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.     

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.     

4‐Hydroxy‐3‐carboxycoumarin as an efficient building block for new ruthenium(II) complexes: synthesis,characterization, antibacterial,antioxidant and anti‐inflammatory activities

A new 4‐hydroxy‐3‐carboxycoumarin ligand and its ruthenium(II) complexes ( 1 – 5 ) have been synthesized, characterized and screened for their in vitro antibacterial activity against a range of Gram‐positive and Gram‐negative bacteria. In addition, compounds 1 – 5 were investigated for antioxidant activities using superoxide radical, 2,2‐diphenyl‐1‐picrylhydrazyl radical and hydroxyl radical scavenging assays, in which most of them displayed significant antioxidant activities. Furthermore, compounds 1 – 5 were evaluated for anti‐inflammatory activity using indirect haemolytic and lipoxygenase inhibition assays and revealed good activity. The new complexes were characterized using spectroscopic methods in addition to elemental analysis.     

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.     

Novel Approach for Rapid and Efficient Synthesis of 2‐(3‐(4‐Aryl)‐1‐isonicotinoyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl)‐3‐phenylthiazolidin‐4‐one Derivatives and Screened Their Antimicrobial Activity

A series of compounds, viz. 2‐(3‐(4‐aryl)‐1‐isonicotinoyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl)‐3‐phenylthiazolidin‐4‐one 4 ( a – n ), have been synthesized by reaction of 3 ( a – n ) with thioglycolic acid in the presence of zinc chloride. Compounds 3 ( a – n ) have been synthesized by amination of formylated pyrazoles 2 ( A – B ), which were synthesized by formylation of 1 ( A – B ) by Vilsmeier–Haack reagent (POCl₃/DMF). Compounds 1 ( A – B ) were synthesized by condensation of hydrazide and substituted acetophenones under conventional method and microwave irradiation method. These compounds were identified on the basis of melting point range, Rf values, infrared, ¹H NMR, and mass spectral analysis. These compounds were evaluated for their in vitro antimicrobial activity, and their minimum inhibitory concentration was determined. Among them, compound 4b and compound 4l possess appreciable antimicrobial and antifungal activities. Antibacterial activity results showed that compounds containing electron‐withdrawing groups were more active than compounds containing electron‐releasing groups.     

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.     

Synthesis and Pharmacological Evaluation of 3‐propyl‐2‐substitutedamino‐3H‐quinazolin‐4‐ones as Analgesic and Anti‐Inflammatory Agents

A variety of novel 3‐propyl‐2‐substitutedamino‐quinazolin‐4(3H)‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐propyl quinazolin‐4(3H)‐one with a variety of aldehydes and ketones. The starting material 2‐hydrazino‐3‐propyl quinazolin‐4(3H)‐one was synthesized from propylamine. The title compounds were investigated for analgesic and anti‐inflammatory activities. The compound 2‐(1‐ethylpropylidene‐hydrazino)‐3‐propyl‐quinazolin‐4(3H)‐one ( SR2 ) emerged as the most active compound of the series, and it is more potent in its analgesic and anti‐inflammatory activities when compared with the reference standard diclofenac sodium.     

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.     

Synthesis,Characterization and Biological Evaluation of a Novel Series of 1,2,4‐Triazolo‐[3,4‐b]‐1,3,4‐thiadiazines Containing an Amide Linkage

Two series of combinatorial library of 3,6‐disubstituted‐7H‐1,2,4‐triazolo‐[3,4‐b]‐1,3,4‐thiadiazines bearing an amide linkage were synthesized. All the newly synthesized compounds were characterized by spectral analyses. The newly synthesized compounds were screened for their cytotoxicity, anti‐inflammatory, and analgesic activities. Among the tested compounds, the compound 9g (Ar = 4‐(methoxybenzyl)piperazine) is the most promising molecule with half maximal inhibitory concentration (IC₅₀) value of 14.24 μM in (MCF‐7) cells. Compounds 9f (Ar = 4‐(chlorobenzyl)piperazine), 9g , and 9k (Ar = 2‐(fluorophenyl)piperazine) exhibited excellent anti‐inflammatory activity at a dose level of 50 mg/kg, almost comparable with the standard drug. In case of analgesic activity among the tested compounds, the compounds 9f , 9g , and 9k showed more potent and consistent activity in both 100 and 200 mg/kg/po doses with less ulcerogenic risk.     

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.     

