Synthesis, anti-inflammatory and analgesic evaluation of thioxoquinazolinone derivatives

A series of 3-substituted-2-thioxoquinazolin-4(3H)-one derivatives have been synthesized and their structures have been elucidated on the basis of IR, (1)H-NMR, elemental analysis and mass spectroscopic studies. Anti-inflammatory and analgesic activity of the synthesized compounds was evaluated by Carrageenan induced rat paw edema method and Eddy's hot plate method respectively. Among the synthesized compounds N-(4-hydroxyphenyl)-N-(4-oxo-3-phenyl-2-thioxo-3,4-dihydroquinazolin-1(2H)methyl)acetamide (PTQ01) showed excellent anti-inflammatory activity. N-(4-ethoxyphenyl)-N-(3-(naphthalen-2yl)-4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)acetamide (NTQ02), N-(4-Hydroxyphenyl)-N-((3-naphthalen-2-yl)-4-oxo-2-thioxo-3,4-dihydorquinazolin-1(2H)-ylmethyl)acetamide (NTQ01), N-((3-(4-ethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydoquinazolin-1(2H)-yl)methyl)-N-(4-hydroxyphenyl)acetamide (ETQ01) N-(3-(4-ethoxyphenyl)-4-oxo-2thioxo-3,4-dihydroquinazolin-1(2H)-ylmethyl)-N-(4-hydroxyphenyl)acetamide (ETQ04), N-(4-ethoxyphenyl)-N-((4-oxo-3-phenyl-2-thioxo-3,4-dihydoquinazolin-1(2H)-yl)methyl)acetamide (PTQ02) and N-(4-ethoxyphenyl)-N-(3-(4-ethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydoquinazolin-1(2H)-yl)methyl)acetamide (ETQ02) at a dose of 20 mg/kg exhibited significant anti-inflammatory activity compared to that of standard drug diclofenac sodium. The compound 2-(2,3-dimethylphenyl)(3-(4-ethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydroquinazolin-1-2H)-1ylmethylamino)benzoic acid PTQ03 and sodium 2-(2-((2,6-dichlrophenyl)(3-(4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)amino)phenylacetate (PTQ04) showed moderate anti-inflammatory activity. The compounds PTQ01, PTQ02, PTQ04, ETQ01 and ETQ02 showed significant analgesic activity compared with that of standard drug pentazocin.     

Identification,isolation and characterization of process-related impurities in Rizatriptan benzoate

Three process-related impurities were observed in routine monitoring of the samples by HPLC. These impurities were identified by LC–MS. One of the impurities, Imp-3 [rizatriptan-2,5-dimer] was reported in literature. Other two impurities were isolated by preparative HPLC and characterized by NMR, Mass and IR. Pure impurities obtained by isolation were co-injected with Rizatriptan benzoate sample to confirm the retention times in HPLC. Structure elucidation of these impurities by spectral data has been discussed in detail. These impurities were identified as 4-(5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-4-(5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-(dimethylamino)ethyl)-1H-indol-2-yl)-N,N-dimethylbutan-1-amine [rizatriptan-1,2-dimer] and [4,4-bis-(5-((1H-1,2,4-triazol-1-yl)methyl)-3-(2-(dimethylamino)-ethyl)-1H-indol-2-yl)-N,N-dimethylbutan-1-amine [rizatriptan-2,2-dimer].     

Synthesis and investigation of anti-inflammatory activity of novel nitric oxide donating hybrid drugs

A small library of nitric oxide donating groups, 4-acetamidophenyl-2-[{2-(nitrooxy)ethyl}(phenyl) amino]benzoate (5a–e) possessing a variety of substituents (–H, –NO₂, –CH₃, –acetamidophenyl, –SO₂NH₂) attached to the fourth position of phenyl ring were synthesized and evaluated for anti-inflammatory, analgesic and ulcerogenic potential. Structure–activity relationship data showed that the 2-phenylaminobenzoic acid skeleton is required for selective COX-2 inhibition. Among all compounds 4-acetamidophenyl-2-[{2-(nitrooxy)ethyl}(phenyl)amino]benzoate (5a) has shown potent anti-inflammatory activity while 4-acetamidophenyl-2-[{4-{(4-acetamidophenoxy)carbonyl} phenyl}{2-(nitrooxy)ethyl}amino]benzoate (5d) has shown potent analgesic activity compared to standard drug diclofenac.     

