- N-Arylalkylbenzo[d]thiazole-2-carboxamides as anti-mycobacterial agents: Design, new methods of synthesis and biological evaluation
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Benzothiazole-2-carboxyarylalkylamides are reported as a new class of potent anti-mycobacterial agents. Forty-one target compounds have been synthesized following a green synthetic strategy using water as the reaction medium to construct the benzothiazole scaffold followed by (i) microwave-assisted catalyst-free and (ii) ammonium chloride-catalyzed solvent-free amide coupling. The anti-mycobacterial potency of the compounds was determined against H37Rv strain. Twelve compounds exhibited promising anti-TB activity in the range of 0.78-6.25 μg mL-1 and were found to be non-toxic (-1) to HEK 293T cell lines with therapeutic index (TI) of 8-64. The most promising anti-TB compound 5bf showed MIC of 0.78 μg mL-1 (TI > 64). The molecular docking studies of 5bf predict it to be a ligand for the M. tuberculosis HisG, the putative drug target for tuberculosis and could serve as a guiding principle for lead optimization.
- Shah, Parth,Dhameliya, Tejas M.,Bansal, Rohit,Nautiyal, Manesh,Kommi, Damodara N.,Jadhavar, Pradeep S.,Sridevi, Jonnalagadda Padma,Yogeeswari, Perumal,Sriram, Dharmarajan,Chakraborti, Asit K.
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Read Online
- Design, synthesis, and biological activity evaluation of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives as broad-spectrum antifungal agents
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To discover antifungal compounds with broad-spectrum and stable metabolism, a series of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives was designed and synthesized. Compounds A30-A34 exhibited excellent broad-spectrum antifungal activity against Candida albicans with MIC values in the range of 0.03–0.5 μg/mL, and against Cryptococcus neoformans and Aspergillus fumigatus with MIC values in the range of 0.25–2 μg/mL. In addition, compounds A31 and A33 showed high metabolic stability in human liver microsomes in vitro, with the half-life of 80.5 min and 69.4 min, respectively. Moreover, compounds A31 and A33 showed weak or almost no inhibitory effect on the CYP3A4 and CYP2D6. The pharmacokinetic evaluation in SD rats showed that compound A31 had suitable pharmacokinetic properties and was worthy of further study.
- Zhao, Liyu,Sun, Yin,Yin, Wenbo,Tian, Linfeng,Sun, Nannan,Zheng, Yang,Zhang, Chu,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
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- 6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects**
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Current common analgesics are mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. However, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that many of these compounds have dual agonism on kappa and mu opioid receptors. In vivo studies on the lead dual kappa and mu opioid receptor agonist demonstrated supraspinal thermal analgesic activity while avoiding anxiogenic effects in male mice, thus providing further strong evidence in support of the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.
- Akins, Nicholas S.,Ashpole, Nicole M.,Dudhipala, Narendar,Harris, Hannah M.,Keasling, Adam W.,Kim, Seong Jong,Le, Hoang V.,Majumdar, Soumyajit,Mishra, Nisha,Paris, Jason J.,Zjawiony, Jordan K.
