Synthesis,Characterization, and Anti‐inflammatory Activity of Novel Isoxazolyl‐4‐(2‐oxo‐2,3‐dihydro‐1H‐3‐indolyl)pyrrole‐3‐carboxylates

A series of novel isoxazolyl‐4‐(2‐oxo‐2,3‐dihydro‐1H‐3‐indolyl)pyrrole‐3‐carboxylates ( 17a – i) were synthesized by a three‐component reaction of 4‐amino‐3‐methyl‐5‐styrylisoxazole 14 , β‐keto ester 15 , and 3‐phenacylideneoxindole 16 , in the presence of CAN catalyst in ethanol. The structures of the synthesized compounds have been established on the basis of spectral and analytical data. The title compounds 17a – i were evaluated for their anti‐inflammatory activity. Compounds 17b and 17c exhibited potent anti‐inflammatory activity as that of standard drug.     

Synthesis and Biological Evaluation of 2‐substituted‐6‐(morpholinyl/piperidinyl)pyridazin‐3(2H)‐ones as Potent and Safer Anti‐inflammatory and Analgesic Agents

A series of 2‐substituted‐6‐(morpholinyl/piperidinyl)pyridazin‐3(2H )‐ones was synthesized and the structures were established using various spectroscopic techniques. The target compounds were screened for anti‐inflammatory and analgesic activities at 20 and 40 mg/kg. The safety of the synthesized derivatives was evaluated by assessing anti‐platelet activity and ulcer index. The obtained pharmacological data revealed that 6‐morpholinyl derivatives 4a–12a were found to be somewhat more potent than 6‐piperidinyl derivatives 4b–6b. The 6‐morpholinyl substituted pyridazinone 12a exhibited maximum anti‐inflammatory and analgesic activities. Homoveratrylamine substituted compounds 6a and 6b emerged as promising leads in both the series with good anti‐inflammatory and analgesic activities without any ulcerogenicity. Anti‐platelet activity results of the compounds of both the series showed significantly low bleeding time in comparison with standard drug aspirin indicating the cardiovascular safety of new pyridazinones.     

A Novel Procedure to Synthesize 3‐Chloro‐1‐(4a,10b‐diazaphenanthrene‐2‐yl)‐4‐phenyl Azetidin‐2‐ones and Exploration of Their Anti‐Inflammatory Activity

Some new derivatives of 3‐chloro‐1‐(4a,10b‐diazaphenanthrene‐2‐yl)‐4‐phenyl azetidin‐2‐one were synthesized through the reaction of N‐{4‐[phenyldiazenyl] phenyl}‐N‐[phenyl methylene] amine with 4‐[phenyldiazenyl] aniline. The resulting 3‐chloro‐4‐phenyl‐1‐{4‐[phenyldiazenyl] phenyl} azetidin‐2‐one intermediate in benzene was irradiated in a Pyrex vessel with 350 nm UV light in a photochemical reactor to give the desired derivatives (4a–j) . Structures of the new compounds were verified on the basis of spectral and elemental methods of analyses. Nine of the prepared compounds were tested for their anti‐inflammatory effects; most of these compounds showed potent and significant results compared with indomethacin.     

A new conjugated addition of trialkyl phosphites and alkylidenephosphoranes to 3‐ω‐azideoacetyl coumarin synthesis of some 1,2,3,4‐triazaphospholes,triazoles, and azido‐coumarin derivatives

A new and efficient conjugate addition of trimethyl and triethyl phosphites to 3‐ω‐azidoacetylcoumarin ( 1 ) has been studied. The reaction proceeded smoothly at r.t. furnishing 1,2,3,4‐triazaphosphole coumarin derivatives 4a , 4b in ～75% yields. Linear substituted triazoles 10b , 11a were also obtained from the reactions of 1 with α‐keto ylides, acetyl‐ and benzoylmethylene triphenylphosphoranes. Contrary to these results, Wittig reaction was occurred when 1 was allowed to react with α‐alkoxycarbonylmethylene‐ and cyanomethylenetriphenylphosphoranes 7c , 7d , 7e as well as with methylidene‐ and benzylidenetriphenylphosphoranes 8b , 10a resulting in the formation of the corresponding olefins either as an intermediate 14b or as final products 11b , 11c , 12a . J. Heterocyclic Chem., (2011).     

