Bromine In Glacial Acetic Acid Research Articles

Synthesis, molecular docking, and in-vivo anti-inflammatory screening of novel substituted pyrazole analogues

A new series of (2E)-3-(4-methyl phenyl) -1-phenylprop-2-en-1-ones (1) were prepared by Claisen Schmidt condensation and it was further cyclized with hydrazine hydrate to yield pyrazole derivatives (2). The pyrazoles were further refluxed with bromine in glacial acetic acid to get bromo pyrazole derivatives (3) which were condensed with thiosemicarbazide in DMF medium to yield thiazolylpyrazoles (4). The title compounds substituted Schiff base derivatives of pyrazole (5a-o) were obtained by reacting thiazolylpyrazoles (4) and substituted aromatic aldehydes. The structural features of designed moieties were established using IR, Mass and 1H–NMR spectral data. All the designed moieties were subjected to their in-vivo anti-inflammatory activity. The Moldock software was used to perform In-Silico Quantitative Structure-Property Relationship (QSPR) studies. The QSPR studies of the designed moieties were carried out to compare the physical properties with pharmacological activities. The docking studies suggested good pharmacological activity with a MolDock score. The COX-2 receptor binding affinity was superior to COX-1 which suggested the good anti-inflammatory property. When compared against a standard, the tested moieties 5i, 5 m showed a good in-vivo anti-inflammatory response.

Synthesis, Cytotoxic Evaluation and Molecular Docking of Bromo-Substituted 1,3,6-Trihydroxyxanthone as Protein Tyrosine Kinase Inhibitor

A series of bromo-substituted hydroxyxanthone were synthesized using bromine in glacial acetic acid as a solvent, producing compounds 3 and 5 with 82.1% and 84.2% yield, respectively. In vitro analyses of these two compounds using MMT assay against murine leukemia P388 cell line resulted in IC50 of 2,550 and 3,455 μg/mL and selectivity index of 43.21 and 74.40, respectively. These results indicated that the bromo-substituted hydroxyxanthone compounds could potentially be developed as selective and sensitive anti-cancer agents. Furthermore, through the molecular docking conducted using Discovery Studio, compound 3 exhibited interactions between amino acid residues and protein tyrosine kinase (1T46.pdb). This article provides supporting data that xanthone derivatives can be used as drugs for cancer chemotherapy through the mechanism of how this compound can inhibit protein tyrosine kinase.

Anti-tumor agents: Design, Synthesis, and Biological study of N-Substituted-7-hydroxy-1-azacoumarin-3-carboxamide derivatives as potent cytotoxic agents

Abstract Synthesis of ethyl 7-hydroxy-1-azacoumarin-3-carboxylate (3) was developed using ethyl-7-hydroxy coumarin-3-carboxylate and ammonium solution as the key synthons. Condensation of ethyl 7-hydroxy-1-azacoumarin-3-carboxylate with ammonium acetate and aniline to give N-substituted-7-hydroxy-1-azacoumarin-3-carboxamides (7-Hydroxy -1-azacoumarin-3-carboxamide (4) and N-phenyl 7-Hydroxy-1-azacoumarin-3-carboxamide (5)). Bromo derivative (N-phenyl 6, 8-dibromo-7-hydroxy-1-azacoumarin-3-carboxamide (6)) was obtained from halogenation of compound N-phenyl 7-Hydroxy-1-azacoumarin-3-carboxamide (5) with bromine in glacial acetic acid. N-phenyl-2,5-diacetoxy-6, 8-disubstituted-Quinoline-3-carboxamides (N-phenyl 2,7-diacetoxy-Quinoline-3-carboxamide (7) and N-phenyl 2,7-diacetoxy-6,8-dibromo-Quinoline-3-carboxamide (8)) were prepared via the acetylation of compounds 5 and 6 with acetic anhydride. Five compounds 4–8 were evaluated in vitro against more than one human tumor cell lines. Among the selected compounds, 6 showed the best in vitro cytotoxicity against the human cancer cell line; MCF-7 (with IC50 = 10.12 μM). In addition, cell cycle analysis of compound 6 demonstrated cell cycle arrest at G2/M phase and Pre-G1 apoptosis.