Design,synthesis and biological evaluation of novel 1,2,3-triazole analogues of Imidazo-[1,2-a]-pyridine-3-carboxamide against Mycobacterium tuberculosis

Twenty-eight novel 1,2,3-triazole analogues of imidazo-[1,2-a]-pyridine-3-carboxamide were designed and synthesized based on hybridization approach. The structure of the final compounds are characterized using ¹HNMR, ¹³CNMR, LCMS and elemental analyses and are screened in vitro for anti-tubercular activity using low-oxygen recovery assay (LORA) non-replicating and using microplate alamar blue assay (MABA) against replicating M. tuberculosis. MIC was determined. From the obtained results, it was observed that, among (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)(4-((1-subtituted phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)methanones and (6-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)(4-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)methanones, compounds with substitution at para position with electron electron releasing groups exhibited the best activity (< 34 μg/mL). Amidst, (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)(4-(2-(4-alkyl/substituted aryl-1H-1,2,3-triazol-1-yl)ethyl)piperazin-1-yl)methanones and (6-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)(4-(2-(4- alkyl/substituted aryl -1H-1,2,3-triazol-1-yl)ethyl)piperazin-1-yl)methanones, compounds with long alkyl chain or cyclo propyl group were most active (< 21 μg/mL) in MABA method against the tested strain of MTB. Compound 10b emerged to be the most active compound in MABA and LORA with MIC values 13.74 and 24.63 μg/mL respectively. In-silico ADMET parameters were also predicted for the significantly active compound. Finally, molecular docking study was carried out to predict the feasible binding pattern of the most active compound at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB-4TZK) using Glide module of Schrodinger software.     

Synthesis and characterization of new types of 2-(6-methoxy-2-naphthyl)propionamide derivatives as potential antibacterial and antifungal agents

A series of novel 2-(6-methoxy-2-naphthyl)propionamide derivatives have been efficiently synthesized in excellent yields via the reaction of naproxenoyl chloride with different amino compounds. Most of the synthesized compounds were screened in vitro for their antibacterial and antifungal activities. Most of the compounds showed significant antibacterial and antifungal activities, reaching, in certain cases, the same level of antimicrobial activity as the standard antibacterial agent Ampicilline and antifungal agent Flucanazole. N-(4-(N-arylsulfamoyl)phenyl)-2-(6-methoxynaphthalen-2-yl)propanamide (4a–c), 4-(4-fluorobenzylidene)-2-(1-(6-methoxynaphthalen-2-yl)ethyl)oxazol-5(4H)-one (10b), 2-(6-methoxynaphthalen-2-yl)-N-((5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)propanamide (12), and N-((4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-2-(6-methoxynaphthalen-2-yl)propanamide (13) were found to be the most potent compounds against most of the tested strains. The antimicrobial activity was further supported by using MIC technique. Structure activity relationship studies revealed several matching pairs.     

Synthesis and primary cytotoxicity evaluation of new 5-bromo-3-substituted-hydrazono-1H-2-indolinones

In this study a new series of 5-bromo-3-[(3-substituted-5-methyl-4-thiazolidinone-2-ylidene)-hydrazono]-1H-2-indolinones (3a-i) and 5-bromo-3-[(2-thioxo-3-substituted-4, 5-imidazolidinedione-1-yl)imino]-1H-2-indolinones (4a-f) was synthesized by the cyclization of 5-bromo-3-(N-substituted-thiosemicarbazono)-1H-2-indolinones (2a-i)with ethyl 2-bromopropionate in anhydrous ethanolic medium and oxalyl cloride in anhydrous diethyl ether, respectively. Six compounds chosen as prototypes were evaluated in the 3-cell line, one dose in vitro primary cytotoxicity assay. Four of them were evaluated against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. Among the compounds tested, the 4-fluoro-phenylthiosemicarbazone derivative 2f showed the most favorable cytotoxicity. This compound demonstrated the most marked effects on a breast cancer cell line (BT-549, log(10)GI(50) value -6.40), a non small cell lung cancer cell line (NCI-H23, log(10)GI(50) value -6.10), and an ovarian cancer cell line (IGROV1, log(10)GI(50) value -6.02).     