1,ω‐Bis(4‐amino‐1,2,4‐triazole‐5(1H)‐thion‐3‐ylsulfanyl)alkanes: Versatile precursors for novel bis(S‐triazolo[3,4‐b][1,3,4]thiadiazines) as well as novel bis(macrocyclic schiff bases)

Two synthetic routes were attempted for the synthesis of the novel bis(5,6‐dihydro‐S‐triazolo[3,4‐b]thiadiazines) 12a,b and 14 . In the first route the bis(aminotriazoles) 4a,b were reacted with the appropriate α‐haloketones or α‐haloesters to give the corresponding bis(S‐triazolo[3,4‐b]thiadiazines) 11a‐d followed by reduction with NaBH₄. In the second route, the bis(Schiff bases) 13d were reacted with the appropriate α‐haloesters in refluxing DMF containing TEA to give the target compound 14 . Cyclocondensation of 4a,b with the appropriate bis(carbonyl) ethers 15a,b in refluxing acetic acid under high dilution conditions afforded the corresponding macrocyclic Schiff bases 16a‐c . The latter underwent alkylation with the appropriate halo compounds to give the corresponding alkylated derivatives 17a‐d .     

Synthesis,Antioxidant, and Anti‐Inflammatory Evaluation of Novel Thiophene‐Fused Quinoline Based β‐Diketones and Derivatives

Novel thieno[2,3‐b ]quinoline‐2‐carboxylic acid derivatives including β‐diketone, pyrazole, and flavone were prepared under ultrasonication and evaluated for in vitro antioxidant and anti‐inflammatory activities. Antioxidant activity was determined by DPPH radical scavenging method and anti‐inflammatory activity by HRBC membrane stabilization method. Some of the Compounds showed good antioxidant activity, whereas, some of the compounds bearing pyrazole core showed good anti‐inflammatory activity. Further in silico physicochemical properties were also calculated for good oral drug bioavailability and drug likeness of synthesized compounds.     

Novel arylpyridine‐based 1,3,4‐oxadiazoles: Synthesis,antibacterial, and anti‐inflammatory evaluation

In view of developing novel bioactive compounds, a series of 2‐(5‐[2‐methyl‐6‐arylpyridin‐3‐yl]‐1,3,4‐oxadiazol‐2‐ylthio)‐1‐arylethanones (6a–n) were designed and synthesized in good yield. Novel compounds were evaluated for their antibacterial and anti‐inflammatory activities. All synthesized compounds were screened for their antibacterial activity against Staphylococcus aureus, Bascillus subtilis, Eschericia coli, and Pseudomonas aeruginosa strains. Compounds 6a , 6b , 6c , 6h , and 6i displayed the highest antibacterial activity with minimal inhibitory concentration (MIC) values ranging from 6.25–12.5 μg/mL in comparison with the standard Ciprofloxacin. The results of anti‐inflammatory activity of carrageenan‐induced footpad edema assay indicated that tested compounds exhibited remarkable anti‐inflammatory activity with percentage of inhibition of 63.9–70.1% (potency 96.8–106.20% of indomethacin activity) after 3 hr. Particularly, 6c – e and 6j – l were found to be excellent inhibitors of inflammation, with potential higher than that of the standard, Indomethacin.     

Synthesis,Characterization, and Biological Evaluation of Novel 3‐(4‐Chlorophenyl)‐2‐(substituted)quinazolin‐4(3H)‐one Derivatives as Multi‐target Anti‐inflammatory Agents

A novel class of 3‐(4‐chlorophenyl)‐2‐(substituted)quinazolin‐4(3H)‐one derivatives were synthesized, and the structure of synthesized compounds was characterized by IR, ¹H NMR, and mass spectroscopy. The newly synthesized compounds ( 4a–g and 6a–g ) were tested for their in vitro cyclooxygenase (COX) inhibition activity. The compounds have inhibitory profile against both COX‐1 and COX‐2, and some of the compounds are found to be selective against COX‐2. The compound 6g showed distinct inhibitory activity on COXs. The synthesized compounds were evaluated for their potential anti‐inflammatory activity as inhibitors of the proinflammatory cytokines IL‐6. Compounds 4d – g showed the highest level of inhibition among all the tested compounds. Thus, our data suggested that these compounds may represent a new class of potent anti‐inflammatory agents.     

