- Synthesis and anticonvulsant activity of some ω-(1H-imidazol-1-yl)-N- phenylacetamide and propionamide derivatives
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In this study, eight new ω-(1H-imidazol-1-yl)-N-phenylacetamide and propionamide derivatives having 2,6-dimethyl, 2,6-dichloro, 2-chloro-6-methyl and 2-isopropyl substitutions on N-phenyl ring were synthesized to evaluate anticonvulsant activity against maximal electroshock test. The most active compounds in the series were the derivatives bearing 2-isopropyl and 2,6-dimethyl substituents on N-phenyl ring.
- Soyer, Zeynep,Kilic, Fatma Sultan,Erol, Kevser,Pabuccuoglu, Varol
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- Synthesis, antimicrobial evaluation, DNA gyrase inhibition, and in silico pharmacokinetic studies of novel quinoline derivatives
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Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66–5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad-spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66–3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC50 value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.
- El-Shershaby, Mohamed H.,El-Gamal, Kamal M.,Bayoumi, Ashraf H.,El-Adl, Khaled,Ahmed, Hany E. A.,Abulkhair, Hamada S.
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- Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines
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Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs), this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANC-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 μM. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-α) inhibitory activity, with IC50 value 0.155 μM. Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.
- Salem, Mohamed S.H.,Abdel Aziz, Yasmine M.,Elgawish, Mohamed S.,Said, Mohamed M.,Abouzid, Khaled A.M.
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- In silico approach towards lipase mediated chemoenzymatic synthesis of (S)-ranolazine, as an anti-anginal drug
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An in silico modelling based biocatalytic approach for the synthesis of drugs and drug intermediates in enantiopure forms is a rationalized methodology over the organo-chemical routes. In this study, enzyme-ligand based docking was carried out using (RS)-ranolazine, as the model drug for the screening of a suitable biocatalyst for the kinetic resolution of the racemic drug. The differential interaction of the two enantiomers with the lipase was analyzed on the basis of docking score and H-bond interaction with the amino acid residues, which helped to define the trans-esterification mechanism. Ranolazine [N-(2,6-dimethylphenyl)-2-[4-(2-hydroxy)-3-(2-methoxyphenoxy)propylpiperazin-1-yl]acetamide], an anti-anginal drug, significantly reduces the frequency of anginal attack and has also been used for the treatment of ventricular arrhythmias, and bradycardia. Various lipases were examined via computational as well as wet lab screening and Candida antartica lipase in the form of CLEA was the most efficient one for the (S)-selective kinetic resolution of (RS)-ranolazine, with highest conversion and enantiomeric excess. This is the first report of the chemo-enzymatic synthesis of (S)-ranolazine where the whole drug molecule was used for lipase catalysis. The present study showed that the combination of in silico studies and a classical wet lab approach could change the paradigm of biocatalysis.
- Sawant, Ganesh,Ghosh, Saptarshi,Banesh, Sooram,Bhaumik, Jayeeta,Chand Banerjee, Uttam
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- Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server
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The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.
- Fitzpatrick, Daniel E.,Maujean, Timothé,Evans, Amanda C.,Ley, Steven V.
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- Design, Synthesis and Computational Studies of Novel Carbazole N-phenylacetamide Hybrids as Potent Antibacterial, Anti-inflammatory, and Antioxidant Agents
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The present study deals with the synthesis of N-phenylacetamide-functionalized carbazole derivatives and their antibacterial, anti-inflammatory, and antioxidant assays. In vitro antibacterial studies of synthesized compounds shows prominent activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. In addition, in silico molecular docking studies corroborated that the methyl substituent (3g), (3h), and (3i) showed promising activity with lower ?G (kcal/mol) values. This study envisages that these compounds can serve as a new leading template in the chemotherapy of various bacterial ailments.
- Pattanashetty, Shivarudrappa H.,Hosamani,Shettar, Arun Kashivishwanath,Mohammed Shafeeulla
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- Synthesis and anticonvulsant activity of 4-(2-(2,6-dimethylphenylamino)-2-oxoethylamino)-N-(substituted)butanamides: A pharmacophoric hybrid approach
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A series of pharmacophoric hybrids of ameltolide-γ-aminobutyric acid (GABA)-amides was designed, synthesized, and evaluated for their anticonvulsant and neurotoxic properties. Initial anticonvulsant screening was performed using intraperitoneal (ip) maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), and subcutaneous picrotoxin (scPIC)-induced seizure threshold tests. All the compounds had improved lipophilicity and the pharmacological activity profile confirmed their blood-brain barrier penetration. The titled compounds showed promising activity in scPIC screen indicating the involvement of GABA-mediation. Compound 4-(2-(2,6-dimethylaminophenylamino)-2-oxoethylamino)-N-(2,6-dimethylphenyl) butanamide (7) emerged as the most potent derivative effective in all the three animal models of seizure with no neurotoxicity at the anticonvulsant dose.
