Synthesis and pharmacological evaluation of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones as analgesic and anti‐inflammatory agents

A new series of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one with different aldehydes and ketones. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic activities in Wistar rats. All test compounds exhibited analgesic and anti‐inflammatory activities. Compound VA2 (2‐(1‐ethylpropylidene‐hydrazino)‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent analgesic activity and compound VA3 (2‐(1‐methylbutylidene‐hydrazino)‐3‐(4‐chlorophenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent anti‐inflammatory activity when compared with the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic side effects when compared with aspirin. Drug Dev Res 69: 226–233, 2008 ©2008 Wiley‐Liss, Inc.     

Synthesis,characterization, molecular modelling and biological evaluation of thieno‐pyrimidinone methanesulphonamide thio‐derivatives as non‐steroidal anti‐inflammatory agents

This study reports the synthesis, molecular docking and biological evaluation of eight ( 5 ‐ 8 and 5a ‐ 8a ) newly synthesized thieno‐pyrimidinone methanesulphonamide thio‐derivatives. The synthetic route used to prepare the new isomers thioaryl and thio‐cycloesyl derivatives of the heterocyclic system 6‐phenylthieno[3,2]pyrimidinone was economically and environmentally very advantageous and characterized by the simplicity of procedure, reduction in isolation steps, purification phases, time, costs and waste production. The study in silico for the evaluation of cyclooxygenase (COX)‐1 and COX‐2 selective inhibition was carried out by AutoDock Vina, an open‐source program for doing molecular docking which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. The research in vitro for the biological evaluation was performed by using human cartilage and chondrocytes cultures treated with 10 ng/mL of interleukin‐1beta as inflammation models. The anti‐inflammatory activity of each new compound at the concentration of 10 μmol/L was determined by assaying COX‐2, inducible nitric oxide synthetase (iNOS) and intercellular adhesion molecule 1 (ICAM 1) through Western blot. The examined derivatives showed interesting pharmacological activity, and the compound N‐[2‐[2,4‐difluorophenyl)thio]‐4‐oxo‐6‐phenylthieno[3,2‐d]pyridine‐34H‐yl]methanesulphonamide ( 7 ) was excellent COX‐2 inhibitor. In agreement with the biological data, compound 7 was able to fit into the active site of COX‐2 with highest interaction energy. These results can support the design of novel specific inhibitors of COX‐2 by the comparative modelling of COX‐1 and COX‐2 enzymes with the available pharmacophore.     

Evaluation of Novel N‐(piperidine‐4‐yl)benzamide Derivatives as Potential Cell Cycle Inhibitors in HepG2 Cells

In this study, a series of novel N‐(piperidine‐4‐yl)benzamide derivatives was designed, synthesized, and evaluated for antitumor activity. Some compounds were found to have potent antitumor activity. In particular, compound 47 showed the most potent biological activity against HepG2 cells, with an IC₅₀ value of 0.25 μm . Western blot analysis demonstrated that compound 47 inhibited the expression of cyclin B1 and p‐Rb and enhanced the expression of p21, p53, Rb, and phospho‐adenosine monophosphate‐activated protein kinase (p‐AMPK). Further, cell cycle arrest was observed by flow cytometry (FCM). In summary, compound 47 was screened to have potential activity for the treatment of hepatocarcinoma via the induction of cell cycle arrest by a p53/p21‐dependent pathway.     

Discovery of Novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole Derivatives as Potential Anti‐Inflammatory Agents

A novel 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 5 with good anti‐inflammatory activity was identified from our in‐house library. Based on hit compound 5 , two series of 2‐(piperidin‐4‐yl)‐1H‐benzo[d]imidazole derivative 6a – g and 7a – h were designed and synthesized as novel anti‐inflammatory agents. Most of synthesized compounds exhibited good inhibitory activity on NO and TNF‐α production in LPS‐stimulated RAW 264.7 macrophages, in which the compound 6e showed most potent inhibitory activity on NO (IC₅₀ = 0.86 μm ) and TNF‐α (IC₅₀ = 1.87 μm ) production. Further evaluation revealed that compound 6e displayed more potent in vivo anti‐inflammatory activity than ibuprofen did on xylene‐induced ear oedema in mice. Additionally, Western blot analysis revealed that compound 6e could restore phosphorylation level of IκBα and protein expression of p65 NF‐κB in LPS‐stimulated RAW 264.7 macrophages.     