Synthesis of Novel Nitro Substituted Benzothiazole Derivatives and Antibacterial activity against Pseudomonas aeruginosa

The resistance to antimicrobial drugs is becoming an increasingly important health and economic problem, and Pseudomonas (P) aeruginosa , one of the main micro-organisms of nosocomial infections, is known for its resistance to a range of antimicrobial agents. Benzothiazole derivatives have great importance in heterocyclic chemistry because of its potent and significant biological activities especially methoxy substitution at benzothiazole. Methoxy substituted benzothiazole derivatives were synthesized by reaction of 3-chloro-4-methoxy-aniline with potassium thiocyanate under temperature control and presence of bromine in glacial acetic acid and ammonia. Substituted nitrobenzamides then synthesized by condensation of, 2-amino-4-chloro-5-methoxy-benzothiazole with 2(3or4)-nitrobenzoylchloride acid in presence of dry pyridine and acetone. Finally, newly synthesized derivatives (K-01 to K-09) were synthesized through replacing of chlorine of nitrobenzamide by reaction with 2-nitroaniline, 3-nitroaniline, and 4-nitroaniline in presence of DMF. Analytical characterization was performed by TLC, melting point, IR and NMR spectra. Antibacterial activity was performed against P. aeruginosa by cup plate method (diffusion technique) using procaine penicillin as standard. Methoxy substituted benzothiazole derivatives comprising nitro group were synthesized and characterized by using analytical techniques. The synthesized derivatives screened for antibacterial activity. Compound K-03, K-05 and K-06 showed potent antibacterial activity against P. aeruginosa at both concentrations 50µg/ml and 100µg/ml as compared to standard.

SYNTHESIS OF NOVEL METHOXY SUBSTITUTED BENZOTHIAZOLE DERIVATIVES AND ANTIBACTERIAL ACTIVITY AGAINST ESCHERICHIA COLI

Objectives: Escherichia coli is a Gram-negative rod (bacillus) in the family Enterobacteriaceae. In general, it is harmless, but some special species could cause harmful infection. In the recent era, the number of antibiotics is available to combat infection caused by E. coli but because of resistance developed against available antibiotics research is continuously going on to synthesize newer antibiotic to overcome this problem. Synthesis and screening of benzothiazole derivatives have great importance in heterocyclic chemistry because of its potent and significant biological activities against E. coli especially methoxy substitution at benzothiazole.Methods: Methoxy substituted benzothiazole derivatives were synthesized by reaction of 3- chloro-4-methoxy-aniline with potassium thiocyanate under temperature control and presence of bromine in glacial acetic acid and ammonia. Substituted nitrobenzamides then synthesized by condensation of 2-amino-4-chloro-5-methoxy-benzothiazole with 2 (3 or 4)-nitrobenzoyl chloride acid in the presence of dry pyridine and acetone. Finally, newly synthesized derivatives (K-01 to K-09) were synthesized through replacing of chlorine of nitrobenzamide by reaction with 2-nitroaniline, 3-nitroaniline, and 4-nitroaniline in the presence of dimethoxy formamide. Analytical characterization was performed by thin-layer chromatography, melting point, infrared, and nuclear magnetic resonance. Antibacterial activity was performed against E. coli by cup plate method (diffusion technique) using streptomycin as standard. Compound K-03 showed potent antibacterial activity against E. coli at both concentrations 50 μg/mL and 100 μg/mL as compared to standard.Results: Compound D-03 exhibited excellent activity among all synthesized compounds.Conclusion: In the present work, efforts have been made to synthesized methoxy substituted benzothiazole derivatives and screened for antibacterial activity. Compound K-03 found as most active against E. coli.

Synthesis and Antimicrobial Activity of 1,2-Benzothiazine Derivatives.