- Yogeeswari, Perumal,Sriram, Dharmarajan,Sahitya, Puppala,Ragavendran, Jegadeesan Vaigunda,Ranganadh, Velagaleti
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- Chloroquinoline-acetamide hybrids: A promising series of potential antiprotozoal agents
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In an endeavour to develop efficacious antiprotozoal agents 2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]acetamide derivatives were synthesized and screened in vitro against the HM1:IMSS strain of E. histolytica and 3D7 strain of P. falciparum. Among the twenty-seven synthesized compounds, eleven evinced propitious anti-amoebic activity with IC50 values ranging from 0.41 to 1.80 μM) lower than the standard drug metronidazole (IC50 1.80 μM). All the compounds inhibited the in vitro growth of P. falciparum (IC50 range: 0.30-33.52 μM). Compounds A22 and A25 were found to be the most active antimalarial derivatives, and compound A16 the most active in inhibiting β-haematin formation; however compound A25 displayed the more favourable safety profile. The crystal structure for the compounds A7, A8, A12 and A21 was also determined. The molecular docking of crystal resolved inhibitors with PfDHFR allowed identification of stabilizing interactions within enzyme active sites. These compounds affirm the potential for further derivatives to enhance antiprotozoal activity whilst retaining their safety profile.
- Inam, Afreen,Van Zyl, Robyn L.,Van Vuuren, Natasha J.,Chen, Chien-Teng,Avecilla, Fernando,Agarwal, Subhash M.,Azam, Amir
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- One pot tandem dual CC and CO bond reductions in the β-alkylation of secondary alcohols with primary alcohols by ruthenium complexes of amido and picolyl functionalized N-heterocyclic carbenes
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Two different classes of ruthenium complexes, namely, [1-mesityl-3-(2,6-Me2-phenylacetamido)-imidazol-2-ylidene]Ru(p-cymene)Cl (1c) and {[1-(pyridin-2-ylmethyl)-3-(2,6-Me2-phenyl)-imidazol-2-ylidene]Ru(p-cymene)Cl}Cl (2c), successfully catalyzed the one-pot tandem alcohol-alcohol coupling reactions of a variety of secondary and primary alcohols, in moderate to good yields of ca. 63-89%. The mechanistic investigation performed on two representative catalytic substrates, 1-phenylethanol and benzyl alcohol using the neutral ruthenium (1c) complex showed that the catalysis proceeded via a partially reduced CC hydrogenated carbonyl species, [PhCOCH2CH2Ph] (3′), to the fully reduced CO and CC hydrogenated secondary alcohol, [PhCH(OH)CH2CH2Ph] (3). Furthermore, the time dependent study showed that the major product of the catalysis modulated between (3′) and (3) during the catalysis run performed over an extended period of 120 hours. Finally, the practical utility of the alcohol-alcohol coupling reaction was demonstrated by preparing five different flavan derivatives (13-17) related to various bioactive flavonoid natural products, in a one-pot tandem fashion.
- Dey, Shreyata,Ghosh, Prasenjit,Prakasham, A. P.,Ta, Sabyasachi
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supporting information
p. 15640 - 15654
(2021/11/30)
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- Rhodium-terpyridine Catalyzed Transfer Hydrogenation of Aromatic Nitro Compounds in Water
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A rhodium terpyridine complex catalyzed transfer hydrogenation of nitroarenes to anilines with i-PrOH as hydrogen source and water as solvent has been developed. The catalytic system can work at a substrate/catalyst (S/C) ratio of 2000, with a turnover frequency (TOF) up to 3360 h?1, which represents one of the most active catalytic transfer hydrogenation systems for nitroarene reduction. The catalytic system is operationally simple and the protocol could be scaled up to 20 gram scale. The water-soluble catalyst bearing a carboxyl group could be recycled 15 times without significant loss of activity.
- Liu, Yuxuan,Miao, Wang,Tang, Weijun,Xue, Dong,Xiao, Jianliang,Wang, Chao,Li, Changzhi
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p. 1725 - 1729
(2021/06/01)
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- Synthesis and antimicrobial evaluations of sulfur inserted fluoro-benzimidazoles
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A new series of fluorinated sulfur inserted benzimidazole analogues Za-i were synthesized and characterized. The new compounds were screened for their antimicrobial and antioxidant potential. The synthesized compounds were obtained by multiple step synthesis, initiating from the synthesis of 5-(difluoromethoxy)-1H-benzimidazole-2-thiol X. The compounds Ya-i prepared by reacting differently substituted anilines with chloroacetylchloride and triethylamine in DMF. Finally, the compound X was reacted with different derivatives of 2-chloro-N-phenylacetamide resulting in formation of titled compounds Za-i. The synthesized compounds (Za-Zi) were characterized by spectral analysis viz.1H & 13C NMR, mass spectra, elemental analysis and IR. The in vitro antimicrobial potential against Gram-positive (S. aureus and E. faecalis) and Gram-negative bacterial (E. coli and P.aeruginosa) strains as well as fungi (A. niger and C. albicans) was recorded for the obtained compounds. Some of the compounds exhibited encouraging results (in MIC) against Gram-positive and Gram-negative bacterial strains. These studies thus suggest that the designed sulfur inserted fluoro-benzimidazoles scaffold may serve as new promising template for further amplification as antimicrobial agents.