Synthesis of New Fused Thienopyrimidines Derivatives as Anti‐inflammatory Agents

5‐Amino‐2‐(p‐tolylamino)‐4‐phenylthieno[2,3‐d]pyrimidine‐6‐carbonitrile 9 , which was synthesized by an innovative method, was used as a versatile precursor for synthesizing pyrimido‐thienopyrimidine, triazolopyrimidothienopyrimidine, and pyrimidothienotriazine compounds. Thus, reaction of aminothienopyrimidinecarbonitrile 9 with chloroacetylchloride in dioxane afforded the chloroacetylaminocarbonitrile derivative 10 , which underwent nucleophilic substitution reactions with various primary and secondary amines gave the corresponding N‐alkyl‐(aryl)amino acetamides 11a,b . On the other hand, the reaction of aminocarbonitrile 9 with triethyl orthoformate followed by cyclization with hydrazine yielded an aminoiminopyrimidine derivative 13 . The latter was used as versatile precursor for synthesis of new heterocyclic compounds. The structures of all the new compounds have been established on the basis of their analytical and spectral data (IR, ¹H NMR, ¹³C NMR, and MS). Some of the synthesized compounds were evaluated in vitro for their anti‐inflammatory activity. All the tested compounds exhibited remarkable anti‐inflammatory activity.     

The behavior of 2‐thioxo‐4‐thiazolidinones toward organophosphorus reagents

The reaction of 2‐thioxo‐4‐thiazolidinone ( 1a ) with phosphorus ylides 2a and 2b afforded compounds 5 and 6. On the other hand, formylmethylenetriphenylphosphorane (2c) reacts with 1a and its N‐methyl derivative 1b to give the new complicated phosphonium ylides 7a,b, respectively. Reactions of 1b with ylides 2a and 2d gave rise to the olefinic compound 8 and the new phosphorane product 9. Moreover, dialkyl phosphites 3a,b and trialkyl phosphites 4a–c react with 1a to give both the alkylated products 10a–c and the dimeric compounds 11,12. A mechanism is proposed to explain the formation of the new products.© 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 337–341, 1999     

Pyrido[1,2‐a]pyrimidin‐4‐ones: Ligand‐based Design,Synthesis, and Evaluation as an Anti‐inflammatory Agent

In the present study, a series of novel pyrido[1,2‐a]pyrimidin‐4‐one derivatives ( 1 – 45 ) were synthesized, characterized, and evaluated for their anti‐inflammatory activity. The structures of all newly synthesized compounds were confirmed by ¹H NMR, ¹³C NMR, mass spectroscopy, and C, H, and N analyses. Preliminary these newly synthesized compounds were evaluated for their in vitro cyclooxygenase (COX)‐2/COX‐1 inhibitory activity. The celecoxib, a COX‐2 inhibitor, was used as a reference standard drug. In this inhibitory study, compounds 42 , 43 , 44 , and 45 were found to have significant in vitro inhibitory profile as compared with the reference drug. These compounds were then subjected to their in vivo anti‐inflammatory assay by using carrageenan‐induced rat paw edema method in next level of screening. Later, these same compounds were tested for their ulcerogenic property. Based on these activity data, the compound 43 (in vitro COX‐2 activity—IC₅₀ = 0.4 μM, SI = 400, in vivo anti‐inflammatory activity—72% inhibition after 3 h, and 0.38%—Ulcer index) was emerged as most promising anti‐inflammatory agent with very low ulcerogenic action.     

An Organocatalyzed Efficient One‐pot Synthesis,Biological Evaluation,and Molecular Docking Studies of 4,4′‐(Arylmethylene)bis‐(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ols)

The synthesis of 4,4′‐(arylmethylene)bis‐(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ol) derivatives catalyzed by ʟ‐proline is a simple, versatile, and efficient method. In vitro antioxidant, anti‐inflammatory, and antimicrobial activities of compounds 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j were studied. Furthermore, to rationalize the observed anti‐inflammatory activity data, molecular docking study has been performed against COX‐2 enzyme which revealed a good binding affinity for these molecules and could provide an insight into the various bonded and non‐bonded interactions guiding their binding affinity.     

