Solvent free synthesis,anti-inflammatory and anticancer activity evaluation of tricyclic and tetracyclic benzimidazole derivatives

Heterocyclic benzimidazole derivatives 3a–h, 5a–c and 7a–d have been synthesized by condensation of succinic acid (1) homophthalic acid (4) and 2,3-pyrazinedicarboxlic acid (6) with various substituted diamines under microwave irradiation in good yields. Structures assigned to 3a–h, 5a–c and 7a–d are fully supported by spectral data. All these compounds were screened for anti-inflammatory and anticancer activities. At a dose of 50 mg/kg po compounds 3b (39.4%) and 3c (39.2%) exhibited anti-inflammatory activity, comparable to standard ibuprofen which showed 39% activity at 50 mg/kg po and compound 7c exhibit good anticancer activity against ovary (IGR-OV-1), breast (MCF-7) and CNS(SF-295) human cancer cell lines.     

Novel 3-substituted-1-aryl-5-phenyl-6-anilinopyrazolo[3,4-d]pyrimidin-4-ones: Docking,synthesis and pharmacological evaluation as a potential anti-inflammatory agents

Novel 3-substituted-1-aryl-5-phenyl-6-anilino-pyrazolo[3,4-d]pyrimidin-4-ones of pharmacological significance were synthesized by the reaction of ethyl-(5-amino-3-methylthio-1-aryl-5-phenyl-2H-pyrazole)-4-carboxylates 3a–c with S-methyl diphenyl thiourea independently to produce 1-aryl-3-thiomethyl-5-phenyl-pyrazolo[3,4-d]pyrimidines 4a–c in DMF with catalytic amount of K₂CO₃, which on further treatment with different aromatic amines independently under same reaction conditions generated for compounds 5a–l. The compounds were screened for the anti-inflammatory activity and evaluated for ulcerogenic potential. The compounds 5i exhibited superior anti-inflammatory activity in comparison with diclofenac sodium and comparable activity with celecoxib at a dose of 25 mg/kg. The other compounds 4c, 5c, 5f and 5l were found as active with inhibition of edema in the range of 35–39 after 3 h of administration of test compounds. The ulcerogenic potential of active compounds was observed to be quite lesser as compared to standard. COX-2 docking score of the active compound 5i was found to be better than standard celecoxib.     

Synthesis,biological evaluation and docking studies of novel benzopyranone congeners for their expected activity as anti-inflammatory,analgesic and antipyretic agents

8-Acetyl-7-hydroxy-4-phenyl-2H-benzopyran-2-one as starting material a number of 8-substituted derivatives (i.e., hydrazones 2a,b, imine 2c, chalcones 3, pyrazoles 4, 3-cyano-2-oxo-dihydropyridines 5, and/or 3-cyano-2-imino-dihydropyridines 6) were synthesized and assayed for their anti-inflammatory, analgesic and antipyretic activities. Compounds 3c, 4b and 4i showed significant anti-inflammatory, analgesic and antipyretic activities. In addition, 1, 3b, 4d, 4e, 5b, 6a, 6c, 6d, 6e showed anti-inflammatory activity, 2b, 4h, 5e exhibit analgesic activity, and 2b, 4h, 5e showed antipyretic effect. In addition, molecular modeling and docking of the tested compounds into cyclooxygenase II complexed with its bound inhibitor indomethacin (4COX) using molsoft icm 3.4-8C program was performed in order to predict the affinity and orientation of the synthesized compounds at the active site. Also, it was found that the active compounds 1, 4i, 6a–e interact with both Serine 530, and Tyrosine 385 amino acids which are the main amino acids involved in the mechanism of cyclooxygenase II inhibition.The synthesis of the pyrazole-containing new compounds 4 proved a successful hit; also, the 2-imino derivatives of 3-cyano-dihydropyridines were more successful than the 2-oxo derivatives.According to these results, we can conclude that compounds 1, 3c, 4b, 4i, and 6c appear to be the most interesting and seem potentially attractive as anti-inflammatory, analgesic, and antipyretic agents.     