Synthesis of Novel 1‐(5‐(Benzylsulfinyl)‐3‐methyl‐1,3,4‐thiadiazol‐2(3H)‐ylidene)‐thiourea/urea Derivatives and Evaluation of Their Antimicrobial Activities

A new series of 1‐(5‐(benzylsulfinyl)‐3‐methyl‐1,3,4‐thiadiazol‐2(3H)‐ylidene)‐thiourea/urea derivatives ( 1a – j ) were designed and synthesized. For the first time, (i) a new process was developed for N‐methylation of 1,3,4‐thiadiazole moiety using dimethyl carbonate an environmentally benign reagent in presence of N,N,N′,N′‐tetramethylethylenediamine and (ii) the sulfide was selectively oxidized to sulfoxide in higher yield by using chlorine (g) in aqueous acetic acid media under mild reaction condition. The synthesized compounds ( 1a – j ) were investigated for their antimicrobial activities. The tested compounds ( 1a – j ) were exhibited moderate to excellent antibacterial activities against both Gram‐positive and Gram‐negative bacterial strains. The same compounds exhibited good antifungal activities against selected fungal strains. Particularly, the compounds 1b , 1d , 1h , and 1i were proved to be promising leads exhibiting both antibacterial and antifungal activities compared with standard drugs, ciprofloxacin, and fluconazole. The presence of 1,3,4‐thiadiazole moiety has a significant role in the display of antimicrobial activity. In addition, the presence of both sulfinyl and thiourea or urea functionalities has enhanced the activity as per obtained antimicrobial activity data.     

Synthesis of Bis‐acridine Derivatives Exhibiting Anticancer and Anti‐inflammatory Activity

A series of bis‐acridine derivatives 3a – j and 5a – j have been synthesized by condensation of 9‐chloro‐2,4‐(un)substituted acridines (1a – e) and 9‐isothiocyanato‐2,4‐(un)substituted acridines (4a – e) with diamine 2a and 2b , respectively. These bis‐acridines were evaluated in vitro for activity against a panel of human cancer cell lines of lung (NCI H‐522), ovary (PA1), breast (T47D), colon (HCT‐15), and liver (HepG2). Several bis‐acridines were found to possess good anticancer activity against various cancer cell lines. Of these, compound 3h exhibited good anticancer activity against all cancer cell lines tested except liver (HepG2) cell line. In addition to this, these compounds were screened for anti‐inflammatory activity at a dose of 50 mg/kg p.o. Compound 3g exhibited 41% anti‐inflammatory activity, which is better than most commonly used standard drug ibuprofen, which showed 39% anti‐inflammatory (at 50 mg/kg p. o.) activity.     

Synthesis of Novel 4‐Substituted Coumarins,Docking Studies,and DHODH Inhibitory Activity

Coumarins are the important class of naturally occurring heterocyclic compounds. Activities like antioxidant, antibacterial, anti‐inflammatory, and anticancer have been reported for coumarin derivatives. Present work details the synthesis of substituted coumarin‐4‐pyrrolones as well as coumarin‐4‐acetyl amino acids and their DHODH inhibitory activity, which is a dual target for malaria and cancer. Coumarin‐4‐acetic acids ( 2a – c ) were coupled with different methyl esters of α‐amino acids ( 3 ) giving rise to corresponding coumarin‐4‐acetyl amino acid methyl esters ( 4a – o ), which on hydrolysis under basic condition underwent cyclization forming substituted dihydropyrrole‐2‐ones ( 5a – i ), dihydroindolizine‐3‐ones ( 5j – l ), and dihydropyrrolizin‐3‐one ( 5m – o ). Acidic hydrolysis of the compounds ( 4a – o ) yielded corresponding coumarin‐4‐acetyl amino acids ( 6a – f ). The docking study was performed with the protein 4IGH (obtained from PDB) using Surflex–Dock module. The newly synthesized compounds were tested for DHODH inhibitory activity using Brequinar as the standard. Compound 6b showed remarkable inhibition compared with the standard, and the other compounds with terminal COOH showed moderate inhibition.     

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.     

Synthesis,Characterization, and Screening for Anti‐inflammatory and Antimicrobial Activity of Novel Indolyl Chalcone Derivatives

Because of the great biological importance of substituted indole derivatives, in the present study, a series of pyrazolylindole, thiazolylindole, and pyrimidinylindole derivatives have been synthesized with good yield. The precursor indolyl chalcone 2a – d was prepared by reaction of 3‐chloro‐1H‐indole‐2‐carbaldehyde 1 with different ketones. Then, compounds 3b – d , 4 , and 5a – d have been synthesized by the reaction of chalcones 2a – d with hydrazine, phenylhydrazine, and thiosemicarbazide. When the chalcone derivative 2b subjected to react with hydroxylamine hydrochloride gave isoxazolylindole derivative 6b . N‐thiazolidine pyrazolyl indole 7 was obtained by reacting compound 5a with ethyl chloroacetate. On the other hand, when chalcone derivative 2b allowed to react with urea and thiourea gave the corresponding pyrimidinylindole derivatives 8 and 9 . Finally, when chalcone derivative 2b reacted with ethyl cyanoacetate or malononitrile gave pyridinylindole derivatives 10 and 11 . The structures of the all synthesized compounds were elucidated on the basis of spectral analysis infrared, NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their antimicrobial and anti‐inflammatory activity. Compound 4b was the highest antibacterial activity against all strains of bacteria with values higher than those of the corresponding reference antibiotics (ciprofloxacin and levofoxacin, respectively) and almost the same as (gemifloxacin, moxifloxacin, clindamycin, gentamycin, and streptomycin). Compounds 4 , 5 , 6 , and 7 showed high anti‐inflammatory activity compared with the standard drug indomethacin.     