Novel 1,3,4‐Oxadiazole Derivatives of Dihydropyrimidinones: Synthesis,Anti‐Inflammatory,Anthelmintic, and Antibacterial Activity Evaluation

The present study depicts synthesis of a series of some novel 5‐(5‐(aryl)‐1,3,4‐oxadiazol‐2‐yl)‐3,4‐dihydro‐6‐methyl‐4‐styrylpyrimidin‐2(1H)‐one derivatives. All the newly synthesized compounds were characterized by FTIR, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. The compounds were evaluated for their in vivo anti‐inflammatory activity by the carrageenan‐induced rat paw edema method. The compounds were also screened for their anthelmintic activity on Indian earthworms and antibacterial activity against some gram positive and gram negative strains of bacteria. This pharmacological activity evaluation revealed that, among all the compounds screened, compounds 4b and 4c were found to have promising anti‐inflammatory activity. Interestingly, compounds 4b , 4c , and 4i exhibited appreciable anthelmintic property, while compounds 4c , 4g , and 4h showed leading antibacterial activity against the selected pathogenic strains of bacteria.     

The behavior of 2‐substituted‐1,3‐diphenylpropane‐1,3‐tione toward organophosphorus reagents

The reaction of 2‐benzylidene‐1,3‐diphenylpropanetrione ( 1a ) with phosphorus ylides 2a–c afforded the new phosphonium ylides 4a–c . Trialkyl phosphites 3a–c react with 1a to give the respective dialkyl phosphonate products 5a–c . On the other hand, the olefinic compounds 6 and 7 were isolated from the reaction of 1b with Wittig reagents 2 . Moreover, trialkyl phosphites reacted with 1b to give products 8a–c . Possible reaction mechanisms are considered, and the structural assignments are based on analytical and spectroscopic evidence. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:57–64, 2000     

Synthesis of Some New Spiro,Isolated and Fused Heterocycles Based on 1H‐indole‐2‐One

The reaction of 3‐benzoylcyanomethylidine‐1(H)‐indole‐2‐one ( 1 ) with a variety of active methylene compounds, thioglycolic acid, glycine, hydrazine hydrate and phenyl hydrazine led to the formation of compounds 4a‐d‐10 . 3‐Thiosemicarbazide‐1(H)‐indole‐2‐one 2 on reaction with α‐halocarbonyl compounds gave compounds 11a‐c, 12a‐c . The latter compounds on heating with phosphoryl chloride, cyclization takes place via losing water to give the angular tetracyclic compounds 13a,b and 14a‐c . Cyanoacetic hydrazone derivative 3 readily cyclized upon heating in triethyl orthoformate to give the tricyclic system, oxopyridazino indole 15 . On the other hand, the reaction of 3 with benzylidine malononitrile and benzylidene ethylcyanoactate gave the pyranyl hydrazone derivatives 16a,b .     

Microwave‐assisted Synthesis of Novel 3,4‐Bis‐chalcone‐N‐arylpyrazoles and Their Anti‐inflammatory Activity

A series of 3,4‐bis‐chalcone‐N‐arylpyrazoles 3a‐h was prepared conveniently from diacetyl pyrazoles 2a,b . All reactions were carried out under conventional thermal heating and/or microwave irradiation. The structure of the latter functionally pyrazoles was confirmed under the bases of their IR, mass, ¹H NMR and ¹³C NMR. The X‐ray diffraction of compound 3e not only confirmed the chemical structure of 3a‐h , but also showed the E configuration of their chalcone moieties. Treatment of compound 3e with phenyl hydrazine in presence of acetic acid afforded the tri‐pyrazle 4 . The anti‐inflammatory activity of the newly synthesized compounds was investigated. Some of these compounds showed a moderate activity when compared with indomethacin as a reference drug. The combination between chalcone and pyrazole moieties revealed a variable effect in anti‐inflammatory activity.     

Synthesis and Molecular Docking Studies of Novel 2‐Phenyl‐4‐Substituted Oxazole Derivatives as Potential Anti‐cancer Agents

A novel series of 2,4‐disubstituted oxazole derivatives were synthesized, screened for their anti‐tumor activity against three cell lines MCF‐ 7 , TK‐10, and UACC‐62. Molecular docking study was carried out against epidermal growth factor receptor. A new series of 2‐phenyl‐4‐substituted oxazole derivatives were synthesized. A series of chiral α‐amino acid derivatives 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 were synthesized by coupling various l ‐acylated amino acid azide 3. The synthesized compounds were tested for their in vitro antitumor activity against MCF‐7, TK‐10, and UACC‐62 cell lines. Compound 6 exhibited the strongest inhibitory activity against TK cell lines, while compound 12 showed the highest activity against MCF‐7 cell lines. Compound 14 was the most active against UACC‐62 cell lines. Furthermore, a molecular docking study of the most active compounds was carried out using epidermal growth factor receptor X‐ray 3D structure (protein data bank ID 1 M17). Docking results revealed that compound 6 showed the highest binding energy of ΔG = ?78.17 Kcal/mol.     