Synthesis and biological screening of a combinatorial library of β-chlorovinyl chalcones as anticancer,anti-inflammatory and antimicrobial agents

A combinatorial library of β-chlorovinyl chalcones (4) were synthesized by Claisen–Schmidt condensation reaction. Catalytic reaction of substituted 3-chloro-3-phenyl-propenal (2) and 1-(2,4-dimethoxy-phenyl)-ethanone or 1-(4-methoxy-phenyl)-ethanone (3) in alkaline conditions furnished the target compound 5-chloro-1-(2,4-dimethoxy-phenyl)-5-phenyl-penta-2,4-dien-1-one (4). The synthesized compounds were screened for their biological activity viz. anticancer, anti-inflammatory and antimicrobial activities. Synthesized compounds 4g and 4h revealed promising anti-inflammatory activity (66–67% TNF-α and 95–97% IL-6 inhibitory activity at 10 μM). Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Furthermore, the anticancer activity (30–40%) was shown by compounds 4d, 4e, 4h and 4b at 10 μM concentrations against ACHN followed by Calu 1, Panc1, HCT116 and H460 cell lines. Some of the compounds 4d, 4e, 4a, 4i and 4b revealed promising antimicrobial activity at MIC 50–100 μg/mL against selected pathogenic bacteria and fungi.     

Synthesis and evaluations of selective COX-2 inhibitory effects: Benzo[d]thiazol analogs

A series of benzo[d]thiazole analogs were synthesized and evaluated for their anti-inflammatory and analgesic effects. Using an ear edema model, except for compounds 2k, 2m-2q and 3a, other compounds showed the anti-inflammatory effects. Among them, compounds 2c, 2d, and 2g showed the best anti-inflammatory activity (inhibition rate: 86.8%, 90.7% and 82.9%, respectively). By the acetic acid-induced abdominal writhing test, except for compounds 2e, 2l, 2m, 2o, 2p and 3a, other compounds showed the analgesic effects with inhibition rate values of 51.9–100% (2a-2r) and 68.6–100% (3a-3g). Next, compounds 2c, 2d, 2g, 3d, 3f, 3g that displayed the excellent anti-inflammatory and analgesic activities were evaluated for their inhibitory effect against ovine COX-1 and COX-2. Compounds 2c, 2d, 2g, 3d, 3f, 3g were weak inhibitors of the COX-1 isozyme but exhibited the moderate COX-2 isozyme inhibitory effects IC₅₀ from 0.28 to 0.77 μM and COX-2 selectivity indexes (SI: 18.6 to 7.2). This benzo[d]thiazole moiety will be proved to be of great significance for developing more potent COX-2 inhibitors.     

Synthesis of novel celecoxib analogues by bioisosteric replacement of sulfonamide as potent anti-inflammatory agents and cyclooxygenase inhibitors

Two series of celecoxib analogues having 1,5-diaryl relationship were synthesized. The key strategy of the molecular design was oriented towards exploring bioisosteric modifications of the sulfonamide moiety of celecoxib. First series (2a–2i) of celecoxib analogues bearing cyano functionality in place of sulfonamide moiety was synthesized by the reaction of appropriate trifluoromethyl-β-diketones (5a–5i) with 4-hydrazinylbenzonitrile hydrochloride (4) in ethanol. Cyano moiety of pyrazoles 2 was then converted into corresponding carbothioamides 3 by bubbling H₂S gas in the presence of triethylamine. All the synthesized compounds (2a–2i and 3a–3i) were screened for their in vivo anti-inflammatory (AI) activity using carrageenan-induced rat paw edema assay. COX-1 and COX-2 inhibitory potency was evaluated through in vitro cyclooxygenase (COX) assays. Compounds 2a, 2b, 2c, 2e and 3c showed promising AI activity at 3–4 h after the carrageenan injection that was comparable to that of the standard drug indomethacin. Although compounds 3d, 3e and 3f exhibited more pronounced COX-2 inhibition but they also inhibit COX-1 effectively thus being less selective against COX-2. Three compounds 2a, 2f and 3a were found to have a COX profile comparable to the reference drug indomethacin. However 2e, 3b, 3c and 3i compounds were the most potent selective COX-2 inhibitors of this study with 3b showing the best COX-2 profile. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data.     

Synthesis and evaluation of pyrazolines bearing benzothiazole as anti-inflammatory agents

The present study aims at the synthesis of pyrazolines bearing benzothiazole and their evaluation as anti-inflammatory agents. The synthesized compounds were evaluated for their anti-inflammatory potential using carrageenan induced paw edema model. Two compounds 5a and 5d alleviated inflammation more than the standard drug celecoxib. Eight compounds 5b, 5c, 5e, 5g, 5h, 6b, 6e and 6f showed anti-inflammatory activity comparable to celecoxib. To understand the mode of action, COX-2 enzyme assay and TNF-α assay were carried out. All the active compounds were assessed for their cytotoxicity. The ulcerogenic risk evaluation was performed on the active compounds that were not found to be cytotoxic. Out of ten active compounds, two compounds (5d and 6f) were finally found to be the most potent anti-inflammatory agents attributing to the suppression of the COX-2 enzyme activity and TNF-α production without being either cytotoxic or ulcerogenic.     