A number of 1,2-benzothiazines have been synthesized in a three-step process. Nine chalcones 1–9 bearing methyl, fluoro, chloro and bromo substituents were chlorosulfonated with chlorosulfonic acid to generate the chalcone sulfonyl chlorides 10–18. These were converted to the dibromo compounds 19–27 through reaction with bromine in glacial acetic acid. Compounds 19–27 were reacted with ammonia, methylamine, ethylamine, aniline and benzylamine to generate a library of 45 1,2-benzothiazines 28–72. Compounds 28–72 were evaluated for their antimicrobial activity using broth microdilution techniques against two Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus) and two Gram-negative bacteria (Proteus vulgaris and Salmonella typhimurium). The results demonstrated that none of the compounds showed any activity against Gram-negative bacteria P. vulgaris and S. typhimurium; however, compounds 31, 33, 38, 43, 45, 50, 53, 55, 58, 60, 63 and 68 showed activity against Gram-positive bacteria Bacillus subtilis and Staphylococcous aureus. The range of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) was 25–600 µg/mL, though some of the MIC and MBC concentrations were high, indicating weak activity. Structure activity relationship studies revealed that the compounds with a hydrogen atom or an ethyl group on the nitrogen of the thiazine ring exerted antibacterial activity against Gram-positive bacteria. The results also showed that the compounds where the benzene ring of the benzoyl moiety contained a methyl group or a chlorine or bromine atom in the para position showed higher antimicrobial activity. Similar influences were identified where either a bromine or chlorine atom was in the meta position.

Crystal Structure of 3-Bromo-7-(dimethylamino)-4-methylcoumarin

Coumarin derivatives are a useful component for developing new materials, such as fluorescence materials and laser dyes; non-linear optical materials and reagents; photorefractive materials; photoresistors; intermediates for drug synthesis; luminescence materials; analytical reagents, etc.1,2 Coumarin 311, 7-(dimethylamino)-4-methylcoumarin, is also used as laser dyes. It gives laser emission at around 453 nm in ethanol. The crystal structure of coumarin 311 has already been reported.3 However the fluorence property and crystal structure of 3-bromo-7-(dimethylamino)-4-methylcoumarin (1) has not yet been reported. We now report on the crystal structure of 1 with the aim of the contributing to a deeper understanding of the substituent effect at the 3-position of coumarin 311 on the structure and crystal packing. Compound (1), shown in Fig. 1, was synthesized by the reaction of 7-(dimethylamino)-4-methylcoumarin with bromine in glacial acetic acid, as reported in a previous paper.4 The spectral data of 1 are as follows: mp 168 – 169 C, 1H NMR (CDCl3) d 2.53 (3H, s), 3.06 (6H, s), 6.48 (1H, d, J = 2.6 Hz), 6.62 (1H, dd, J = 9.0 Hz, 2.6 Hz), and 7.43 (1H, d, J = 9.0 Hz). 13C NMR (CDCl3) d 19.15, 40.1(2C), 97.7, 106.2, 109.3, 109.4, 125.8, 151.5, 152.8, 154.1, and 158.0. Compound (1) gave a strong emission band at 442 nm in chloroform solution (1.0 ¥ 10–5 M) when excited at 380 nm. Single crystals of 1 were grown in chloroform at room temperature. Data collection and refinement parameters are listed in Table 1. The H atoms were positioned with the idealized geometry, and were refined to be isotropic (Uiso(H) = 1.2Ueq(C)) using a riding model with C–H = 0.95 A for aromatic H atoms and C–H = 0.98 A for methyl H atoms. The selected bond distances and angles are collected in Table 2. An ORTEP drawing of the molecule of 1 is shown in Fig. 2. The molecule is almost planar with a maximum deviation of –0.154(2)A for N1. The dihedral angle between the pyrone ring Crystal Structure of 3-Bromo-7-(dimethylamino)-4-methylcoumarin