Two new aromatic compounds from the resin of Styrax tonkinensis (Pier.) Craib

Two new aromatic compounds, trans-(tetrahydro-2-(4-hydroxy-3-methoxyphenyl)-5-oxofuran-3-yl)methyl benzoate (1), 3-(4-hydroxy-3-methoxyphenyl)-2-oxopropyl benzoate (2) and one new natural product, 4-((E)-3-ethoxyprop-1-enyl)-2-methoxyphenol (3) together with five known aromatic compounds have been isolated from the resin of Styrax tonkinensis (Pier.) Craib. Their structures were determined by physical and spectroscopic methods.     

Synthesis and characterization of 2-(4-((1-alkyl or aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)naphtho[1,2-d]oxazoles for protein tyrosine phosphatase 1B inhibitory activity

2-(4-((1-Alkyl/aryl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)naphtho[1,2-d] were prepared and evaluated as protein tyrosine phosphatase 1B (PTP1B) inhibitors. In this study, two new compounds with potent PTP1B inhibitory activity were identified.     

Leukotriene (LT) receptor antagonists. Heterocycle-linked tetrazoles and carboxylic acids. LY203647

LY171883, 1-[2-hydroxy-3-propyl-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl] ethanone, is an orally active antagonist of LTD4- and LTE4-induced responses in a variety of test systems. We prepared a new series of LT antagonists based on a proposed model of LY171883 binding to the LTE4 receptor in which the n-propyl and tetrazole moieties of LY171883 occupy those parts of the receptor to which the C1-C5 chain and the cysteinyl carboxyl of LTE4 bind, respectively. The new compounds have an acidic function corresponding to the glycine carboxyl of LTD4 linked through a heterocyclic group which is proposed to bind to the LTD4 receptor where the cysteinyl glycine amide bond of LTD4 binds. LY203647, 1-[2-hydroxy-3-propyl-4-[4-[2-[4-(1H-tetrazol-5-yl)butyl]-2H- tetrazol-5-yl]butoxy]phenyl] ethanone, showed good LTD4 antagonist activity with a suitable pharmacologic and toxicologic profile and has been chosen for clinical evaluation.     

Anti-inflammatory, antiproliferative, and cytoprotective activity of NO chimera nitrates of use in cancer chemoprevention

Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown promise in colorectal cancer (CRC), but they are compromised by gastrotoxicity. NO-NSAIDs are hybrid nitrates conjugated to an NSAID designed to exploit the gastroprotective properties of NO bioactivity. The NO chimera ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094), a novel nitrate containing an NSAID and disulfide pharmacophores, is effective in vivo in rat models of CRC and is a lead compound for design of agents of use in CRC. Preferred chemopreventive agents possess 1) antiproliferative and 2) anti-inflammatory actions and 3) the ability to induce cytoprotective phase 2 enzymes. To determine the contribution of each pharmacophore to the biological activity of GT-094, these three biological activities were studied in vitro in compounds that deconstructed the structural elements of the lead GT-094. The anti-inflammatory and antiproliferative actions of GT-094 in vivo were recapitulated in vitro, and GT-094 was seen to induce phase 2 enzymes via the antioxidant responsive element. In the variety of colon, macrophage-like, and liver cell lines studied, the evidence from structure-activity relationships was that the disulfide structural element of GT-094 is the dominant contributor in vitro to the anti-inflammatory activity, antiproliferation, and enzyme induction. The results provide a direction for lead compound refinement. The evidence for a contribution from the NO mimetic activity of nitrates in vitro was equivocal, and combinations of nitrates with acetylsalicylic acid were inactive.     