- Dwivedi, Parmesh Kumar,Chaturvedi, Devdutt
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p. 1525 - 1529
(2021/07/02)
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- Synthesis of (2-chloroquinolin-3-yl)-1,3,4-thiadiazole-2-carboxamides
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(2-Chloroquinolin-3-yl)-1,3,4-thiadiazole-2-carboxamides were synthesized from hydrazones obtained via the reaction of 3-formyl-2-chloroquinoline with oxamic acid thiohydrazides.
- Aksenov, A. N.,Krayushkin, M. M.,Yarovenko, V. N.
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p. 1131 - 1134
(2021/07/21)
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- New Mercaptoacetamide Derivatives: Synthesis and Assessment as Antimicrobial and Antimycobacterial Agents
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During last few years, the frightening elevation of bacterial resistance was accompanied by dramatic decline in recent treatments of infectious diseases, which became a point of anxiety for healthcare industries. MDR and XDR strains of Mycobacterium tuberculosis (Mtb) result in the tuberculosis. In this regard, herein, a series of new mercaptoacetamide derivatives were synthesized via multipot synthetic pathway and the rationale was the appraisal of bioactivity in compact heteronuclei and their assessment as potential antimicrobial and antimycobacterial agents against virulent strain of Mtb, H37Ra for structure–activity relationship (SAR) studies. The inhibition zones of compounds 4c and 4e were found to be nearest to that of standard drug Ciprofloxacin, while compounds 4h and 4j were mild to moderately active against Gram positive bacteria (Staphylococcus aureus, Streptococus pneumonia) and Gram negative bacteria (Pseudomonas aeruginosa, Salmonella typhimurium and Escherichia coli). MIC90 assays indicated that new mercaptoacetamides did not exhibit in vitro activity against Mtb in contrast to Rifampicin and Streptomycin, first-line antimycobacterial chemotherapeutic agents. According to the present study, it was concluded that mercaptoacetamides of the new series succeeded as antimicrobial agents but could not develop as potential lead compounds against Mtb when tested in concentrations of 50, 25, 12.5 and 6.25 μg/mL.
- Hashim, Syed Riaz,Hegde, Rahul Rama,Pal, Dilipkumar,Rani, Priyanka
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p. 715 - 723
(2021/10/27)
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- Antidiabetic compounds
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Compounds for the treatment of hyperglycemia and/or diabetes are provided. The compounds, which inhibit the enzyme dipeptidyl peptidase (DPP-4), are based on the structure where X may be present or absent an may be OH, Ar is an aryl group; and n ranges from 0 to 5.
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Page/Page column 13-14
(2020/06/16)
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- Method for preparing lidocaine intermediate alpha-chloroacetyl-2, 6-dimethylaniline and lidocaine without adding extra alkali
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The invention relates to a method for preparing lidocaine intermediate alpha-chloroacetyl-2, 6-dimethylaniline and lidocaine without adding extra alkali, which belong to the technical field of organicsynthesis. The invention discloses the method for preparing alpha-chloroacetyl-2, 6-dimethylaniline, which comprises the following steps: in the process of generating alpha-chloroacetyl-2, 6-dimethylaniline by carrying out a chloroacetylation reaction on 2, 6-dimethylaniline and chloroacetyl chloride, taking one or a mixed solution of more than two of an alkane solvent, an ether solvent and an ester solvent as an organic solvent. No extra alkali is added, so that the separation process can be reduced; the method can be applied to one-pot reaction to directly prepare lidocaine, namely, 2, 6-dimethylaniline, chloroacetyl chloride and diethylamine directly react to obtain lidocaine, the method is simple, no extra alkali is added, the separation process is simplified, the used solvents are three types of solvents, operation is safer, and the obtained product is high in purity, high in yield, low in cost and environmentally friendly.
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Paragraph 0043-0047; 0048-0050; 0052-0054; 0056-0058; 0059
(2020/06/30)
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- Method for preparing lidocaine
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The invention discloses a method for preparing lidocaine. The method comprises the following steps of: (1) by using 2, 6-dimethylnitrobenzene as a raw material, Pd/C as a catalyst and methanol as a solvent, carrying out reduction reaction with hydrogen at normal temperature and normal pressure to obtain an intermediate 2, 6-dimethylaniline; (2) reacting the obtained intermediate 2, 6-dimethylaniline with chloroacetyl chloride in the presence of potassium carbonate, and taking dichloromethane as a solvent to prepare an intermediate chloroacetyl-2, 6-dimethylaniline; and (3) reacting the obtained intermediate chloroacetyl-2, 6-dimethylaniline with diethylamine, taking normal hexane as a solvent, performing refluxing until the reaction is complete, performing washing with water and cooling toobtain lidocaine. The method disclosed by the invention is simple and convenient in technological process, few in operation links and relatively high in lidocaine yield, and the prepared lidocaine isgood in purity which reaches 99.5% or above, so that the method has a good industrial application prospect.
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Paragraph 0031; 0034; 0035; 0038; 0041; 0042; 0045; 0048
(2020/04/17)
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- Preparation method of lidocaine hydrochloride
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The invention relates to a preparation method of lidocaine hydrochloride, which comprises the following steps: carrying out acylation reaction by using 2, 6-dimethylaniline and chloroacetyl chloride as raw materials, directly adding diethylamine into the system to carry out amination reaction after the reaction is finished, filtering the product, and adding hydrochloric acid into the filtrate to carry out salification reaction. The preparation method of lidocaine hydrochloride provided by the invention is a one-pot method, avoids repeated purification of an intermediate product in a traditional process, and is simple in process, mild in condition, easy to control, high in product yield and high in purity.