Design,Synthesis and Molecular Modeling of Nonsteroidal Anti‐inflammatory Drugs Tagged Substituted 1,2,3‐Triazole Derivatives and Evaluation of Their Biological Activities

A novel series of 1,4‐disubstituted‐1,2,3‐triazole derivatives 3a – l and 5a – i were one‐pot synthesized via CuAAC‐alkyne click chemistry and evaluated for their antibacterial activity against four organisms and screened for their anticancer activity against human colon cancer cell line HT‐29 and human lung cancer cell line HTB‐29. These hybrid molecules structure elucidation has been performed by IR, ¹H‐NMR, ¹³C‐NMR, and mass spectral analysis. Synthesized nonsteroidal anti‐inflammatory drugs‐triazoles evaluated for their antibacterial activities against bacterial microorganisms Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Klebsiella pneumonia. Final compounds 3i , 3c , and 5b showed magnificent broad spectrum activity against P. aeruginosa, K. pneumonia, E. coli, and S. aureus with zone of inhibition values of 20, 15, 17, and 16 mm, respectively. Among the series of compound, 3j showed the best antibacterial activity against all the strains. Further, the compounds 3i and 5a were more cytotoxic than cisplatin against all tested two human cancer cell lines, with 50.8%, and 52.3% and 73.4% and 75.3% of growth, respectively. The synthesized compounds were tested for kinase inhibitory activity against glycogen synthase kinase‐3 protein kinases, in addition, for cytotoxic activity against two different human cancer cell lines.     

Synthesis and Characterization of Some Heteroaromatic Derivatives of 3‐But‐2‐enoyl‐chromen‐2‐one and Their Potential as Anti‐inflammatory Agents

A novel series of chromen‐2‐ones containing pyrazole, isoxazole, oxazine, and thiazine substitutions have been synthesized by reacting 3‐[3‐(4‐chloro‐phenyl)‐acryloyl]‐chromen‐2‐one and 3‐[3‐(3‐methoxy‐phenyl)‐acryloyl]‐chromen‐2‐one with various cyclizing agents such as hydrazine, phenylhydrazine, urea, and thiourea. The structures of all the synthesized compounds were confirmed by the use of IR, ¹H‐NMR, mass spectroscopy, and elemental analysis data. All the newly synthesized compounds were evaluated for their anti‐inflammatory activity at a dose of 100 mg/kg body weight in carrageenan‐induced rat paw edema model. The entire series of the compounds exhibited moderate to good anti‐inflammatory activity, with the percentage inhibition of edema formation ranging from 39.99 to 63.15 against the reference drug ibuprofen (100 mg/kg) that showed 78.96% inhibition at the third hour. Compounds 3a , 3c , and 3d showed good inhibitory activity, whereas compounds 3b , 3e , 3f , and 3j showed moderate inhibitory activity at the third hour.     

Synthesis ofN1‐3‐{(4‐Substituted aryl‐3‐chloro‐2‐oxo‐azetidine)‐iminocarbamyl}‐propyl‐6‐nitroindazole Derivatives and Their Biological Significance

Synthesis ofN¹‐3‐{(4‐substitute daryl‐3‐chloro‐2‐oxo‐azetidine)‐iminocarbamyl}‐propyl‐6‐nitroindazole 4a – 4s was conducted by a conventional method. All the compounds were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, FAB‐Mass techniques and chemical methods. All the final synthesized compounds were evaluated for their antimicrobial activity and antitubercular activity with MIC values against some selected microorganisms.     

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.     

Facile Synthesis of Novel 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one Derivatives as Potential Anticancer Agents

A series of 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 6a – l ) derivatives has been efficiently synthesized by straightforward sequential reactions. Tandem Vilsmeier Hack reaction/cyclization/bromination/Suzuki cross‐coupling reactions were successfully applied to the preparation of title compounds in good‐to‐high yields. In the synthetic sequences, 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehydes ( 2 ) were found to react with ammonium thiocyanate to yield the corresponding 3‐(isothiazol‐5‐yl)‐2H‐chromen‐2‐ones ( 3 ). These derivatives were brominated with N‐bromo succinamide to yield the corresponding regioselective 3‐(4‐bromoisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 4 ). Finally, compound 4 was treated with various phenyl/pyrazole/7H –pyrrolo[2,3‐d]pyrimidinyl boronic acids 5a – l in the presence of K₂CO₃ and Pd catalyst in dimethylformamide to yield the corresponding title derivatives 6a – l . All the synthesized compounds were characterized by analytical and spectral studies. All the final compounds were screened against different cancer cell lines (A549, PC3, SKOV3, and B16F10), and among these compounds, 6b , 6g , 6h , and 6l displayed moderate cytotoxic activity against the tested cell lines.