Synthesis,In Vitro Protoporphyrinogen Oxidase Inhibition,and Herbicidal Activity of N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones and N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones

Protoporphyrinogen oxidase ( EC 1.3.3.4 ) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase‐inhibiting herbicides, N‐(benzothiazol‐5‐yl)tetrahydroisoindole‐1,3‐dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones ( 1a – o ) and N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones ( 2a – i ). These newly prepared compounds were characterized by elemental analyses, ¹H NMR, and ESI‐MS, and the structures of 1h and 2h were further confirmed by X‐ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a , ethyl 2‐((6‐fluoro‐5‐(4,5,6,7‐tetrahydro‐1‐oxo‐1H‐isoindol‐2(3H)‐yl)benzo[d]thiazol‐2‐yl)‐sulfanyl)acetate, was recognized as the most potent candidate with K_i value of 0.0091 μm . Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha.     

Synthesis and evaluation of [123I]‐indomethacin derivatives as COX‐2 targeted imaging agents

A novel series of iodinated indomethacin derivatives was synthesized, and evaluated as selective inhibitors of COX‐2. Two candidate compounds N‐(p‐iodobenzyl)‐2‐(1‐(p‐chlorobenzoyl)‐5‐methoxy‐2‐methyl‐1H‐indol‐3‐yl)acetamide (3) and 1‐(p‐iodobenzyl)‐5‐methoxy‐2‐methyl‐3‐indoleacetic acid (9) possessed optimum properties suitable for potential in vivo imaging. Arylstannane precursors for radioiododestannylation were synthesized in 70–85% yield from the iodo compounds by reaction with hexabutylditin and tetrakis(triphenylphosphine)palladium(0) in refluxing dioxane. Radioiododestannylation was conducted by reaction with carrier‐added Na[¹²³I] in the presence of Chloramine‐T in an EtOAc/H₂O binary system under acidic conditions (pH 3.5), allowing direct isolation of the labeled products by separation of the organic phase. Radioiodinated products [¹²³I]3 and [¹²³I]9 were recovered in a decay‐corrected radiochemical yield of 86–87% and radiochemical purity of 98–99%. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis,molecular docking and biological evaluation of 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives as novel potential tubulin assembling inhibitors

A series of new 1‐phenylsulphonyl‐2‐(1‐methylindol‐3‐yl)‐benzimidazole derivatives were designed, synthesized and evaluated as potential inhibitors of tubulin polymerization and anthropic cancer cell lines. Among them, compound 33 displayed the most potent tubulin polymerization inhibitory activity in vitro (IC₅₀ = 1.41 μM) and strong antiproliferative activities against A549, Hela, HepG2 and MCF‐7 cell lines in vitro with GI₅₀ value of 1.6, 2.7, 2.9 and 4.3 μM, respectively, comparable with the positive control colchicine (GI₅₀ value of 4.1, 7.2, 9.5 and 14.5 μM, respectively) and CA‐4 (GI₅₀ value of 2.2, 4.3, 6.4 and 11.4 μM, respectively). Simultaneously, we evaluated that compound 33 could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Immunofluorescence microscopy also clearly indicated compound 33 a potent antimicrotubule agent. Docking simulation showed that compound 33 could bind tightly with the colchicine‐binding site and act as a tubulin inhibitor. Three‐dimensional‐QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent tubulin assembling inhibitory activity in the future.     

Synthesis of 2‐(methylsulfonyl)‐5‐(4‐(methylsulfonyl) phenyl)‐4‐phenyl‐1H‐[5‐14C]imidazole,a selective COX‐2 inhibitor,via asymmetrical benzoins

4,5‐Diarylimidazoles labeled with carbon‐14 in the 5‐position of the imidazole ring were prepared as a part of three‐step sequence from 2‐hydroxy‐1‐(4‐(methylthio)phenyl)‐2‐phenyl[1‐¹⁴C]ethanone as a key synthetic intermediate which has been synthesized from potassium [¹⁴C]cyanide.     