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Paragraph 0031; 0033-0034
(2020/01/25)
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- Preparation method of 2, 6-dimethylaniline long-chain compound
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The invention discloses a preparation method of a 2, 6-dimethylaniline long-chain compound. The method comprises S1, mixing a compound II and a compound III with a first solvent, and adding in a firstbase catalyst for reaction at 0-80 DEG C to obtain a compound IV; S2, uniformly mixing the compound IV prepared in S1, a compound V and a second solvent for mixed reaction at 70-120 DEG C, washing reaction products through ethyl acetate, and filtering out precipitates, namely a compound VI; S3, mixing the compound VI prepared in S2, a second base catalyst, a reactant A, alcohols and a third solvent for mixed reaction at 30-80 DEG C to obtain a compound I, wherein the reactant A is an acyl chloride or ester compound. According to the preparation method of the 2, 6-dimethylaniline long-chain compound, the applied raw materials are all common chemical materials and accordingly are wide in resource and low in prices, products of every reaction save complicated column chromatography and can berecrystallized into high-purity products, so that the preparation method of the 2, 6-dimethylaniline long-chain compound has an industrial scaled synthesis prospect.
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Paragraph 0023-0027; 0041-0046
(2019/04/17)
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- Benzyl and sulfonyl derivatives of n-(2,6-dimethylphenyl)-2(piperazin-1-yl)acetamide (t2288): biological screening and fingerprint applications
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A series of five N-(2,6-dimethylphenyl)-2-(piperazin-1-yl)acetamide (T2288) sulfonamides 6a-e and its five alkylated piperazine derivatives 8a-e have been synthesized, characterized and screened for antibacterial, antifungal and anthelmintic activity. Some of the compounds showed significant biological activities. Molecular docking to crystal structures of target proteins revealed that, active compounds show similar binding poses as that of standards, indicating good correlation of the binding energy with observed in vitro data for the active compounds. Finally, the study of latent fingerprint analysis showed that the compound 6c exhibits good stickiness and finger rhythm without dense dust. The resulting compound can be used to detect fingerprints on all types of flat surfaces and hence easily accepted for detecting hidden fingerprints. This research can offer an excellent setting that can lead to the discovery of potential antibacterial, antifungal, anthelmintic and fingerprint agents.
- Khan, Ghouse,Sreenivasa, Swamy,Govindaiah, Shivaraja,Chandramohan, Vivek
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p. 157 - 166
(2019/06/05)
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- Overcoming solid handling issues in continuous flow substitution reactions through ionic liquid formation
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Substitutions such as acylations, arylations, and alkylations are some of the most commonly run reactions for building complex molecules. However, the requirement of a stoichiometric base to scavange acid by-products creates significant challenges when operating in continuous flow due to solid handling issues associated with precipitating base·HX salts. We present a general and simple strategy to overcome these solid handling issues through the use of acid scavenging organic bases that generate low- to moderate-melting ionic liquids upon protonation. The application of these bases towards the most commonly run substitutions are demonstrated, enabling reactions to be run in flow without requiring additional equipment, specific solvents, or dilute reaction conditions to prevent clogging.
- Kashani, Saeed,Sullivan, Ryan J.,Andersen, Mads,Newman, Stephen G.
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supporting information
p. 1748 - 1753
(2018/04/30)
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- IMPROVED PROCESS FOR THE SYNTHESIS OF 2, 6-XYLIDINE AND ITS DERIVATIVES
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The disclosure herein provides a composition of compound of formula 1. The disclosure also provides a method of synthesizing the compound of formula 1 and its improved processes. The compound of formula 1 or its pharmaceutical acceptable salts, as well as polymorphs, solvates, and hydrates thereof may be formulated as pharmaceutical composition to be used for treatment of pain. The pharmaceutical composition of compound of formula 1 or the final compound may be formulated for noninvasive peroral, topical (example transdermal), enteral, transmucosal, targeted delivery, sustained release delivery, delayed release, pulsed release and parenteral methods. Such compositions may be used to treat chronic pain manifested with chronic diseases or its associated complications. The compound of formula 1 may also be offered as a kit.
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Paragraph 00042; 00043; 00056
(2017/06/12)
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- Versatile Bulky N,N′,N′-Substituted 1,2-Ethanediamine Ligands and Their Lithium, Aluminium, and Gallium Derivatives
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Sterically demanding N,N′,N′-substituted 1,2-ethanediamine ligands have been prepared from commercially available starting materials by applying a facile one-step procedure. These ligands offer advantages compared to known systems: a suppressed delocalization due to the saturated backbone inhibits a noninnocent behaviour and the low symmetry of the related metal complexes makes them potential candidates for asymmetric catalysis. The ligands are readily transformed into the corresponding lithium derivatives 4, which in turn act as starting materials to access the corresponding aluminium and gallium dichlorides 5 and 6, respectively. In addition, deprotonation by Al(CH3)3gives rise to the related dimethylalane 7. All main-group element compounds have been studied by means of single X-ray crystallography and spectroscopic methods.