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- PRODUCTION METHOD OF BENZOTHIAZOLE DERIVATIVE
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PROBLEM TO BE SOLVED: To provide: a production method of a benzothiazole derivative; as well as a production method of a polymerizable compound produced from the benzothiazole derivative; a polymerizable composition including the polymerizable compound; a polymer obtained by polymerizing the polymerizable composition; and an optical isomer utilizing the polymer. SOLUTION: A production method of a compound represented by the following general formula (III) is provided, and also a production method of a polymerizable compound produced from the compound represented by the general formula (III), a polymerizable composition, a polymer obtained by polymerizing the polymerizable composition, and an optical isomer utilizing the polymer are provided. When the polymerizable composition containing the compound is polymerized and the obtained film-like polymer is irradiated with ultraviolet light, change of color and change of phase difference scarcely take place. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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- MANUFACTURING INTERMEDIATE AND MANUFACTURING METHOD OF POLYMERIZABLE COMPOUND
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PROBLEM TO BE SOLVED: To provide a manufacturing intermediate hardly generating discoloration and change of haze, when ultraviolet is radiated to a film-shaped polymer obtained by manufacturing a polymerizable compound and polymerizing a polymerizable composition containing the compound, and a manufacturing method of the manufacturing intermediate. SOLUTION: There are provided a compound represented by the formula (II), a manufacturing method of the compound, a polymerizable compound manufactured from the compound, a polymerizable composition, a polymer obtained by polymerizing the polymerizable composition, and an optical isomer using the polymer. In the formula, R1, R2 and L1 represent organic groups, n1 represents an integer of 1 to 4, when a plurality of L1 exist, it may be same or different, and neighboring L1 each other may form a condensed ring. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0172; 0175; 0189-0190
(2020/04/09)
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- Benzothiazole diazole derivative and preparation method and application thereof
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The invention belongs to the field of drug synthesis, and particularly relates to a benzothiazole diazole derivative and a preparation method thereof. The invention further relates to application of the diazole derivative in preparing drugs for treating various diseases caused by fungal infection or bacterial infection. The compound defined by the method is high in anti-fungal and anti-bacterial activity, compared with an existing anti-bacterial drug, the benzothiazole diazole derivative has the advantages of being novel in structure, efficient, broad in spectrum and the like, and therefore, the compound has a wide application prospect.
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- Thiazole carboxamide compound and synthesis and application thereof
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The invention relates to a novel thiazole carboxamide compound. R1, R2, Z, X1, X2, X3, n and m have meanings defined in right claims. The compound has a main inhibiting effect on alpha-glucosidase inhibitor, and can be used for preventing or treating dise
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Paragraph 0067; 0072; 0073
(2019/04/26)
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- Structure-activity relationships of thiazole and benzothiazole derivatives as selective cannabinoid CB2 agonists with in vivo anti-inflammatory properties
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The strong therapeutic potential of CB2 receptor agonists for use as anti-inflammatory agents that lack psychiatric side effects has attracted substantial interest. We herein describe the rational design and synthesis of novel thiazole and benzothiazole derivatives and the evaluation of their binding affinity and functional activity on CB1 and CB2 receptors. The series with the general formula N-(3-pentylbenzo [d]thiazol-2(3H)-ylidene) carboxamide (compounds 6a-6d) exhibited the highest affinity and selectivity towards CB2 receptors with Kis in the picomolar or low nanomolar range, and selectivity indices (Ki hCB1/Ki hCB2) reaching up to 429 fold. Notably, these compounds also demonstrated an agonistic functional activity in cellular assays with EC50s in the low nanomolar range. More interestingly, compound 6d, the 3-(trifluoromethyl)benzamide derivative, exhibited remarkable protection against DSS-induced acute colitis in mice model.
- Ghonim, Aya E.,Ligresti, Alessia,Rabbito, Alessandro,Mahmoud, Ali Mokhtar,Di Marzo, Vincenzo,Osman, Noha A.,Abadi, Ashraf H.
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p. 154 - 170
(2019/07/12)
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- Benzo[d]thiazole-2-carbanilides as new anti-TB chemotypes: Design, synthesis, biological evaluation, and structure-activity relationship
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Tuberculosis is the second leading cause of deaths worldwide. The inadequacy of existing drugs to treat TB due to developed resistance and TB-HIV synergism urges for new anti-TB drugs. Seventy-two benzo[d]thiazole-2-carbanilides have been synthesized through CDI-mediated direct coupling of benzo[d]thiazole-2-carboxylic acids with aromatic amines using a three step methodology which includes a green protocol for synthesis of ethyl benzo[d]thiazole-2-carboxylates, precursor of the desired carboxylic acids. The compounds were evaluated in vitro for anti-tubercular activity against M. tuberculosis H37Rv (ATCC27294 strain). Thirty-two compounds exhibiting MIC values in the range of 0.78–6.25 μg/mL (1.9–23 μM) were subjected to cell viability test against RAW 264.7 cell lines and thirty compounds were found to be non-toxic (50% inhibition). The most active compounds with MIC of 0.78 μg/mL (e.g., 4i, 4n, 4s, 4w, 6f, 6h, 6u, 7e, 7h, 7p, 7r and 7w) exhibit therapeutic index of 64. The structure activity relationship of the N-arylbenzo[d]thiazole-2-carboxamides has been established for anti-mycobacterial activity. Molecular docking suggests that the compounds 7w, 4i and 4n bind to the catalytic site of the enzyme ATP Phosphoribosyltransferase (HisG) and might be attributed to their anti-TB potential. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.