Screening of curcumin‐derived isoxazole,pyrazoles, and pyrimidines for their anti‐inflammatory,antinociceptive, and cyclooxygenase‐2 inhibition

Curcumin has shown pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its numerous derivatives for diverse and improved therapeutic roles. In this study, we have synthesized curcumin derivatives containing isoxazole, pyrazoles, and pyrimidines and then the synthesized molecules were evaluated for their anti‐inflammatory and antinociceptive activities in experimental animal models. Acute toxicity of synthesized molecules was evaluated in albino mice by oral administration. Any behavioral and neurological changes were observed at dose of 10 mg/kg body weight. Additionally, cyclooxygenase‐2 (COX‐2) enzyme inhibition studies were performed through in vitro assays. In vivo anti‐inflammatory studies showed that curcumin with pyrimidines was the most potent anti‐inflammatory agent which inhibited induced edema from 74.7% to 75.9%. Compounds 7 , 9 , and 12 exhibited relatively higher prevention of writhing episodes than any other compound with antinociceptive activity of 73.2%, 74.9%, and 71.8%, respectively. This was better than diclofenac sodium (reference drug, 67.1% inhibition). Similarly, COX‐2 in vitro inhibition assays results revealed that compound 12 (75.3% inhibition) was the most potent compound. Molecular docking studies of 10 , 11 , and 12 compounds in human COX‐2 binding site revealed the similar binding modes as that of other COX‐2‐selective inhibitors.     

One‐pot cascade synthesis and in vitro evaluation of anti‐inflammatory and antidiabetic activities of S‐methylphenyl substituted acridine‐1,8‐diones

Various S‐methylphenyl substituted acridine‐1,8‐dione series ( 4a–i ) were synthesized through a one‐pot cascade synthetic approach involving the reaction of 4‐(methylthio)benzaldehyde and dimedone with a variety of amines as nitrogen source under reflux in ethanol. All the synthesized derivatives were characterized by using spectroscopic methods. In vitro evaluations of anti‐inflammatory and antidiabetic efficacies of all the synthesized compounds were investigated. The anti‐inflammatory results infer that the compounds 4c and 4d are showing excellent activity with an inhibition percentage of 80.58 ± 0.42, 81.72 ± 1.72 by membrane stabilization and 77.72 ± 0.76, 78.76 ± 0.81 by albumin denaturation methods, which is comparable with the standard diclofenac at a concentration of 100 μg/ml. Further, the antidiabetic assay revealed the moderate activity for the synthesized compounds at a concentration of 100 μg/ml with respect to their standard drug, acarbose.     

Synthesis of N‐(2‐chloro‐3,4‐dimethoxybenzylideneamino)guanidinium acetate [α‐14C]

¹⁴C‐Labelled N‐(2‐chloro‐3,4‐dimethoxybenzylideneamino)guanidinium acetate has been synthesized as a part of a four‐step procedure which involved decarboxylation of 2‐chloro‐3,4‐dimethoxybenzoic acid by Pb(OAc)₄ to give 2‐chloro‐3,4‐dimethoxy‐1‐iodobenzene, followed by a selective lithiation at the iodine position and electrophilic substitution with N,N‐dimethylformamide [α‐¹⁴C] and final reaction with aminoguanidine bicarbonate. The specific activity was 59 mCi/mmol and the overall yield 49%. Copyright © 2002 John Wiley & Sons, Ltd.     

Discovery of naphthyl‐N‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity

Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen‐activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti‐inflammatory profile of new naphthyl‐N‐acylhydrazone derivatives using animal models. Although all tested compounds ( 3a–d ) have been characterized as p38α MAPK inhibitors and have showed in vivo anti‐inflammatory action, LASSBio‐1824 ( 3b ) presented the best performance as p38α MAPK inhibitor, with IC₅₀ = 4.45 μm , and also demonstrated to be the most promising anti‐inflammatory prototype, with good in vivo anti‐TNF‐α profile after oral administration.