1-Malonyl-1,4-dihydropyridine as a novel carrier for specific delivery of drugs to the brain

A group of 1-malonyl-1,4-dihydropyridine derivatives were synthesized as novel carrier systems for site-specific and sustained drug delivery to the brain. Such carriers are expected to be stable against air oxidation due to the presence of the carbonyl group close to nitrogen of the dihydropyridine. These carrier systems were attached to a group of different aldehydes to afford novel quaternary pyridinium derivatives 9a–e, 11a–d, 13 and 18a–b. Reduction of the prepared quaternary pyridinium derivatives with sodium dithionite afforded a novel group of 1-malonyl-1,4-dihydropyridine chemical delivery systems (CDSs) 10a–e, 12a–d, 14 and 19a–b. The synthesized 1-malonyl-1,4-dihydropyridine CDSs were subjected to various chemical and biological investigations to evaluate their ability to cross the blood–brain barrier, and to be oxidized biologically into their corresponding quaternary derivatives. The in vitro oxidation studies showed that most of the 1-malonyl-1,4-dihydropyridine CDSs could be oxidized into their corresponding quaternary derivatives at an adequate rate. The in vivo studies showed that compounds 10c and 14 were able to cross the blood–brain barrier at detectable concentrations. Moreover, the pyridinium quaternary intermediates 9a, 9c, 13, 18a and their corresponding dihydro derivatives 10a, 10c, 14 and 19a were screened for their antidepressant activity using tail suspension behavioral despair test compared to imipramine as a reference at a dose level of 10 mg/kg. The results indicated that compounds 13, 14 and 19a induced remarkable antidepressant activity comparable to imipramine. Compounds 10a, 10c and 18a exhibited good antidepressant activity, their activities nearly equal to 92.8%, 86.7% and 90.20% of the activity of imipramine, respectively. The other derivatives 9a and 9c exhibited moderate antidepressant activity compared with imipramine.     

Novel fluorinated acridone derivatives. Part 1: synthesis and evaluation as potential anticancer agents

We report on the synthesis of a novel series of fluorinated acridones from 5-trifluoromethyl-1,3-cyclohexanedione. The cytotoxic activities of the compounds were studied in several cancer cells. Compounds 9a, 9c, 9e, 9f, and 9h exhibited significant anticancer activities in selected cell lines. Compound 9c is the most active showing GI₅₀ that ranged in values from 0.13 to 26 μM, covering a wide range of cancer cell lines.     

Synthesis,pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents

A novel series of 5-[2-(2,6-dichlorophenylamino)benzyl]-3-(substituted)-1,3,4-oxadiazol-2(3H)-thione (4a–k) derivatives have been synthesized by the Mannich reaction of 5-[2-(2,6-dichlorophenylamino)benzyl]-1,3,4-oxadiazol-2(3H)-thione (3) with an appropriately substituted primary/secondary amines, in the presence of formaldehyde and absolute ethanol. Structures of these novel compounds were characterized on the basis of physicochemical, spectral and elemental analysis. The title compounds (4a–k) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 10 mg/kg b.w. Compound 4k exhibited the most promising and significant anti-inflammatory profile while compounds 4a, 4d, 4e, 4i, and 4j showed moderate to good inhibitory activity at 2nd and 4th h, respectively. These compounds were also found to have considerable analgesic activity (acetic acid induced writhing model) and antipyretic activity (yeast induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. Compounds that displayed promising anti-inflammatory profile were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 4a, 4e, 4g and 4k exhibited effective inhibition against COX-2. In an attempt to understand the ligand–protein interactions in terms of the binding affinity, docking studies were performed using Molegro Virtual Docker (MVD-2013, 6.0) for those compounds, which showed good anti-inflammatory activity. It was observed that the binding affinities calculated were in agreement with the IC₅₀ values.     