- Kretschmer, Robert,Dehmel, Maximilian,Bodensteiner, Michael
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supporting information
p. 965 - 970
(2017/02/15)
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- A convenient modified synthesis of 5-pyridinyl-1,3,4-thiadiazole-2-carboxamides
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A general one-pot procedure is developed for the synthesis of 5-pyridinyl-1,3,4-thiadiazole-2-carboxamides by the reaction of pyridine carboxaldehydes with oxamic acid thiohydrazides. (Figure Presented).
- Myannik,Yarovenko,Rodionova,Baryshnikova,Krayushkin
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p. 316 - 325
(2017/10/16)
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- Synthesis and analgesic properties of lidocaine derivatives with substituted aminobenzothiazoles
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Local anesthetics are the most widely consumed drugs in the practice of medicine which provide a loss of sensation in a certain body part without loss of consciousness or impairment of central control of essential functions. Lidocaine (I) is the most commonly local anaesthetic drug which is widely used in all species due to its fabulous diffusing and penetrating properties as well as prompt onset of surgical analgesia. In this study, new aminobenzothiazole (with many useful biological and pharmacological properties) analogues were synthesized by changing of amine moiety of I. Both acute and chronic pain properties of new compounds (II-VI) were studied by using the tail immersion and formalin tests on mice and the outcomes were compared with control and lidocaine groups. According to the results, aminobenzothiazole derivatives are better candidates than diethylamine group for replacement on amine moiety of I. Also, derivatives with electron-withdrawing groups on this amine (V and VI) could decrease pain better than electron-donating ones (II and III) (specially on position 6 of this amine, II and V) which may be of concern for blockade of specific sodium channels by these new compounds.
- Ahmadi, Abbas,Khalili, Mohsen,Mohammadinoude, Mohammad Kazem,Nahri-Niknafs, Babak
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p. 507 - 512
(2016/07/06)
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- NOVEL PROCESS FOR THE PREPARATION OF RANOLAZINE
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The present invention relates to novel processes for the preparation of Ranolazine (I) and its acid addition salts and the novel process for the preparation of compound of formula (7).
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Page/Page column 16
(2016/09/26)
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- Rapid Vortex Fluidics: Continuous Flow Synthesis of Amides and Local Anesthetic Lidocaine
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Thin film flow chemistry using a vortex fluidic device (VFD) is effective in the scalable acylation of amines under shear, with the yields of the amides dramatically enhanced relative to traditional batch techniques. The optimized monophasic flow conditions are effective in ≤80seconds at room temperature, enabling access to structurally diverse amides, functionalized amino acids and substituted ureas on multigram scales. Amide synthesis under flow was also extended to a total synthesis of local anesthetic lidocaine, with sequential reactions carried out in two serially linked VFD units. The synthesis could also be executed in a single VFD, in which the tandem reactions involve reagent delivery at different positions along the rapidly rotating tube with in situ solvent replacement, as a molecular assembly line process. This further highlights the versatility of the VFD in organic synthesis, as does the finding of a remarkably efficient debenzylation of p-methoxybenzyl amines.
- Britton, Joshua,Chalker, Justin M.,Raston, Colin L.
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supporting information
p. 10660 - 10665
(2015/07/20)
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- Design and development of novel Mycobacterium tuberculosis l-alanine dehydrogenase inhibitors
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In the present study, we used crystal structure of MTB L-AlaDH protein complex with N6-methyl adenosine for structure based virtual screening of in house database to identify new small molecule inhibitors for MTB-L-AlaDH. Two molecules identified as better leads and were modified synthetically to obtain thirty novel analogues belonging to 2-iminothiazolidine-4-ones and 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamides. Among the screened compounds four (4n, 4o, 12 and 14) emerged as potent inhibitors displaying IC50 values ranging from 0.58 ± 0.02 to 1.74 ± 0.03 μM against MTB-L-AlaDH and were non-cytotoxic at 50 μM. Some of these synthesized compounds also exhibited good activity against nutrient starved dormant MTB cells. The most potent inhibitors were found to stabilize the protein which was confirmed biophysically through differential scanning fluorimetry.
- Saxena, Shalini,Samala, Ganesh,Sridevi, Jonnalagadda Padma,Devi, Parthiban Brindha,Yogeeswari, Perumal,Sriram, Dharmarajan
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p. 401 - 414
(2015/03/04)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT ANGINA AND CARDIOVASCULAR CONDITIONS
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of angina and cardiovascular conditions may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of chronic aneurysm, angina, atherosclerosis, cerebrovascular accident (stroke), cerebrovascular disease, congestive heart failure, coronary artery disease, myocardial infarction (heart attack), peripheral vascular disease, aortic dissection, aortic stenosis, arrhythmia (irregular heartbeat), atrial fibrillation, cardiomyopathy, chest pain, claudication, congenital heart disease.
