions. In the present studies, the oxadiazole system has been functionalized onto the diclofenac acid moiety and 18 compounds in this series were synthesized. The structures of new compounds are characterized by TLC, FTIR, 1H NMR and Mass spectral data. These compounds were tested in vivo for their anti-inflammatory activity. The compounds, which showed significant activity (comparable to the standard drug diclofenac sodium), were screened for their analgesic activity and to check their ability to induce ulcers by ulcerogenicity and histopathology studies. Eight new compounds, out of 18, were found to have significant anti-inflammatory activity in the carrageenan induced rat paw oedema model, with significant analgesic activity in the acetic acid induced writhing model with no ulcerogenicity. The compounds, which showed negligible ulcerogenic action, also showed promising results in histopathology studies, that is, they were found to be causing no mucosal injury.     

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.     

Synthesis,molecular docking and anti-inflammatory screening of novel quinoline incorporated pyrazole derivatives using the Pfitzinger reaction II

In continuation of our study of novel quinolines with anti-inflammatory activity using the Pfitzinger reaction, several new quinoline derivatives were synthesized and tested for their anti-inflammatory and ulcerogenic effect. A docking study on the COX-2 binding pocket was carried out for the target compounds to rationalize the possible selectivity of them against COX-2 enzyme. The most active compounds (5a, 8a and 11a) were found to be superior to celecoxib. Compound 11a demonstrated the highest anti-inflammatory activity as well as the best binding profiles into the COX-2 binding site. Moreover, compounds 9c, 9e, 10a and 11a were devoid of ulcerogenic activity.     

Synthesis of modified steroids as a novel class of non-ulcerogenic, anti-inflammatory and anti-nociceptive agents

The identification of compounds able to treat both pain and inflammation with limited side effects is one of the prominent goals in biomedical research. This study aimed at the synthesis of new modified steroids with structures justifying non-ulcerogenic, anti-inflammatory and anti-nociceptive activities. The steroid derivatives were synthesized via straightforward and efficient methods and their structures were established based on the analytical and spectral data. The in vivo anti-inflammatory, anti-nociceptive and anti-ulcerogenic activities of some of these compounds were studied. The newly synthesized compounds 8b, 19b, 24 and 31a showed anti-inflammatory, anti-nociceptive and anti-ulcerogenic activity with various intensities. Oedema was significantly reduced by either dose 25 or 50 mg/kg of all tested compounds at 3 and 4 h post-carrageenan. Compound 19b was the most effective in alleviating thermal pain. The analgesic activity of either dose of the compounds 8b, 24, 31a as well as the high dose 19b was significantly higher than that for indomethacin (IND). Gastric mucosal lesions caused in the rats by the administration of 96% EtOH and IND were inhibited by all tested compounds administered at (50 mg/kg) dose in the study.     

Design,synthesis of celecoxib-tolmetin drug hybrids as selective and potent COX-2 inhibitors

Three novel series of diarylpyrazole 10b-d and triarylpyrazole derivatives 11a-d &12a-d were synthesized through Vilsmier-Haack condition. The structures of prepared compounds were determined through IR, ¹H NMR, ¹³C NMR, Mass spectral and elemental analysis. Docking of the synthesized compounds over COX-2 active site ensure their selectivity. Moreover, the target compounds were evaluated for both in vitro and in vivo inhibitory activity. All compounds were more selective for COX-2 isozyme than COX-1 isozyme and with excellent anti-inflammatory activity. Compounds 11b, 11d and 12b showed the highest anti-inflammatory activity (67.4%, 62.7%, 61.4% respectively), lower ulcerogenic liability (UI = 2.00, 2.75, 3.25 respectively) than indomethacin (UI = 14) and comparable to celecoxib (UI = 1.75) which were confirmed from the histopatholgical study.     

New 1,3,4-oxadiazole/oxime hybrids: Design,synthesis, anti-inflammatory,COX inhibitory activities and ulcerogenic liability

A series of new 1,3,4-oxadiazole/oxime hybrids were synthesized and designed as potent COX inhibitors. The prepared compounds were evaluated for their anti-inflammatory, antioxidant and ulcerogenic activities. The results indicated that the prepared compounds exhibited remarkable anti-inflammatory activity with (69.60–109.60% of indomethacin activity) after 4 h. In vitro COX inhibitory assay showed that compounds 6d and 7h are potent COX inhibitors with IC₅₀ of (1.10–0.94) and (2.30–5.00) µM on both COX-1 and COX-2 respectively. Compound 7h was found to inhibit both COXs non-competitively with K_i values of 73 µM and 89 µM. Most of the tested compounds showed ulcer-free stomachs compared to indomethacin.     

