- Polyhydroxybenzoic acid derivatives as potential new antimalarial agents
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With more than 200 million cases and 400,000 related deaths, malaria remains one of the deadliest infectious diseases of 2021. Unfortunately, despite the availability of efficient treatments, we have observed an increase in people infected with malaria since 2015 (from 211 million in 2015 to 229 million in 2019). This trend could partially be due to the development of resistance to all the current drugs. Therefore, there is an urgent need for new alternatives. We have, thus, selected common natural scaffolds, polyhydroxybenzoic acids, and synthesized a library of derivatives to better understand the structure–activity relationships explaining their antiplasmodial effect. Only gallic acid derivatives showed a noticeable potential for further developments. Indeed, they showed a selective inhibitory effect on Plasmodium (IC50 ~20 μM, SI > 5) often associated with interesting water solubility. Moreover, this has confirmed the critical importance of free phenolic functions (pyrogallol moiety) for the antimalarial effect. Methyl 4-benzoxy-3,5-dihydroxybenzoate (39) has, for the first time, been recognized as a potential lead for future research because of its marked inhibitory activity against Plasmodium falciparum and its significant hydrosolubility (3.72 mM).
- Degotte, Gilles,Francotte, Pierre,Pirotte, Bernard,Frédérich, Michel
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- Structure-Activity Study of Nitazoxanide Derivatives as Novel STAT3 Pathway Inhibitors
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We identified nitazoxanide (NTZ) as a moderate STAT3 pathway inhibitor through immunoblot analysis and a cell-based IL-6/JAK/STAT3 pathway activation assay. A series of thiazolide derivatives were designed and synthesized to further validate the thiazolide scaffold as STAT3 inhibitors. Eight out of 25 derivatives displayed potencies greater than that of NTZ, and their STAT3 pathway inhibitory activities were found to be significantly correlated with their antiproliferative activities in HeLa cells. Derivatives 15 and 24 were observed to be more potent than the positive control WP1066, which is under phase I clinical trials. Compared with NTZ, 15 also exhibited much improved in vivo pharmacokinetic parameters in rats and efficacies against proliferations in multiple cancer cell lines, indicating a broad-spectrum effect of these thiazolides as antitumor agents targeted on STAT3.
- Lü, Zirui,Li, Xiaona,Li, Kebin,Wang, Cong,Du, Tingting,Huang, Wei,Ji, Ming,Li, Changhong,Xu, Fengrong,Xu, Ping,Niu, Yan
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supporting information
p. 696 - 703
(2021/05/04)
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- Reversible Covalent End-Capping of Collagen Model Peptides
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The combination of supramolecular aggregation of collagen model peptides with reversible covalent end-capping of the formed triple helix in a single experimental set-up yielded minicollagens, which were characterized by a single melting temperature. In spite of the numerous possible reaction intermediates, a specific synthetic collagen with a leading, middle and trailing strand is formed in a highly cooperative self-assembly process.
- Priem, Christoph,Geyer, Armin
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supporting information
p. 14278 - 14283
(2019/11/03)
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- COMPOUND HAVING EFFECT OF INHIBITING PLATELET AGGREGATION AND SALT THEREOF, AND COMPOSITION FOR PREVENTING OR TREATING THROMBOTIC DISEASES, CONTAINING SAME
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The present invention relates to a novel compound having an effect of inhibiting platelet aggregation and a salt thereof and, more specifically, to: a novel platelet aggregation inhibitor specifically inhibiting shear stress-induced platelet aggregation; a pharmaceutical composition containing the same as an active ingredient; and a preparation method therefor.
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Paragraph 0034
(2018/07/29)
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- Examination of α-exosite inhibitors against Botulinum neurotoxin A protease through structure-activity relationship studies of chicoric acid
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Botulinum neurotoxins (BoNT) are among the most toxic known substances and currently there are no effective treatments for intraneuronal BoNT intoxication. Chicoric acid (ChA) was previously reported as a BoNT/A inhibitor that binds to the enzyme's α-exosite. Herein, we report the synthesis and structure-activity relationships (SARs) of a series of ChA derivatives, which revealed essential binding interactions between ChA and BoNT/A. Moreover, several ChA-based inhibitors with improved potency against the BoNT/A were discovered.
- Xue, Song,Seki, Hajime,Remes, Marek,?ilhár, Peter,Janda, Kim
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supporting information
p. 4956 - 4959
(2017/10/23)
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- First and efficient synthesis of 4-[((3,4-dihydroxybenzoyl)-oxy)methyl]phenyl β-D-glucopyranoside, an antioxidant from Origanum vulgare
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4-[((3,4-Dihydroxybenzoyl)oxy)methyl]phenyl β-D-glucopyranoside (DBPG, 1), a polyphenolic glycoside previously isolated from oregano (Origanum vulgare L.) in 0.08 % isolated yield, was synthesized in five chemical steps with 41.4 % overall yield. First, 4-(hydroxymethyl)phenyl ?-D-glucopyranoside 2,3,4,6-tetraacetate (4) was obtained in 53.2 % yield by selective glycosylation of 4-hydroxybenzyl alcohol (3) with 2,3,4,6-tetra-O-acetyl-a-D- -glucopyranosyl bromide (2) in a mixture of chlorobenzene and aqueous CsOH using triethylbenzylammonium chloride (TEBAC) as a phase transfer catalyst. Then, this product was esterified with 3,4-diacetoxybenzoyl chloride (7) to generate 4-[((3,4-diacetoxybenzoyl)oxy)methyl]phenyl ?-D-glucopyranoside 2,3,4,6-tetraacetate (8) in 95 % yield. Finally, selectively global deacetylation of 8 was performed in a mixture of dibutyltin oxide and methanol under reflux to afford 1 in 94.8 % yield.
