- Structure-Based Discovery of Pyrimidine Aminobenzene Derivatives as Potent Oral Reversal Agents against P-gp- And BCRP-Mediated Multidrug Resistance
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Overexpression of ATP binding cassette (ABC) transporters, including P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), is an important factor leading to multidrug resistance (MDR) in cancer treatments. Three subclasses of dual inhibitors of P-gp and BCRP were designed based on the active moieties of BCRP inhibitors, tyrosine kinase inhibitors, and P-gp inhibitors, of which compound 21 possessed low cytotoxicity, high reversal potency, and good lipid distribution coefficient. 21 also increased the accumulation of Adriamycin (ADM) and Mitoxantrone (MX), blocked Rh123 efflux, and made no change in the protein expression of P-gp and BCRP. Importantly, coadministration of 21 can significantly improve the oral bioavailability of paclitaxel (PTX). It was also demonstrated that 21 significantly inhibited the growth of K562/A02 xenograft tumors by increasing the sensitivity of ADM in vivo. In summary, 21 has the potential to overcome MDR caused by P-gp and BCRP and to improve the oral bioavailability of PTX.
- Qiu, Qianqian,Zou, Feng,Li, Huilan,Shi, Wei,Zhou, Daoguang,Zhang, Ping,Li, Teng,Yin, Ziyu,Cai, Zilong,Jiang, Yuxuan,Huang, Wenlong,Qian, Hai
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p. 6179 - 6197
(2021/06/01)
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- Design, Synthesis, and Structural Analysis of Cladosporin-Based Inhibitors of Malaria Parasites
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Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite (Plasmodium falciparum) lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with in vitro pharmacokinetics. Co-crystallization of the most potent compound in our series (CL-2) with PfKRS revealed its structural basis of enzymatic binding and potency. Further, we report that CL-2 has performed better than cladosporin in terms of metabolic stability. It thus represents a new lead for further optimization toward the development of antimalarial drugs. Collectively, along with a lead compound, the series offers insights on how even the slightest chemical modification might play an important role in enhancing or decreasing the potency of a chemical scaffold.
- Babbar, Palak,Das, Pronay,Manickam, Yogavel,Mankad, Yash,Yadav, Swati,Parvez, Suhel,Sharma, Amit,Reddy, D. Srinivasa
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p. 1777 - 1794
(2021/05/10)
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- Synthesis of novel of 2, 5-disubstituted 1, 3, 4- oxadiazole derivatives and their in vitro anti-inflammatory, anti-oxidant evaluation, and molecular docking study
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A series of novel 2, 5-disubstituted 1, 3, 4-Oxadiazole derivatives as a potential anti-inflammatory, and anti-oxidant agent were synthesized via cyclisation. Hydrazide molecule treated with substituted acids in the presence of phosphorus oxychloride (POCl3) as an efficient reagent as well as solvent by conventional method with shorter reaction time and excellent yield. The newly synthesized 1, 3, 4- oxadiazole derivatives exhibited excellent to good anti-inflammatory and anti-oxidant activities compaired to the standard drugs. Molecular docking study on the crucial anti-inflammatory target–cyclooxygenase-2 (COX-2) revealed the ability of the scaffold to correctly recognize the active site and achieve significant bonded and non-bonded interactions with key residues therein. This study could identify potential compounds which can be pertinent starting points for structure-based drug design to obtain newer anti-inflammatory agents.
- Dongare, Balasaheb B.,Ghanwat, Anil A.,Kashid, Bharat B.,Khedkar, Vijay M.,More, Kishor R.,Salunkhe, Pravin H.
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- Synthesis and biological evaluation of (3-arylisoxazol-5-yl)methyl 6-fluoro-4-oxo-4H-chromene-2-carboxylates as antioxidant and antimicrobial agents
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A series of novel (3-arylisoxazol-5-yl)methyl 6-fluoro-4-oxo-4H- -chromene-2-carboxylate derivatives (C1-C12) were synthesized by the Cu(I)- -catalyzed reaction of in situ generated nitrile oxides with prop-2-ynyl 6-fluoro- 4-oxo-4H-chromene-2-carboxylate in good yields and their antioxidant and antimicrobial activities were investigated. Among all the synthesized compounds, C1 (IC50: 16.43±0.57 μM) and C12 (IC50:15.98±0.72 μM) registered good antioxidant activity as compared to the standard drug trolox. Compounds C1, C3 and C6 registered very good inhibition against all the tested Gram-positive and Gram-negative bacterial strains with MIC values ranging from 9.375 to 37.5 μg mL-1. Compounds C7-C11 registered good inhibition against Bacillus subtilis and Staphylococcus aureus with MIC values ranging from 18.75 to 37.5 μg mL-1. Compounds C10 and C11 against Pseudomonas aeroginosa showed more prominent activity than the standard drug penicillin (MIC: 12.5 μg mL-1) with an MIC value of 9.375 μg mL-1 (≈ 1.33-fold more potent than penicillin). Compounds C7-C9 registered good to moderate antifungal activity against the four tested fungal strains with MIC values ranging from 18.75 to 37.5 μg mL-1.
- Battula, Kumaraswamy,Narsimha, Sirassu,Nagavelli, Vasudeva Reddy,Rao, Mutheneni Srinivasa
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- 6-fluoro-chroman-2-carboxylic acid
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The invention discloses a preparation method of 6- fluorochroman-2-formic acid. The method comprises the following steps: with p-fluorophenol and dimethyl acetylenedicarboxylate as initial raw materials, carrying out an addition reaction on p-fluorophenol and dimethyl acetylenedicarboxylate to generate dimethyl 2-(p-fluorophenoxy) acetylenedicarboxylate, hydrolyzing under an alkaline condition to generate 2-(p-fluorophenoxy) butenedioic acid, dissolving obtained 2-(p-fluorophenoxy) butenedioic acid in concentrated sulfuric acid to perform cyclization to generate 6-fluoro-4-oxo-4H-1-benzopyran-2-formic acid, and finally, carrying out pressurized hydrogenation catalytic reduction to obtain 6-fluorochroman-2-formic acid. The method disclosed by the invention has the advantages of simple operation, low cost and high product yield, and reactions in the steps are safe and environment-friendly, so that the method is especially suitable for industrial production.
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Paragraph 0058; 0059
(2017/02/17)
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- METHOD FOR PREPARING NEBIVOLOL
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The present invention relates to a process for the preparation of nebivolol and, more particularly, to an improved process of synthesizing an alpha-haloketone of formula a key intermediate in the preparation of nebivolol.
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Page/Page column 5
(2011/10/12)
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- NEBIVOLOL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS, PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS OF NEBIVOLOL
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The present invention provides an improved process for the synthesis of nebivolol or its pharmaceutically acceptable salts, more particularly hydrochloride salt of formula (I). The present invention further provides a new Form T1 of nebivolol and its pharmaceutically acceptable salts. The present invention also provides pharmaceutical compositions and process for the preparation of a solid oral dosage form of nebivolol hydrochloride of formula (I), without the use of wetting agent, and optionally using binder and /or disintegrant.
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Page/Page column 12-13
(2010/10/20)
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- Process for the preparation of optically active 4-oxo-1-benzopyran-2-carboxylic acid derivatives and intermediates thereof
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A process for the preparation of optically active 4-oxo-1-benzopyran-2-carboxylic acid derivatives of the formula STR1 wherein X and Y are hydrogen atom, halogen atom or alkyl group, and R1 is hydrogen atom or alkyl group, intermediates thereof, as well as a process for the preparation of the intermediates.
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