Synthesis and the hepatoprotective activity of dibenzocyclooctadiene lignan derivatives

The halogenated and oxidized derivatives (1a–1e, 1a′–1c′, 2a–2d, 2a′–2b′, 3a–3e, 3′ and 3a′–3b′) of schizandrin (1), schizandrin B (2) and schisanhenol (3) were synthesized. The hepatoprotective effects of these dibenzocyclooctadiene lignan analogues against CCl₄-induced injury were preliminarily evaluated. Most of the analogues exhibited higher protective effects than the positive control biphenyldicarboxylate (DDB). Among these active analogues, dichloroschisanhenol (3a) exhibited the strongest protective activity (cell survival rate exceeding 98.0%).     

Design,synthesis, molecular docking of new lipophilic acetamide derivatives affording potential anticancer and antimicrobial agents

Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33–40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives were the most active compounds especially 5f and 6f ones. Further EGFR enzymatic investigation was carried out for these most active compounds 5f and 6f resulting in inhibitory activity by 1.89 and 2.05 µM respectively. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds toward the enzyme target, EGFR protein kinase enzyme. The results revealed good compounds placement in the active sites and stable interactions similar to the co-crystallized reference ligand. Collectively, the analogs 5f and 6f could be further utilized and optimized as good cytotoxic agents.     

Indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones: Synthesis,characterization and evaluation of anticancer and antimicrobial activities

A series of novel 10-((1H-indol-3-yl)methylene)-7-aryl-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-ones (8a–t) have been synthesized in good yields by the reaction of benzo[h]quinazoline-2(1H)-thiones (4a–f) with 2-chloro-N-phenylacetamide (5) followed by Knoevenagel condensation with various indole-3-carbaldehydes (7a–d) under conventional method. All the synthesized compounds were characterized by spectral studies and screened for their in vitro anticancer and antimicrobial activities. Compound 8c has exhibited excellent activity against MCF-7 (breast cancer cell line) than the standard drug Doxorubicin. Compound 8d against both the cancer cell lines, 8q against MCF-7 and 8c, 8h against HepG2 have also shown good activity. Remaining compounds have shown moderate activity against both the cell lines. Antimicrobial activity revealed that, the compound 8q and 8t against Staphylococcus aureus and 8i, 8k, 8l, 8q & 8t against Klebsiella pneumoniae have shown equipotent activity on comparing with the standard drug Streptomycin. Remaining compounds have shown significant antibacterial and comparable antifungal activities against all the tested microorganisms.     

Synthesis of 4-substituted pyrido[2,3-d]pyrimidin-4(1H)-one as analgesic and anti-inflammatory agents

4-Substituted-pyrido[2,3-d]pyrimidin-4(1H)-ones 4a–c were synthesized by oxidation of 4-substituted-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones 3a–c which were in turn prepared from arylidenemalononitriles 1a–c and 6-aminothiouracil 2. The reactivity of compounds 4a–c towards some reagents such as formamide, carbon disulfide, urea, thiourea, formic and acetic acids were studied. All the synthesized compounds were characterized by spectroscopic means and elemental analysis. Compound 4c exhibited 64% and 72% analgesic activity. Also, compound 4b showed 50% and 65% anti-inflammatory activity. Interestingly these compounds showed one-third of ulcer index of the reference aspirin and diclofenac.     

New bithiazolyl hydrazones: Novel synthesis,characterization and antitubercular evaluation

New bithiazolyl hydrazones (6a–l) have been first time synthesized by carrying novel one pot cyclocondensation of 5-acyl thiazoles (1a–b), thiosemicarbazide (2) and substituted phenacyl chlorides (4a–f) in freshly prepared ionic liquid, diisopropyl ethyl ammonium acetate (DIPEAc) at room temperature. The newly synthesized compounds have been evaluated for their antitubercular activity and the compounds 3b, 6a, 6b, 6d, 6e, 6f, 6g, and 6l have displayed noticeable antitubercular activity compared to Rifampicin with tolerable cytotoxicity. All these compounds were also screened for their antibacterial activity and found that, compounds 6j and 6k have exhibited a very good antibacterial activity. Molecular docking study has shown better harmony with the evaluation trend shown by these compounds under in vitro antitubercular screening.     

