- 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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- Chromene-containing aromatic sulfonamides with carbonic anhydrase inhibitory properties
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Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.
- Angeli, Andrea,Kartsev, Victor,Petrou, Anthi,Pinteala, Mariana,Brovarets, Volodymyr,Slyvchuk, Sergii,Pilyo, Stepan,Geronikaki, Athina,Supuran, Claudiu T.
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- 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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- Discovery of novel chromone derivatives containing a sulfonamide moiety as potential anti-TSWV agents
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A number of chromone derivatives containing sulfonamide structure were designed and synthesized. Firstly, the target compounds were evaluated for anti-TSWV activities in vivo by the half-leaf method. We found that most of the compounds had good anti-TSWV activities. Among them, compound 12B had excellent anti-TSWV inactivating activity with an EC50 of 80.5 μg/mL, which was significantly better than xiangcaoliusuobingmi (765.7 μg/mL). Secondly, TSWV nucleocapsid protein (N) was expressed and purified, and the affinity between the compounds and TSWV N was tested by microscale thermophoresis (MST). Compound 12B had a good affinity for TSWV N with a Kd value of 5.02 μM, which was superior to xiangcaoliusuobingmi (29.83 μM). Finally, in order to study the mode of interaction between the compound 12B and TSWV N, we carried out molecular docking. The results indicated that compound 12B might inactivate the virus by destroying the TSWV N oligomer structure. These results lay a solid foundation for the further discovery of chromone derivatives containing sulfonamide structure with high anti-TSWV activities.
- Jiang, Donghao,Zhang, Jian,He, Hongfu,Li, Jiao,Hu, Deyu,Song, Baoan
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- Optimizing the synthetic route of chromone-2-carboxylic acids: A step forward to speed-up the discovery of chromone-based multitarget-directed ligands
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6-Bromochromone-2-carboxylic acid (3) was synthesized by a microwave-assisted process. The optimization of the reaction was performed varying parameters, such as type of base/number of reagent equivalents, solvent, temperature and reaction time. The yield of the reaction was improved to 87%. The new synthetic route is versatile as several chromone-2-carboxylic acids (compounds 4B-10B) were obtained with good yields (54-93%). Only in the case of the nitro substituent (compound 11B), an ester was obtained instead of the desired carboxylic acid. Following this synthetic route chromone carboxylic acids can be attained with a high degree of purity, without the need of the tedious and expensive purification processes through column chromatography. The reaction is safe, cost-effective, fast and robust, and can be used in the development of concise and diversity-oriented libraries based on chromone scaffold. The overall study can be looked as a step forward to speed-up the discovery of chromone-based multitarget-directed ligands.
- Cagide, Fernando,Oliveira, Catarina,Reis, Joana,Borges, Fernanda
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- Synthesis, nematicidal activity and docking study of novel chromone derivatives containing substituted pyrazole
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A series of chromone derivatives containing substituted pyrazole were designed and synthesized. Preliminary bioassays showed that most of the synthesized compounds exhibited good nematicidal activity in vivo against Meloidogyne incognita at 10 mg/L. Among the tested compounds, A10 and A11 exhibited 100% inhibition rates. In addition, the molecular docking results indicated that both compound A10 and A11 interacts with amino acid residue Tyr121, Trp279, Tyr70, Trp84 and Phe330 of AChE via hydrogen bond and π–π stacking. This investigation suggested that the chromone containing substituted pyrazole scaffold could be further optimized to explore novel, high-bioactivity nematicidal leads.
- Li, Wei,Li, Jiuhui,Shen, Hongfeng,Cheng, Jiagao,Li, Zhong,Xu, Xiaoyong
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supporting information
p. 911 - 914
(2017/11/01)
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- Synthesis of some novel N-alkyl/acyl/aroyl 2-(chroman/6-bromochroman-2-yl)- 1H-benzimidazoles using ionic liquids and their antibacterial activity
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(Chemical Presented) Synthesis of some novel N-substituted 2-(chroman/6-bromochroman-2-yl)-1H-benzimidazoles by the condensation of 3,4-dihydro-2H-chroman-2-carboxylic acid and 6-bromo-3,4-dihydro-2H-chroman-2- carboxylic acid with o-phenylenediamine in ionic liquid (IL) [bmim]BF 4 and subsequent reactions at the benzimidazole-NH with different types of electrophiles in ILs [bmim]BF4 = 1-butyl-3-methylimidazolium tetrafluoroborate, [bmim]PF6 = 1-butyl-3-methylimidazolium hexafluorophosphate and [buPy]BF4 = butylpyridinium tetrafluoroborate in the presence of sodium hydroxide as a base have been reported. All the synthesized compounds were screened for their antibacterial activity. Some compounds exhibited promising antibacterial activity against Staphylococcus aureus and Salmonella typhimurium when compared to Cephalexin as a reference standard.