Synthesis and Antiviral Activity of Quercetin Brominated Derivatives

Reaction of quercetin (QR) (1) with bromine under various conditions was studied. Interaction of QR with 2-3 equiv. of bromine in glacial acetic acid at 35-40°C for 2-4 h and 20-22°C for 24 h led to the formation of QR 6,8-dibromide (2) (52-54% yields, 96-98% purity by HPLC). Interaction of QR with 2-5 equiv. bromine in absolute ethanol at 0-5°C and 20-22°C for 24 h led to the formation of 3-O-ethyl-QR-2,3,6,8,5'-pentabromide (3) (95-97% purity by HPLC) the output of which depends on the quantity of bromine. It was shown in MDCK cell culture that compound 2 exhibits a moderate inhibitory activity against pandemic influenza virus A/H1N1/pdm09 (EC50 6.0 µg/mL, CTD50 97.7 µg/mL, SI 16). Compound 3 was inactive.

Влияние бромирования метилового эфира 1-аллил-4-гидрокси-2,2-диоксо-1<i>H</i>-2λ<sup>6</sup>,1-бензотиазин-3-карбоновой кислоты на фармакологические свойства

С помощью рентгеноструктурного анализа установлено, что, в отличие от близких по строению алкил-1-аллил-4-гидрокси-2-оксо-1,2-дигидрохинолин-3-карбоксилатов, взаимодействие метилового эфира 1-аллил-4-гидрокси-2,2-диоксо-1H-2λ6,1-бензотиазин-3-карбоновой кислоты с молекулярным бромом в среде ледяной уксусной кислоты представляет собой не гетероциклизацию, а классическое присоединение брома к ненасыщенной аллильной связи. Фармакологические испытания показали, что в случае сложных эфиров удаление из 1-N-алкильного фрагмента двойной связи сопровождается спадом анальгетической активности.

4-HYDROXY-2-QUINOLONES. 203. REACTION OF 1-HEXYL- 4-HYDROXY-2-OXO-1,2-DIHYDROQUINOLINE-3-CARBOXYLIC ACID 4-PYRIDYLMETHYLIDENE HYDRAZIDE WITH BROMINE

It has been shown experimentally that upon the reaction of 1-hexyl-4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid 4-pyridylmethylidene hydrazide with molecular bromine in glacial acetic acid not only the azomethine carbon atom is brominated, but also the position 6 of the quinolone ring. Authors: I. V. Ukrainets, E. V. Mospanova, and S. V. Shishkina English Translation in Chemistry of Heterocyclic Compounds , 2012, 48 (8), pp 1200-1203 http://link.springer.com/article/10.1007/s10593-012-1122-z

Synthesis and Evaluation of Antimicrobial activity of several new Maleimides to Benzothiazole moiety

In this work, a series of new maleimides linked to substituted benzothiazole moiety were synthesized. Synthesis of these new cyclic imides were performed via three steps, the first one involved preparation of a series of 2-aminobenzothiazole substituted with different substituents via reaction of different primary aromatic amines with ammonium thiocyanate and bromine in glacial acetic acid. The prepared 2- amino benzothiozoles were introduced in the second step in reaction with maleic anhydride producing a series of N-(substituted benzothiazole-2-yl) maleamic acids.The resulted maleamic acids were dehydrated in the third step via treatment with acetic anhydride and anhydrous sodium acetate to afford a series of the desirable N-(substituted benzothiazole -2-yl) maleimides.The synthesized maleimides were screened for thier antibacterial activity against two types of bacteria including (staphylococcus aureus) Gram positive and (Klebsiella pneumoniae) Gram negative bacteria respectively.Antifungal activity of the prepared imides also were tested against (Candida albicans) fungi.The new compounds were found to exhibit good antibacterial and antifungal activities.