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Paragraph 0126; 0127; 0128
(2015/06/03)
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- Homologation of isocyanates with lithium carbenoids: A straightforward access to α-halomethyl- and α,α-dihalomethylamides
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Treatment of widely available isocyanates with monohalolithium and dihalolithium carbenoids provides a valuable protocol for the one-pot preparation of α-halo- and α,α-dihaloacetamide derivatives. While monohalolithium carbenoids can be prepared by a smoo
- Pace, Vittorio,Castoldi, Laura,Mamuye, Ashenafi Damtew,Holzer, Wolfgang
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p. 2897 - 2909
(2015/01/16)
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- "All water chemistry" for a concise total synthesis of the novel class anti-anginal drug (RS), (R), and (S)-ranolazine
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A novel strategy of 'all water chemistry' is reported for a concise total synthesis of the novel class anti-anginal drug ranolazine in its racemic (RS) and enantiopure [(R) and (S)] forms. The reactions at the crucial stages of the synthesis are promoted by water and led to the development of new water-assisted chemistries for (i) catalyst/base-free N-acylation of amine with acyl anhydride, (ii) base-free N-acylation of amine with acyl chloride, (iii) catalyst/base-free one-pot tandem N-alkylation and N-Boc deprotection, and (iv) base-free selective mono-alkylation of diamine (e.g., piperazine). The distinct advantages in performing the reactions in water have been demonstrated by performing the respective reactions in organic solvents that led to inferior results and the beneficial effect of water is attributed to the synergistic electrophile and nucleophile dual activation role of water. The new 'all water' strategy offers two green processes for the total synthesis of ranolazine in two and three steps with 77 and 69% overall yields, respectively, and which are devoid of the formation of the impurities that are generally associated with the preparation of ranolazine following the reported processes.
- Kommi, Damodara N.,Kumar, Dinesh,Chakraborti, Asit K.
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p. 756 - 767
(2013/03/29)
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- Process for the Preparation of Ranolazine
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A process for the preparation of ranolazine comprises the step of condensing N-(2,6-dimethylphenyl)-1-piperazinyl acetamide with a compound of formula (I) to obtain ranolazine, in which X is chlorine or bromine Ranolazine is prepared by condensing ring-opening halide which replaces epoxide in this process.
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Paragraph 0027; 0028
(2013/04/13)
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- Discovery of novel inhibitors of signal transducer and activator of transcription 3 (STAT3) signaling pathway by virtual screening
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Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers that harbor aberrantly-active STAT3. In this study, nearly 204,000 compounds in Specs database were screened by virtual screening, and samples of top 100 compounds identified as candidate small-molecule inhibitors of STAT3 were evaluated by STAT3-dependent luciferase reporter assay as well as other cell-based assays. A benzothiazole core scaffold containing compound, 9, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 3.567 μM. It is the first time to discover benzothiazole scaffold as a potent STAT3 signaling inhibitor. We further investigated the (structure-activity relationship) SAR of the benzothiazole analogues, and discovered compound 16w as a better small-molecule inhibitor. Both compounds inhibited the phosphorylation of STAT3 and had no obvious effect on upstream JAK2 kinase.
- Zhang, Mingming,Zhu, Weiliang,Li, Yingxia
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p. 301 - 310
(2013/05/22)
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- New thiazolidinyl analogs containing pyridine ring: Synthesis, biological evaluation and QSAR studies
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A series of pyridine derivatives of thiazolidin-4-ones (4a-4o) has been synthesized. Structures of these compounds were established on the basis of elemental analysis, IR, 1H NMR, 13C NMR, and Mass spectral data. All the synthesized compounds have been evaluated for their anti-inflammatory and analgesic effects. The results showed that compound 2-[4-methylphenylimino]-5-(1H-pyridin-2-ylmethylidene)-1,3-thiazolidin-4-one (4d), 2-(2,4-dinitro-phenylhydrazinylidine)-5-(1H-pyridin-2-yl-methylidene)-1,3- thiazolidin-4-one (4h), and 2-[3-nitro-phenylimino]-5-(1H-pyridin-2-yl- methylidene)-1,3-thiazolidin-4-one (4j) exhibited good anti-inflammatory and analgesic activity. Compound 4h was found to be the most active compound of the series with an interesting dual anti-inflammatory and analgesic activity. Docking simulation was performed to position synthesized compounds into the active site of COX-2. The relationships of energy-based docking score with analgesic and anti-inflammatory activities were also investigated by linear regression method. The QSAR models with R 2 of 0.621 and 0.740 were developed for analgesic and anti-inflammatory activities, respectively.
- Ranga, Reetu,Sharma, Vikas,Kumar, Vipin
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p. 1538 - 1548
(2013/07/26)
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- Addition of lithium carbenoids to isocyanates: A direct access to synthetically useful N-substituted 2-haloacetamides
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The addition of lithium carbenoids to isocyanates provides a versatile access to N-substituted 2-haloacetamides: the reaction tolerates the presence of variously functionalized substituents on the nitrogen atom, including sterically demanding ones and reactive halogens. No erosion of the enantiopurity was observed in the case of optically active isocyanates. One of the substrates prepared has been employed in Charette's type chemoselective addition of a Grignard reagent to access an α-chloroketone.