1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成及抗真菌活性

报道了29个新的1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成与体外抗菌试验。结果表明,大多数化合物对大部分真菌有抑菌活性,化合物T₁,T₄,T₆,T₁₁,T₁₂,B₁,B₃,B₄和B₆对部分真菌抑菌活性优于或相当于奥昔康唑。     

Synthesis and evaluation of anticancer activity of some imidazothiazolyl,imidazobenzothiazolyl and dihydroimidazothiazolyl coumarins

A series of 6-(2H-1-benzopyran-2-one-3-yl)imidazo[2,1-b]thiazoles (1), 2-(2H-1-benzopyran-2-one-3-yl)imidazo[2,1-b]benzothiazoles (2) and 3-(2H-1-benzopyran-2-one-3-yl)-5,6-dihydroimidazo[2,1-b]thiazoles (3) have been synthesized and evaluated for anticancer activity in vitro. The compounds showed very good activity against different tumor cell lines.     

Selaginellin C,a new natural pigment from Selaginella pulvinata Maxim (Hook et Grev.)

A novel compound, selaginellin C (1), was isolated from Selaginella pulvinata Maxim (Hook et Grev.) as (R,S)-4-((1,2-dihydroxyethyl)-2′,4′-dihydroxy-3-((4-hydroxyphenyl)ethynyl)biphenyl-2-yl)((4-hydroxyphenyl)methylene)cyclohexa-2,5-dienone, along with two known compounds, selaginellin (2) and selaginellin A (3). The structure of the new compound was elucidated on the basis of 1D and 2D NMR as well as HR-ESI-MS spectroscopic analysis.     

Synthesis, cytotoxicity testing, and structure-activity relationships of novel 6-chloro-7-(4-phenylimino-4H-3,1-benzoxazin-2-yl)-3-(substituted)-1,4,2-benzodithiazine 1,1-dioxides

A new series of 16 6-chloro-1,1-dioxo-7-{4-[(4-R(1)-phenyl)imino]-4H-3,1-benzoxazin-2-yl}-3-(substituted amino)-1,4,2-benzodithiazines 7-22 was prepared in order to evaluate the cytotoxic activity against six human cancer cell lines. The structures of the new compounds were confirmed by IR, (1)H-, and (13)C-NMR, elemental analysis and in the cases of 11 and 31 by X-ray crystal structure analysis. This analysis showed that contrary to our earlier report the structures contain a benzoxazine ring instead of the proposed quinazolinone ring. The bioassay indicated that the benzodithiazine derivatives 7-22 possess cancer cell growth-inhibitory properties. Some compounds showed a high level of selectivity for certain cell lines. The most active compounds 11, 12, 16, 19, 21, and 22 exhibited potency higher or comparable to cisplatin. The compounds were particularly effective in LCLC-103H and MCF-7 cell lines with IC(50) values of 0.49-1.60 μM. Quantitative structure activity relationships (QSAR) revealed that a chloro substituent R(1) in the phenyl ring as well as the shape of the substituted amino group at R(2) (e.g., unsaturation is beneficial) are important for potency.     

Synthesis and cytotoxic activity of imidazo[1,2-a]-1,3,5-triazine analogues of 6-mercaptopurine

A series of 2-substituted imidazo[1,2-a]-1,3,5-triazines with various aliphatic and aromatic amines has been prepared and characterized by IR,1H-NMR, and elemental analysis. The initial in-vitro cytotoxicity studies with five human cancer cell lines showed that all but one of the compounds are without cytotoxic activity. The one active compound, 2-(indolin-1-yl)-7,8-dihydroimidazo[1,2-a]-1,3,5-triazine-4(6H)-thione 12, was tested on 12 human cancer cell lines. Of these, two lines, RT-4 and MCF-7, were the most sensitive to the compound, with IC50 values of 6.98 microM and 8.43 microM, respectively. When compared with the reference anticancer drug 6-mercaptopurine, only the RT-4 urinary bladder and KYSE-70 oesophagus cancer cell lines were more sensitive to the new compound. The antimetabolite thioguanine was more cytotoxic than 12 for all common cell lines tested.     