Synthesis and Evaluation of Antimicrobial activity of several new Maleimides to Benzothiazole moiety

In this work, a series of new maleimides linked to substituted benzothiazole moiety were synthesized. Synthesis of these new cyclic imides were performed via three steps, the first one involved preparation of a series of 2-aminobenzothiazole substituted with different substituents via reaction of different primary aromatic amines with ammonium thiocyanate and bromine in glacial acetic acid. The prepared 2- amino benzothiozoles were introduced in the second step in reaction with maleic anhydride producing a series of N-(substituted benzothiazole-2-yl) maleamic acids.The resulted maleamic acids were dehydrated in the third step via treatment with acetic anhydride and anhydrous sodium acetate to afford a series of the desirable N-(substituted benzothiazole -2-yl) maleimides.The synthesized maleimides were screened for thier antibacterial activity against two types of bacteria including (staphylococcus aureus) Gram positive and (Klebsiella pneumoniae) Gram negative bacteria respectively.Antifungal activity of the prepared imides also were tested against (Candida albicans) fungi.The new compounds were found to exhibit good antibacterial and antifungal activities.

4-hydroxy-2-quinolones. 203*. Reaction of 1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 4-pyridylmethylidene hydrazide with bromine

It has been shown experimentally that upon the reaction of 1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 4-pyridylmethylidene hydrazide with molecular bromine in glacial acetic acid not only the azomethine carbon atom is brominated, but also the position 6 of the quinolone ring.

Synthesis and Functionalization of 8‐Methyl‐2h‐pyrimido [2,1‐c][1,2,4]triazine‐3,6(1h,4h)‐dione

6‐Methyl‐2‐methylthio‐4‐oxopyrimidin‐3(4H)‐yl)acetohydrazide on heating in benzylamine undergo cyclization to 8‐methyl‐2H‐pyrimido[2,1‐c][1,2,4]triazine‐3,6(1H, 4H)‐dione, which under treatment with bromine in glacial acetic acid was converted to 7‐bromo substituted derivative and at reflux with Lawesson's reagent yielded 3‐thioxo compound. The latter reacted with primary and secondary amines to give 3‐amino substituted pyrimidotriazines and on alkylation—the corresponding S‐alkyl derivatives.

New synthesis and reactivity of 3‐bromoacetyl‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one with binucleophilic amines

Abstract 3‐(Bromoacetyl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one was synthesized by the reaction of dehydroacetic acid (DHAA) with bromine in glacial acetic acid. Novel heterocyclic products were synthesized from the reaction of bromo‐DHAA with alkanediamines, phenylhydrazines, ortho‐phenylenediamines, and ortho‐aminobenzenethiol. The obtained new products 3‐(2‐N‐substituted‐acetyl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐ones, 4‐hydroxy‐3‐[1‐hydroxy‐2‐(2‐phenylhydrazinyl)vinyl]‐6‐methyl‐2H‐pyran‐2‐one, 1‐(2,4‐dinitrophenyl)‐7‐methyl‐2,3‐dihydro‐1H‐pyrano[4,3‐c]pyridazine‐4,5‐dione, 3‐(3,4‐dihydroquinoxalin‐2‐yl)‐4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one/3‐(3,4‐dihydroquinoxalin‐2‐yl)‐6‐methyl‐2H‐pyran‐2,4(3H)‐dione, 6‐methyl‐3‐(3,4‐dihydroquinoxalin‐2‐yl)‐2H‐pyran‐2,4(3H)‐dione, and (E)‐3‐(2H‐benzo[b][1,4]thiazin‐3(4H)‐ylidene)‐6‐methyl‐2H‐pyran‐2,4(3H)‐dione were fully characterized by IR, 1H and 13C NMR, and mass spectra. J. Heterocyclic Chem., 2011.

ChemInform Abstract: Reactions of 2H,5H-Imidazo(1,5-b)isoquinoline-1,3-diones with Bromine.