- Pace, Vittorio,Castoldi, Laura,Holzer, Wolfgang
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supporting information
p. 8383 - 8385
(2013/09/23)
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- Improved process for ranolazine: An antianginal agent
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An improved process has been developed for the active pharmaceutical ingredient, ranolazine with 99.9% purity and 47% overall yield (including three chemical reactions and one recrystallization). Formation and control of all the possible impurities is described. All the solvents used in the process were recovered and reused. The unreacted piperazine is recovered as piperazine monophosphate monohydrate salt.
- Aalla, Sampath,Gilla, Goverdhan,Anumula, Raghupathi Reddy,Kurella, Srinivas,Padi, Pratap Reddy,Vummenthala, Prabhakar Reddy
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experimental part
p. 748 - 754
(2012/08/27)
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- 2, 6 XYLIDINE DERIVATIVES FOR THE TREATMENT OF PAIN
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The disclosure herein provides a composition compound of formula 1. The disclosure also provides a method of synthesizing the compound of formula 1. The compound of formula 1 or its pharmaceutical acceptable salts, as well as polymorphs, solvates, and hydrates thereof may be formulated as pharmaceutical composition to be used for treatment of pain. The pharmaceutical composition of compound of formula 1 or the final compound may be formulated for non-invasive peroral, topical (example transdermal), enteral, transmucosal, targeted delivery, sustained release delivery, delayed release, pulsed release and parenteral methods. Such compositions may be used to treat chronic pain manifested with chronic diseases or its associated complications. The compound of formula 1 may also be offered as a kit.
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Page/Page column 4
(2012/02/03)
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- Determination of stability constants and acute toxicity of potential hepatotropic gadolinium complexes
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Due to their high specificity for the hepatobiliary system, iminodiacetic acid derivatives are known to form a class of hepatobiliary agents. In this paper we present new hepatotropic gadolinium complexes to be used as potential MRI contrast agents. Derivatives of N-(2-phenylamine-2-oxoethyl)iminodiacetic acid are introduced as ligands into such complexes. In this way, we hope to achieve a valuable diagnostic tool for investigating of pathological changes in the liver. Stability constants of complexes were determined by potentiometric titration in 0.1 mol L-1 NaNO3 solution at 20.0 ± 0.1OC. Stability and selectivity constants were also determined for endogenous metal ions such as Cu2+, Ca2+, and Zn2+ with the use of SUPERQUAD computer program. Acute toxicity of new gadolinium complexes was assessed in mice and histopathology examinations were carried out.
- Mikiciuk-Olasik, Elzbieta,Wojewoda, Emilia,Bilichowski, Ireneusz,Witczak, Malgorzata,Karwowski, Boleslaw,Wagrowska-Danilewicz, Malgorzata,Stasikowska, Olga
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experimental part
p. 119 - 127
(2011/08/05)
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- PREPARATION OF RANOLAZINE, ITS SALTS AND INTERMEDIATES THEREOF
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The present patent application relates to an improved process for the preparation of Ranolazine, pharmaceutically acceptable salts and intermediates thereof. Specifically it relates to processes for preparation of 1-(2-methoxy phenoxy)-2,3-epoxy propane in substantially aqueous solvent medium and 2-chloro-N-(2,6-dimethylphenyl) acetamide without using any additional base, which are intermediates, useful in the preparation of Ranolazine and pharmaceutically acceptable salts thereof.
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Page/Page column 15
(2010/04/06)
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- PREPARATION OF RANOLAZINE
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Preparation of ranolazine and intermediates thereof, for use in pharmaceutical compositions comprising ranolazine.
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Page/Page column 50
(2010/04/06)
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- Synthesis and biological evaluation of 1,4-diazepane derivatives as T-type calcium channel blockers
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We have synthesized and biologically evaluated 1,4-diazepane derivatives as T-type calcium channel blockers. In this study, we discovered compound 4s, a potential T-type calcium channel blocker with good selectivity over hERG and N-type calcium channels. In addition, it exhibited favorable pharmacokinetic characteristics for further investigation of T-type calcium channel related diseases.
- Gu, Su Jin,Lee, Jae Kyun,Pae, Ae Nim,Chung, Hye Jin,Rhim, Hyewon,Han, So Yeob,Min, Sun-Joon,Cho, Yong Seo
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scheme or table
p. 2705 - 2708
(2010/07/15)
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- A PROCESS FOR THE PREPARATION OF RANOLAZINE
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The present invention relates to an improved and novel process for preparation of ranolazine.
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Page/Page column 8
(2010/09/17)
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- Synthesis of ranolazine metabolites and their anti-myocardial ischemia activities
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The anti-anginal drug Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, is thought to modulate the metabolism during myocardial ischemia by activating pyruvate dehydrogenase activity to promote glucose oxidation. Ranolazine and its five principal metabolites: CVT-2512, CVT-2513, CVT-2514, CVT-2738 and CVT-4786, were synthesized. The effect of Ranolazine and its metabolites on the ECG (electrocardiogram) of mice with myocardial ischemia induced by isoprenaline and their effect on alleviating the symptom of myocardial ischemia were tested and compared. The results showed that CVT-2738 and CVT-2513 could be protective against mice myocardial ischemia induced by isoprenaline. Within all the metabolites tested in this study, CVT-2738 exhibited the best potency, however, it was still less potent than Ranolazine.