Patent Evaluation: Thioxoheterocycles as 5-lipoxygenase Inhibitors

Summary

Novelty: Novel thioxoheterocycles and their preparation are disclosed. Also described are pharmaceutical compositions containing the novel compounds and their use in the production of medicaments for use in a leukotriene mediated disease or medical condition.

Biology: The thioxoheterocycles are inhibitors of the enzyme 5-LPO. The effects of this inhibition are demonstrated by standard procedures. No other biological data are provided.

Chemistry: Three specifically claimed compounds illustrate the preparation of novel compounds and intermediates. A preferred class of novel compounds are specifically claimed including 4-[5-fluoro-3-(1-methyl-2-thioxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-4-meth-oxytetrahydropyran.

Chemistry: Three specifically claimed compounds illustrate the preparation of novel compounds and intermediates. A preferred class of novel compounds are specifically claimed including 4-[5-fluoro-3-(1-methyl-2-thioxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-4-meth-oxytetrahydropyran.

Structure:      

Two new aromatic compounds from the resin of Styrax tonkinensis (Pier.) Craib

Two new aromatic compounds, trans-(tetrahydro-2-(4-hydroxy-3-methoxyphenyl)-5-oxofuran-3-yl)methyl benzoate (1), 3-(4-hydroxy-3-methoxyphenyl)-2-oxopropyl benzoate (2) and one new natural product, 4-((E)-3-ethoxyprop-1-enyl)-2-methoxyphenol (3) together with five known aromatic compounds have been isolated from the resin of Styrax tonkinensis (Pier.) Craib. Their structures were determined by physical and spectroscopic methods.     

Non-Steroidal Anti-inflammatory Agents: Novel Pyrazolyl-, 1,2-Oxazolyl-, and 1,3-Diazinyl Derivatives of 4(3H)-Quinazolinones

Four novel series of 4(3H)-quinazolinone derivatives have been prepared by cyclization of the key intermediates 3-aryl-2-(3-aryl-3-oxopropenyl)-4-(3H)-quinazolinones with different reagents: 3-aryl-1-iminocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolinones, 3-aryl-2-(3-aryl-1-thiocarbamoyl-1H-pyrazol-5-yl)-4(3H)-quinazolinones, 3-aryl-2-(3-aryl-4,5-dihydro-1,2-oxazol-5-yl)-4(3H)-quinazolinones, and 3-aryl-2-(4-aryl-2-thioxo-1,2,5,6-tetrahydro-1,3-diazin-6-yl)-4(3H)-quinazolinones. The anti-inflammatory activity of representatives of these compounds is comparable to or higher than that of proquazone.     

Identification of benzoxazin-3-one derivatives as novel, potent, and selective nonsteroidal mineralocorticoid receptor antagonists

Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H)-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.     

4-(1,2-Benzisothiazol-3-yl)alkanoic and phenylalkanoic acids: synthesis and anti-inflammatory, analgesic and antipyretic activities.

Continuing their studies on benzisothiazolyl derivatives, Authors refer to the preparation and pharmacological properties of 4-(1,2-benzisothiazol-3-yl) alkanoic and phenylalkanoic acids. All substances were tested for anti-inflammatory, analgesic and antipyretic properties. As reference compounds, 1,2-benzisothiazolin-3-one and 4-(3-oxo-1,2-benzisothiazolin-3-yl) phenylacetic acid, as prototypes of benzisothiazolinonic derivation. Ibuprofen, as a prototype of substituted arylalkanoic acids, and Phenylbutazone were used. Analysis of the data leaded to the following conclusions. Introduction of the aryl moiety, passing from benzisothiazolylalkanoic to benzisothiazolyl-phenylalkanoic structures, produced a remarkable increase of activity. 2-[4-(1,2-benzisothiazol-3-yl)phenyl] propionic and 2-[4-(1,2-benzisothiazol-3-yl)phenyl]butyiric acids showed anti-inflammatory, analgesic and antipyretic properties comparable to those of Ibuprofen. Substantial differences in variations in activities were observed comparing the properties of benzisothiazolylphenylalcanoic acids with those of the benzisothiazolinonic series, object of preceding studies.