- Dhameliya, Tejas M.,Tiwari, Rishu,Banerjee, Arkaprabha,Pancholia, Sahaj,Sriram, Dharmarajan,Panda, Dulal,Chakraborti, Asit K.
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p. 364 - 380
(2018/06/14)
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- Benzothiazole - 2 - carboxylic acid synthesis process (by machine translation)
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The invention relates to a benzothiazole - 2 - carboxylic acid synthesis process, comprising the following steps: step one, the benzothiazole, methanol, oxidizing agent, phosphorus-containing catalyst in the closed reaction container and heating, thermal insulation and agitating the reaction, to obtain 2 - benzothiazole dimethyl acetal; step two, will the 2 - benzothiazole dimethyl acetal in organic solvent is added to DMF, adding acid catalyst reaction, results in the benzene and thiazole - 2 - formaldehyde; step three, in manganese and potassium permanganate under catalysis of, the surfactant-benzothiazole - 2 - formaldehyde and access of oxygen oxidation reaction, results in the benzene and thiazole 2 - carboxylic acid. This invention adopts the phosphorus-containing catalyst effective to promote the intermediate 2 - benzothiazole dimethyl acetal synthesis efficiency, and raw materials are easy, low cost, simple steps, the operation is convenient, beneficial to the post-further synthesis of benzothiazole - 2 - formaldehyde and benzothiazole - 2 - carboxylic acid, which is applicable to industrial large-scale synthesis of benzothiazole - 2 - carboxylic acid. (by machine translation)
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Paragraph 0022; 0027; 0033
(2017/10/13)
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- Synthesis and characterization of novel benzothiazole amide derivatives and screening as possible antimitotic and antimicrobial agents
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Abstract: A new series of benzothiazole amide derivatives (9a–l) were synthesized and characterized by Fourier-transform infrared (FT-IR), mass, and 1H and 13C nuclear magnetic resonance (NMR) spectroscopic techniques. The antimitotic activity of the newly synthesized compounds was determined by the Allium assay method, from which mitotic index values were calculated. Here, 9g (14.0?%) and 9l (14.5?%) showed mitotic index values most comparable to that of standard drug (14.4?%), while the remaining compounds showed lower mitotic index values; hence, these compounds inhibit the regular cell division process and are the most promising antimitotic agents. Based on the structural activity relationship, the maximum percentage inhibition was observed for compounds containing electron-withdrawing group, revealing enhanced antimitotic activity, while compounds with electron-donating groups such as furan (9g) and methyl (9l) were comparable to standard. The newly synthesized compounds were also screened for antimicrobial activity, with some of them showing remarkable activity. Graphical Abstract: [Figure not available: see fulltext.]
- Bhat, Mahesh,Belagali,Hemanth Kumar,Mahadeva Kumar
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p. 361 - 378
(2017/01/14)
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- A benzothiazole - 2 - carboxylic acid
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The invention relates to a preparation method of benzothiazole-2-carboxylic acid, and relates to the technical field of benzothiazole-2-carboxylic acid. According to the method, 2-methylbenzothiazole is adopted as a raw material; water and ethanol are adopted as a solvent, wherein the contents of water and ethanol are respectively 0-80% and 20-100%; 10-200ppm of mononuclear metalloporphyrin with a structure represented by the formula (I) or (II) is adopted as a catalyst; sodium hydroxide with a concentration of 0.5-2mol/L is adopted as an auxiliary agent; 0.5-2.0MPa oxygen and 30% hydrogen peroxide are adopted as oxidants; and a reaction is carried out for 2-12h under a temperature of 40-140 DEG C, such that benzothiazole-2-carboxylic acid is obtained. According to the invention, metalloporphyrin is adopted as the catalyst, such that dose is low, and pollution is prevented. Ethanol or an alkali solution of an ethanol and water mixed system is adopted as the solvent, such that the solvent is green, nontoxic and environment-friendly. Oxygen and hydrogen peroxide are adopted as oxidants, such that equipment corrosion caused by potassium permanganate and concentrated sulfuric acid is greatly reduced, and experimental operation safety and environment-friendliness are greatly improved.