- Raut, Changdev Namdev,Bagul, Sandeep Madhukar,Janrao, Ravindra Ashok,Vaidya, Sanjay Dashrath,Kumar, Bobba Venkata Siva,Mahulikar, Pramod Pandurang
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scheme or table
p. 582 - 588
(2010/09/05)
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- Pharmaceutically acceprable salts of aporphine compounds of carboxyl group-containing agents and methods for preparing the same
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The present invention discloses novel pharmaceutically acceptable salts of aporphine compounds and carboxyl-group containing agents. Also, the present invention discloses methods for preparing the pharmaceutically acceptable salts. These pharmaceutically acceptable salts are suitable for use in treating and/or preventing hyperglycemic disease and/or several oxidative stress related diseases.
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- NOVEL SULFONAMIDE SUBSTITUTED CHROMAN DERIVATIVES USEFUL AS BETA-3 ADRENORECEPTOR AGONISTS
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This invention relates to novel sulfonamide substituted chroman derivatives which are useful in the treatment of beta-3 receptor mediated conditions.
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Page/Page column 31
(2008/12/07)
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- Carboxyl substituted chroman derivatives useful as beta 3 adrenoreceptor agonists
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This invention is related to novel carboxyl substituted chroman derivatives which are useful in the treatment of beta-3 receptor mediated conditions.
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- CARBOXYL SUBSTITUTED CHROMAN DERIVATIVES USEFUL AS BETA 3 ADRENORECEPTOR AGONISTS
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This invention is related to novel carboxyl substituted chroman derivatives which are useful in the treatment of beta-3 receptor mediated conditions.
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- SULFONAMIDE SUBSTITUTED CHROMAN DERIVATIVES USEFUL AS BETA 3 ADRENORECEPTOR AGONISTS
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This invention related to novel sulfonamide substituted chroman derivatives which are useful in the treatment of beta-3 receptor mediated conditions.
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- Benzopyran derivatives and their use
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This invention relates to a compound represented by the formula: STR1 wherein B represents a hydrogen atom or a lower alkyl group; ring A represents a benzene ring which may have one or more substituents; ***** represents a single or double bond; Q1 represents the group represented by the formula, STR2 or a hydrocarbon residue substituted with the group represented by the formula, STR3 wherein X represents a bond or a spacer having a chain length of 1 to 4 atoms as the linear moiety which may have one or more side chains; R1 and R2, whether identical or not, independently represent a hydrogen atom or a lower alkyl, or may bind together to form a ring; Q2 represents a hydrogen atom, a hydrocarbon residue which may be substituted or a heterocyclic ring residue which may be substituted; or a salt thereof.
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- INVESTIGATION IN THE CHROMONE SERIES. PART XIX. REACTION OF THE CHLORIDES OF CHROMONE-2- AND -3-CARBOXYLIC ACID WITH PHOSPHITES. PERKOW REACTION IN THE PRESENCE OF CONJUGATE DOUBLE BONDS
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4-Oxo-4H-1-benzopyran-3-carbonyl chloride forms in a Michaelis-Arbuzov reaction the corresponding α-ketophosphonate.As a result of further Michaelis-Arbuzov and Perkow reactions with tertiary phosphites 4-oxo-4H-1-benzopyran-2-carbonyl chloride forms two stereoisomeric products (E) and (Z).The mechanism of their formation and the structure has been suggested on the basis of spectroscopic dates and reactions with proton nucleophilic reagents.Key words: Dimethyl (4-oxo-4H-1-benzopyran-3-yl)carbonylphosphonate, (E) and (Z) 2(dialkylphosphato, dialkylphosphono)methylene-4-2H-1-benzopyran; synthesis, structure, reaction mechanism.
- Kostka, Krzysztof,Modranka, Roman
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- Benzopyrones. Part 17. The Synthesis of some Bischromones and the Reaction of Cyanomethyl Esters with Sodium Azide
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Treatment of 4-oxochromen-2-carboxyl chloride with dimethylcadmium gave 1-methyl-1-(4-oxochromen-2-yl)ethyl 4-oxochromen-2-carboxylate (11) which was synthesized unequivocally and degraded to the carboxylic acid and 2-(1-methylvinyl)chromen-4-one. 2-Acetylchromen-4-one was synthesized by a new and more efficient method from 4-oxochromen-2-carbonyl chloride.The synthesis and some reactions of 4-oxochromen-2-yl isocyanate, and the cyanomethyl esters of 4-oxochromen-2-carboxylic and -2,6-dicarboxylic acids are descibed.
- Bevan, Peter S.,Ellis, Gwynn P.,Wilson, H. Kerr
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p. 2552 - 2556
(2007/10/02)
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