Comparative analysis of stilbene and benzofuran neolignan derivatives as acetylcholinesterase inhibitors with neuroprotective and anti-inflammatory activities

Stilbenes and benzofuran neolignans are important groups of plant phenolics therefore they play a significant role in plants and human health. The objective of this study was to investigate the structure-activity relationships of naturally occurring stilbene and benzofuran neolignan derivatives as acetylcholinesterase inhibitors. A series of these compounds were prepared and assessed for their inhibition on acetylcholinesterase activity. δ-Viniferin, pterostilbene trans-dehydrodimer, pallidol, grossamide, and boehmenan exerted acetylcholinesterase inhibitory potential. The several oligomeric compounds protected against cell damage resulting from t-BHP exposure and inhibited lipopolysaccharide/interferon-gamma (LPS/IFNγ)-induced NO production in vitro. Our findings highlight the great potential of pterostilbene trans-dehydrodimer, pallidol, and boehmenan as multifunctional nutraceuticals for management of neurodegenerative diseases.     

Design and synthesis of 3-pyrazolyl-thiophene, thieno[2,3-d]pyrimidines as new bioactive and pharmacological activities

Two series of 5-ethyl-2-amino-3-pyrazolyl-4-methylthiophenecarboxylate and 2-thioxo-N(3)-aminothieno[2,3-d]pyrimidines were prepared from 3,5-diethyl-2-amino-4-methylthio-phenecaboxylate and evaluated as anti-inflammatory, analgesic and ulcerogenic activities. Among the compounds studied, compounds which containing the substituted hydrazide at C-3 position 7, 16, and 17a showed more potent anti-inflammatory and analgesic activities than the standard drug (Indomethacin and Aspirin), along without ulcerogenity. While compounds 2, 5, 9, 10, and 11c showed moderate activities. Some of the newly synthesized compounds have good to excellent antimicrobial activity.     

5-Thioxoimidazolidine-2-one derivatives: Synthesis,anti-inflammatory activity,analgesic activity,COX inhibition assay and molecular modelling study

A series of 5-imino-4-thioxo-2-imidazolidinone derivatives with different substituents at N¹ and N³ was synthesized with high yield and excellent purity by the reaction of different N-arylcyanothioformamide derivatives with isocyanate derivatives. Treatment 5-imino-4-thioxo-2-imidazolidinone derivatives with acidic medium afforded 4-thioxoimidazolidin-2,5-dione derivatives. The structures of the obtained products were established based on spectroscopic IR, ¹H NMR, ¹³C NMR, ¹H, ¹H-COSY, HSQC and elemental analyses. The anti-inflammatory activity of the synthesized compounds through the carrageenan-paw edema model as well as in vitro COX-1 and COX-2 inhibition assay were evaluated where most of the synthesized compounds showed significant anti-inflammatory activity. Mostly, all of our synthesized compounds have greater activity more than celecoxib toward both cyclooxygenase enzymes. All of the tested compounds (except one compound) exhibited IC₅₀ valves for COX-2 ranged from 0.001 × 10⁻³ to 0.827 × 10⁻³ µM while the reference drug has IC₅₀ 40.0 × 10⁻³ µM. Furthermore, the analgesic activity of such compounds was also determined. Molecular modeling study was also conducted to rationalize the potential as anti-inflammatory agents of our synthesized compounds by predicting their binding modes, binding affinities and optimal orientation at the active site of the COX enzymes.     

Synthesis and highly potent anti-inflammatory activity of licofelone- and ketorolac-based 1-arylpyrrolizin-3-ones

Since NSAIDs are commonly used anti-inflammatory agents that produce adverse effects, there have been ongoing efforts to develop more effective and less toxic compounds. Based on the structure of the anti-inflammatory pyrrolizines licofelone and ketorolac, a series of 1-arylpyrrolizin-3-ones was synthesized. Also prepared was a series of substituted pyrroles, mimicking similar known anti-inflammatory agents. The anti-inflammatory activity of the test compounds was determined with a phorbol ester (TPA)-induced murine ear edema protocol. For the most active derivatives, 19b–c/20b–c, the anti-inflammatory effect was the same as that of the reference compound (indomethacin) and was dose-dependent. These compounds have an aryl ring at the C-1 position and a methoxycarbonyl group at the C-2 position of the pyrrolizine framework, which represent plausible pharmacophore groups with anti-inflammatory activity. The anti-inflammatory activity of 1-substituted analogs containing a five- or six-membered heterocycles was lower but still good, while that of the pyrroles was only moderate. Although the docking studies suggests that the effect of analogs 19a–c/20a–c is associated with the inhibition of cyclooxygenase-2, experimental assays did not corroborate this idea. Indeed, a significant inhibition of NO was found experimentally as a plausible mechanism of action.