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Paragraph 0034; 0036; 0038; 0040; 0042; 0044; 0092; 0093
(2017/08/25)
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- Acylaminoimidazole derivative and use thereof
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The invention belongs to the technical field of medicines and relates to an acylaminoimidazole derivative shown in the general formula I and its stereisomer and pharmaceutical acceptable salt, hydrate, solvate or prodrug. In the formula I, substituents R, R1, Ar, M and X are defined in the specification. The invention also relates to a method for preparing the compound shown in the formula I, a medicinal composition containing the compound and a use of the compound and the medicinal composition in preparation of drugs for treating and/or preventing cancers and other skin proliferative diseases. An antifungal experiment proves that the compound has strong resistance to shallow and deep fungi and can be used for preparation of an antibacterial drug.
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- Design, synthesis, and biological evaluation of amide imidazole derivatives as novel metabolic enzyme CYP26A1 inhibitors
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All-trans-retinoic acid (ATRA) as a physiological metabolite of vitamin A is widely applied in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. CYP26A1 enzyme, induced by ATRA in liver and target tissues, metabolizes ATRA into 4-hydroxyl-RA. Inhibition of CYP26A1 metabolic enzyme represents a promising strategy for discovery of new specific anticancer agents. Herein, we describe the design, synthesis and biological evaluation of a series of new amide imidazole derivatives as retinoic acid metabolism blocking agents (RAMBAs) toward CYP26A1 enzyme. First, based on the recent theoretical models (Sun et al., J. Mol. Graph. Model., 2015, 56, 10-19) a series of RAMBAs with novel scaffolds were designed using fragment-based drug discovery approach. Subsequently, the new RAMBAs were synthesized and evaluated for their biological activities. All the compounds demonstrated appropriate enzyme activities and cell activities. The promising inhibitors 20 and 23 with IC50 value of 0.22 μM and 0.46 μM toward CYP26A1, respectively, were further evaluated for CYP selectivity and the metabolic profile of ATRA. Both compounds 20 and 23 showed higher selectivity for CYP26A1 over other CYPs (CYP2D6, CYP3A4) when compared to liarozole. They also showed better inhibitory activities for the metabolism of ATRA when also compared to liarozole. These studies further validated the pharmacophore and structure-activity relationship models obtained about CYP26A1 inhibitors and highlighted the promising activities of the new series of CYP26A1 inhibitors designed from such models. They also paved the way for future development of those candidates as potential drugs.
- Sun, Bin,Liu, Kai,Han, Jing,Zhao, Li-Yu,Su, Xiao,Lin, Bin,Zhao, Dong-Mei,Cheng, Mao-Sheng
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p. 6763 - 6773
(2015/10/20)
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- COMPOUNDS FOR TREATMENT OF DRUG RESISTANT AND PERSISTENT TUBERCULOSIS
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Described herein are compounds and compositions for treating drug resistant and persistent tuberculosis. Also described herein is a method of screening for identifiying biofilm formation inhibitors.
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Paragraph 00264
(2014/12/12)
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- Hydroxylamine as an oxygen nucleophile: Substitution of sulfonamide by a hydroxyl group in benzothiazole-2-sulfonamides
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Benzothiazole-2-sulfonamides react with an excess of hydroxylamine in aqueous solutions to form 2-hydroxybenzothiazole, sulfur dioxide, and the corresponding amine. Mechanistic studies that employ a combination of structure-reactivity relationships, oxygen labeling experiments, and (in)direct detection of intermediates and products reveal that the reaction proceeds via oxygen attack, and that oxygen incorporated in the 2-hydroxybenzothiazole product derives from hydroxylamine. The reaction, which is performed under mild conditions, can be used as a deprotection method for cleavage of benzothiazole-2-sulfonyl-protected amino acids.