Isolation,Structural Characterization,and Validation of a New Compound Present in Non‐Carbonyl Curcuma longa (NCCL): A Potential Lead for Stroke

The hexane soluble extract of Curcuma longa (Turmeric) [herbal medicament (HM)] developed by Central Drug Research Institute, India, as a new antistroke agent. It contains carbonyl as well as non‐carbonyl compounds. To see the activity of non‐carbonyl compounds, HM was reacted with semicarbazide hydrochloride to remove the carbonyl compounds. This chemically modified fraction [non‐carbonyl Curcuma longa (NCCL)] of HM was found to be active at lower dose than HM against endothelial mediated inflammation in myocardial ischemia/reperfusion induced rats. It reduced significantly the serum CK‐MB levels, inflammatory cytokine mediators (TNF‐α, IL‐6, IFN‐γ), plasma endothelial microparticle level and also found useful in improving the endothelial functionality. It was also found active in anti‐inflammatory and cytotoxic activity for sepsis and leukemia. To find out the compounds that are responsible for its enhanced activity in comparison of HM, we have isolated two major peaks present in the high‐performance liquid chromatography (HPLC) fingerprint of NCCL and their structures were characterized. Based on the characterization, we found that these compounds are not the non‐carbonyl compounds present in HM but the new cyclic structures formed by the reaction of ar‐turmerone, α‐turmerone, and β‐turmerone with semicarbazide hydrochloride used in the reaction. This hypothesis was validated by isolation of ar‐turmerone, α‐turmerone, and β‐turmerone from HM and reacting them with semicarbazide hydrochloride using the same reaction conditions of NCCL formation. The same mass spectral data and same retention time (RT) value in high‐performance liquid chromatography analysis further confirms our hypothesis.     

SpinPhox/Iridium(I)‐Catalyzed Asymmetric Hydrogenation of Cyclic α‐Alkylidene Carbonyl Compounds

Optically active medium‐sized cyclic carbonyl compounds bearing an α‐chiral carbon center are of interest in pharmaceutical sciences and asymmetric synthesis. Herein, SpinPhox/Ir^I catalysts have been demonstrated to be highly enantioselective in the asymmetric hydrogenation of the CC bonds in the exocyclic α,β‐unsaturated cyclic carbonyls, including a broad range of α‐alkylidene lactams, unsaturated cyclic ketones, and lactones. It is noteworthy that the procedure can be successfully used in the asymmetric hydrogenation of the challenging α‐alkylidenelactam substrates with six‐ or seven‐membered rings, thus affording the corresponding optically active carbonyl compounds with an α‐chiral carbon center in generally excellent enantiomeric excesses (up to 98 % ee). Synthetic utility of the protocol has also been demonstrated in the asymmetric synthesis of the anti‐inflammatory drug loxoprofen and its analogue, as well as biologically important ε‐aminocaproic acid derivatives.     

Synthesis,X‐ray crystal structure and biological activities of α‐phenoxyl‐1,2,3‐thiadiazoleacetamide

The annelation of 1,2,3‐thiadiazole rings was accomplished by the reaction of N‐acylhydrazone 2a bearing an adjacent α‐methyl with thionyl chloride to give α‐chloro‐N‐methyl‐1,2,3‐thiadiazole‐4‐acetamide 4 and was demonstrated by the X‐ray crystal structure of its derivative 5a. A novel series of α‐substituted phenoxy‐N‐methyl‐1,2,3‐thiadiazole‐4‐acetamide 5 were synthesized through the reaction of the compound 4 and phenols. The results of bioassays show that the title compounds exhibit good anti‐HBV activities. The crystal of compound 5a , N‐methyl‐α‐2‐bromophenyl‐1,2,3‐thiadiazole‐4‐acetamide, has been prepared and determined by X‐ray diffraction.