- Yao, Zhangyu,Gong, Shubo,Guan, Teng,Li, Yunman,Wu, Xiaoming,Sun, Hongbin
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scheme or table
p. 1218 - 1222
(2010/06/16)
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- IMPROVED PROCESS FOR THE PREPARATION OF RANOLAZINE
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The present invention provides an improved process for the preparation of ranolazine of formula I and pharmaceutically acceptable salts thereof, by reacting 2,6-dimethylaniline derivative with chloroacetyl chloride in the presence of base in water and resulting amide intermediate is reacted with piperazine and the resulting piperazinc derivative is further condensed with an appropriate oxirane derivative ( prepared by the reaction of 2-methoxyphenol with epichlorohydrin in the presence of base using phase transfer catalyst) in an inert solvent, and highly pure ranolazine is isolated and converted to its acid salts using excess of mineral acid.
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Page/Page column 16; 17
(2008/12/05)
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- SUBSTITUTED PIPERAZINES
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Disclosed herein are substituted piperazine late Na+ channel modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 31
(2009/01/24)
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- Synthesis and antispasmodic activity of lidocaine derivatives endowed with reduced local anesthetic action
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The present structure-activity relationship (SAR) study focused on chemical modifications of the structure of the local anesthetic lidocaine, and indicated analogues having reduced anesthetic potency, but with superior potency relative to the prototype in preventing anaphylactic or histamine-evoked ileum contraction. From the SAR analysis, 2-(diethylamino)-N-(trifluoromethyl-phenyl) and 2-(diethylamino)-N-(dimethyl-phenyl) acetamides were selected as the most promising compounds. New insights into the applicability of non-anesthetic lidocaine derivatives as templates in drug discovery for allergic syndromes are provided.
- Costa, Jorge C.S.,Neves, Josiane S.,de Souza, Marcus V.N.,Siqueira, Rodrigo A.,Romeiro, Nelilma C.,Boechat, Nubia,Silva, Patricia M.R.e,Martins, Marco A.
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p. 1162 - 1166
(2008/09/20)
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- Synthesis and spectral characterisation of new amido-ether Schiff bases
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Series of new compounds prepared by condensing the sodium salt of 4-[(4-methoxy-benzylidene)-amino]-phenol with chloroacetanilides carrying various substituents in different positions has been synthesised and characterised by UV-VIS, FTIR, MS, 1H and 13C NMR spectrometry. The effect of type and position of different substituents on thermal and on mesomorphic behaviour has been investigated by polarizing optical microscopy and differential scanning calorimetry studies. All compounds possess relatively high phase transition temperatures due to possibility of forming molecular associations and only the 2,4-substituted ones possess the liquid crystalline behaviour, namely the nematic phase.
- Stamatoiu, Oana,Bubnov, Alexej,?arcomnicu, Isabela,Iovu, Mircea
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experimental part
p. 187 - 196
(2009/02/04)
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- Palladium-catalyzed silane/siloxane reductions in the one-pot conversion of nitro compounds into their amines, hydroxylamines, amides, sulfonamides, and carbamates
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A combination of palladium(II) acetate, aqueous potassium fluoride, and polymethylhydrosiloxane (PMHS) facilitates the room-temperature reduction of aromatic nitro compounds to anilines. These reactions tend to be quick (30 min), high-yielding, and tolerate a range of other functional groups. Replacement of PMHS/KF with triethylsilane allows for the reduction of aliphatic nitro compounds to their corresponding hydroxylamines. Depending on the substrate, both conditions can allow for the in situ conversion of the product amines into amides, sulfonamides, and carbamates. Georg Thieme Verlag Stuttgart.
- Rahaim Jr., Ronald J.,Maleczka Jr., Robert E.
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p. 3316 - 3340
(2008/09/17)
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- Heteroaryl alkyl piperazine derivatives
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Novel compounds of the general formula: and pharmaceutically acceptable acid addition salts thereof, wherein the compounds are useful in therapy to protect skeletal muscles against damage resulting from trauma or to protect skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, in the treatment of diabetes, in the treatment of cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
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- The synthesis and anticonvulsant activity of some omega-phthalimido-N-phenylacetamide and propionamide derivatives.
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In this study, by combining anilide and N', N'-phthaloylglycinamide pharmacophores which are known to produce potent anticonvulsant compounds, sixteen omega-phthalimido-N-phenylacetamide and propionamide derivatives bearing substituents at positions 2 or 2, 6 on N-phenyl ring have been synthesized. The structural confirmation of the title compounds was achieved by interpretation of spectral and analytical data. The anticonvulsant activity of the title compounds was determined against maximal electroshock seizure at 100 mg/kg dose level in mice. The preliminary screening results indicated that omega-phthalimido-N-phenylacetamide and propionamide nuclei have pronounced anticonvulsant activity against maximal electroshock seizure.
- Soyer, Zeynep,Kilic, Fatma Sultan,Erol, Kevser,Pabuccuoglu, Varol
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p. 105 - 111
(2007/10/03)
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- Acetamides and benzamides that are useful in treating sexual dysfunction
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The present invention relates to the use of compounds of formula (I) for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.
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