- Kamps, Jos J. A. G.,Belle, Roman,Mecinovi?, Jasmin
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supporting information
p. 1103 - 1108
(2013/03/28)
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- CARBOXYLATION CATALYSTS
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The use of a complex of the form Z—M—OR in the carboxylation of a substrate is described. The group Z is a two-electron donor ligand, M is a metal and OR is selected from the group consisting of OH, alkoxy and aryloxy. The substrate may be carboxylated at a C—H or N—H bond. The metal M may be copper, silver or gold. The two-electron donor ligand may be a phosphine, a carbene or a phosphite ligand. Also described are methods of manufacture of the complexes and methods for preparing isotopically labelled caboxylic acids and carboxylic acid derivatives.
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Paragraph 0093
(2013/04/13)
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- Direct C-H carboxylation with carbon dioxide using 1,2,3-triazol-5-ylidene copper(I) complexes
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1,2,3-Triazol-5-ylidene copper(I) complexes (tzNHC-Cu) efficiently catalyzed the direct C-H carboxylation of benzoxazole and benzothiazole derivatives with CO2 to give the corresponding esters in excellent yields after treatment with alkyl iodi
- Inomata, Hiroshi,Ogata, Kenichi,Fukuzawa, Shin-Ichi,Hou, Zhaomin
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supporting information; experimental part
p. 3986 - 3989
(2012/09/10)
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- Carbon dioxide as the C1 source for direct C-H functionalization of aromatic heterocycles
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(Equation Presented). A simple and straightforward method has been developed for the direct carboxylation of aromatic heterocylces such as oxazoles, thiazoles, and oxadiazoles using CO2 as the C1 source. The reactions require no metal catalyst and only Cs2CO3 as the base. A good functional group tolerance is achieved.
- Vechorkin, Oleg,Hirt, Nathalie,Hu, Xile
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supporting information; experimental part
p. 3567 - 3569
(2010/10/02)
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- Carboxylation of N-H/C-H bonds using n-heterocyclic carbene copper(I) complexes
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Greenhouse gas makes good: A simple copper-mediated protocol has been developed where N-H or C-H bonds can be directly functionalized using an easily prepared catalyst. The novel [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene] copper(I) hydroxide, [Cu(IPr)(OH)], permits the facile activation and carboxylation of N-H and C-H bonds with pKavalues of less than 27.7 (see scheme).
- Boogaerts, Ine I. F.,Fortman, George C.,Furst, Marc R. L.,Cazin, Catherine S. J.,Nolan, Steven P.
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supporting information; scheme or table
p. 8674 - 8677
(2011/01/06)
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- Carboxylation of C-H bonds using N -heterocyclic carbene gold(I) complexes
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A highly efficient [(NHC)AuI]-based (NHC = N-heterocyclic carbene) catalytic system for the carboxylation of aromatic and heteroaromatic C-H bonds was developed. The significant base strength of the Au-OH species is at the origin of the activation process and permits the facile functionalization of C-H bonds without the use of other organometallic reagents.
- Boogaerts, Ine I. F.,Nolan, Steven P.
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supporting information; experimental part
p. 8858 - 8859
(2010/08/21)
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- Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
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The present invention provides compounds, and pharmaceutical compositions containing those compounds, that are active at metabotropic glutamate receptors. The compounds are useful for treating neurological diseases and disorders. Methods of preparing the compounds also are disclosed.
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- A New and Facile Iodine(III) Mediated Method for the Cleavage of Hydrazides
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Hypervalent iodine oxidation of the various hydrazides 1a-h using iodobenzene diacetate (IBD) in methanol, ethanol, and water in acetonitrile, leads to facile cleavage of hydrazino moiety with the formation of corresponding methyl, ethyl esters and carboxylic acids, respectively (Scheme 1).
- Prakash, Om,Sharma, Vijay,Sadana, Anil
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p. 100 - 101
(2007/10/03)
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- HETEROCYCLIC RENIN INHIBITORS
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A renin inhibiting compound of the formula: STR1 wherein A is a substituent; R 1 is loweralkyl, loweralkenyl, alkoxyalkyl, [(alkoxy) alkoxy]alkyl, alkoxycarbonylalkyl, carboxyalkyl, (thioalkoxy) alkyl, benzyl or heterocyclic ring substituted methyl; R 2 i
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