Novel pyrimidine-pyridine hybrids: Synthesis,cyclooxygenase inhibition,anti-inflammatory activity and ulcerogenic liability

Some derivatives containing pyrido[2,3-d:6,5d′]dipyrimidine-4,5-diones (9a-f), tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles (11a-c) and 6-(4-acetylphenyl)-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrimido[4,5-d]pyrimidin-4-one (12) were synthesized from 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (8). The anti-inflammatory effect of these candidates was determined and the ulcer indices were calculated for active compounds. 7-Amino-5-(3,4,5-trimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile (11c) exhibited better edema inhibition than celecoxib. Moreover, compounds 9b, 9d and 11c revealed better COX-2 inhibitory activity in a range (IC₅₀ = 0.25–0.89 µM) than celecoxib (IC₅₀ = 1.11 µM). Regarding ulcerogenic liability, all of the compounds under the study were less ulcerogenic than indomethacin. Molecular docking studies had been carried on active candidates 9d and 11c to explore action mode of these candidates as leads for discovering other anti-inflammatory agents.     

Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents

A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3-a]carbazole-3-carboxylic acids (13a–e) and a structurally related 6-fluoro-4-oxothieno[2′,3′:4,5]pyrrolo[3,2-h]quinoline (13f) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a–f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere (13f) emerged as the most active antibacterial, while the 9-fluoro derivative (13e) was the most potent against multidrug-resistant staphylococci. Compounds 13a, 13c–f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC₅₀ 0.8 and 1.6 μM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics.     

Selective cyclooxygenase inhibition and ulcerogenic liability of some newly prepared anti-inflammatory agents having thiazolo[4,5-d]pyrimidine scaffold

Novel candidates of thiazolo[4,5-d]pyrimidines (9a-l) were synthesized and their structures were elucidated by spectral and elemental analyses. All the novel derivatives were screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity, especially 1-(4-[7-(4-nitrophenyl)-5-thioxo-5,6-dihydro-3H-thiazolo[4,5-d]pyrimidin-2-ylideneamino]phenyl)ethanone (9g) was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively. Furthermore, this derivative 9g recorded higher anti-inflammatory activity than celecoxib which showed 43%, 43% and 54% inhibition after 1, 3 and 5h, sequentially. Moreover, the target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2 (IC₅₀ = 0.87–3.78 µM), in particular, the derivatives 9e (IC₅₀ = 0.92 µM), 9g (IC₅₀ = 0.87 µM) and 9k (IC₅₀ = 1.02 µM) recorded higher COX-2 inhibitory effect than the selective COX-2 inhibitor drug celecoxib (IC₅₀ = 1.11 µM). The in vivo potent compounds (9e, 9g and 9k) caused variable ulceration effect (ulcer index = 5–12.25) in comparison to that of celecoxib (ulcer index = 3). Molecular docking was performed to the most potent COX-2 inhibitors (9e, 9g and 9k) to explore the binding mode of these derivatives with Cyclooxygenase-2 enzyme.     

COX-1/COX-2 inhibition assays and histopathological study of the new designed anti-inflammatory agent with a pyrazolopyrimidine core

Four pyrazolopyrimidine series were prepared with a substitution at position- 4 by Schiff base, triazole, oxadiazole and pyrazole moieties (7a-f, 8a,b, 9a-f, 10a,b and 13a,b), respectively. All the synthesized compounds were evaluated in vitro against COX-2 and in vivo against carrageenan-induced rat paw edema as anti-inflammatory agents. Regarding the anti-inflammatory activity (AI) compounds 7c, 7f, 8a, and 9a showed higher activity with respect to celecoxib. Compounds 9a, 7d, and 7f were closely selective to celecoxib. Also, 7c and 7d were safer than indomethacin and similar to celecoxib as resulted from the histopathological study. In addition, the docking study that showed the binding mode of prominent pyrazolopyrimidine compounds inside the COX-2 receptor. Formation of unexpected pyrazole 13a and 13b was briefly discussed using 2D NMR.     

D-ring substituted 1,2,3-triazolyl 20-keto pregnenanes as potential anticancer agents: Synthesis and biological evaluation

A facile synthesis of 21-triazolyl derivatives of pregnenolone and their potential antitumour activity is reported. The scheme involves the transformation of the starting pregnenolone acetate into pregnenolone, conversion of pregnenolone to 21-bromo pregnenolone and finally the one-pot, two-step in situ conversion of the bromo derivative to the 21-triazolyl pregnenolone using the ‘click chemistry’ approach. These derivatives were screened for their anticancer activity against seven human cancer cell lines. The compounds especially 5a, 5b, 5c, 5e, 5g and 5h exhibited significant anticancer activity with compound 5e as the most active in this study.