Treatment of 2H,5H-imidazo[1,5-b]isoquinoline-1,3-diones 1 with one molar proportion of bromine in glacial acetic acid gave complex mixtures. The major component of each mixture was the corresponding 1,3-dioxoimidazo[1,5-b]isoquinolinium bromide 4; other constituents shown to be present included the 1,3-dioxo-10-bromoimidazo[1,5-b]isoquinoliniumbromides 5,2H,5H-imidazo[1,5-b]isoquinoline-1,3-diones 3, isocarbostyryl derivatives 9, dihydroisocarbostyryl derivatives 10, and 3-carbamoylisoquinolines 8. Reaction of the 2H,5H-imidazo[1,5-b]isoquinoline-1,3-diones 1 in glacial acetic acid with excess of bromine afforded 1,3-dioxo-10-bromoimidazo[1,5-b]isoquinolinium bromides 5 as principal products. Bromination of compounds 1 in carbon tetrachloride yielded mainly 1,3-dioxo-2H-imidazo[1,5-b] isoquinolinium bromides 12.

4-hydroxy-2-quinolones. 169*. synthesis and bromination of 1-allyl-3-(arylamino-methylene)quinoline-2,4-(1h,3h)-diones

Bromination of 1-allyl-substituted 3-(arylaminomethylene)quinoline-2,4-(1H,3H)-diones with one equivalent of molecular bromine in glacial acetic acid and subsequent dilution of the reaction mixture with water is accompanied by halocyclization and hydrolysis to form 2-bromomethyl-5-oxo-1,2 dihydro-5H-oxazolo[3,2-a]quinoline-4-carbaldehyde.

4-Hydroxy-2-quinolones. 168*. Synthesis, chemical and antitubercular properties of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pyrazin-2-ylamides

1-R-4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid pyrazin-2-ylamides have been synthesized as potential antitubercular agents. In contrast to pyrimidin-2-ylamides the compounds prepared are brominated by molecular bromine in glacial acetic acid at position 6 of the quinolone ring rather than in the amide part of the molecule. The 1-N-allyl derivative behaves similarly but undergoes halocyclization to give 2-bromomethyl-5-oxo-1,2-dihydro-5H-oxazolo[3,2-a]quinoline-4-carboxylic acid pyrazin-2-ylamide. A comparative analysis of the antimycobacterial properties of the synthesized compounds and their isomeric pyrimidin-2-ylamides has been carried out.

Synthesis and antimicrobial studies of novel methylene bridged benzisoxazolyl imidazo[2,1-b][1,3,4]thiadiazole derivatives

Novel methylene bridged benzisoxazolyl imidazo[2,1-b][1,3,4]thiadiazoles (3a-f) were synthesized from benzisoxazolyl-3-acetic acid and thiosemicarbazide. Reaction of 3 with bromine in glacial acetic acid in the presence of anhydrous sodium acetate yielded the corresponding 5-bromo derivatives (4a-f). While compound 3 furnished the 5-nitroso derivatives (5a-f) on refluxing with sodium nitrite solution. Thiocyanato derivatives (6a-f) were obtained by treating the imidazothiadiazole 3 with bromine and potassium thiocyanate in glacial acetic acid at room temperature. The structures of the newly synthesized compounds were confirmed by IR, NMR, mass and elemental analysis. All the compounds were screened for their antibacterial and antifungal activities. Some of the compounds displayed very good antibacterial and antifungal activity.

Effect of a Novel Series of Benzothiazolo‐Quinazolones on Epidermal Growth Factor Receptor (EGFR) and Biological Evaluations

A newly designed benzothiazolo-quinazolone series was synthesized by an aromatic amine and potassium thiocyanate in the presence of bromine in glacial acetic acid, and the final product was obtained by subsequent reaction with 5-arylamido/imidoalkyl-2-chlorobenzoic acid in the presence of potassium carbonate and further cyclization with sulphuric acid. A preliminary radiolabelling study with technetium shows a promising potential for further in vivo evaluation. Anti-bacterial, anti-viral and anti-tumor activities were evaluated for biological properties. Lead compounds are able to block epidermal growth factor receptor (EGFR) in human breast adenocarcinoma cell line, MCF-7.