- Li, Yu-Wen,Ma, Cui-Li
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- Design, synthesis, and biological evaluation of novel Tempol derivatives as effective antitumor agents
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Two series of novel Tempol derivatives T1–T6 based on the piperidine nitroxide Tempol and phenolic acids were designed and synthesized, and their biological evaluation is also described. The chemical structure was verified by HRMS, IR, and EPR analysis. The antitumor activity was tested against two tumor cell lines (A549 and Hela cells). Simultaneously, HK-2 cells were selected to investigate cytotoxicity and selectivity of synthetic compounds to the normal cells. The antioxidant property was also studied by DPPH radical scavenging assay and hydrogen peroxide-induced cell injury assay. The results demonstrated that most of the Tempol derivatives exhibited more active antioxidant activity than Tempol, and all synthesized Tempol derivatives exhibited more potent antitumor activity than Tempol. Among them, compound T6 displayed the highest antitumor activity (IC50?=?29.4?μg/mL for A549 cells; IC50?=?16.2?μg/mL for Hela cells). The results indicated that T6 exhibited efficient antitumor performance, having the potential of being excellent antitumor agents for cancer treatment.
- Sun, Xiao-Liang,Wang, Shi-Yu,Qi, Zhi-Min,Wan, Ning,Zhang, Bang-Le,He, Wei
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p. 7659 - 7673
(2016/09/20)
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- BETA-LACTAMASE INHIBITORS
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Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
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Paragraph 0481
(2014/07/22)
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- Flavonoid metabolism: The synthesis of phenolic glucuronides and sulfates as candidate metabolites for bioactivity studies of dietary flavonoids
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Epidemiological studies indicate that flavonoid intake is inversely associated with the risk of coronary heart disease, yet the mechanisms responsible for their bioactivity are still a matter of debate. Based on the rapid and extensive metabolism of most flavonoids, their health effects most likely result from the biological activity of their metabolites. However, a lack of commercially available compounds/standards has prevented the study of metabolite bioactivity and resulted in a focus on non-physiologically relevant precursor/parent structures. This paper details the synthesis of a series of phenolic glucuronide 1a-e and sulfate 2a-e derivates as candidate metabolites for use as reference compounds in metabolic profiling studies and for the exploration of flavonoid bioactivity.
- Zhang, Qingzhi,Raheem, K. Saki,Botting, Nigel P.,Slawin, Alexandra M.Z.,Kay, Colin D.,O'Hagan, David
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experimental part
p. 4194 - 4201
(2012/07/14)
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- Synthesis and antiradical/antioxidant activities of caffeic acid phenethyl ester and its related propionic, acetic, and benzoic acid analogues
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Caffeic acid phenethyl ester (CAPE) is a bioactive component isolated from propolis. A series of CAPE analogues was synthesized and their antiradical/antioxidant effects analyzed. The effect of the presence of the double bond and of the conjugated system on the antioxidant effect is evaluated with the analogues obtained from 3-(3,4-dihydroxyphenyl) propanoic acid. Those obtained from 2-(3,4-dihydroxyphenyl) acetic acid and 3,4-dihydroxybenzoic acid allow the evaluation of the effect of the presence of two carbons between the carbonyl and aromatic system.
- LeBlanc, Luc M.,Pare, Aurelie F.,Jean-Francois, Jacques,Hebert, Martin J.G.,Surette, Marc E.,Touaibia, Mohamed
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p. 14637 - 14650
(2013/03/13)
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- Nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors: Synthesis, structure-activity relationship analysis, and biological activity
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Four series of forty-five nitrogen-containing polyhydroxylated aromatics based on caffeic acid phenethyl ester were designed and synthesized as HIV-1 integrase (IN) inhibitors. Most of these compounds inhibited IN catalytic activities in low micromolar range. Among these new analogues, compounds 9e and 9f were the most potent IN inhibitors with IC50 value of 0.7 μM against strand transfer reaction. Their key structure-activity relationships were also discussed.
- Yu, Shenghui,Zhang, Linna,Yan, Shifeng,Wang, Peng,Sanchez, Tino,Christ, Frauke,Debyser, Zeger,Neamati, Nouri,Zhao, Guisen
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p. 628 - 640
(2012/10/29)
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- MULTI-ARMED CATECHOL COMPOUND BLENDS
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The invention describes families of compounds that utilize multihydroxyl phenyl groups to provide adhesive properties. Selection of the multihydroxy phenyl group along with linkers or linking groups and the linkages between the linkers or linking groups with polyalkylene oxides, provides materials that can be engineered to afford controllable curing time, biodegradation and/or swelling.
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Page/Page column 55-56
(2010/04/27)
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- Studies on depigmenting activities of dihydroxyl benzamide derivatives containing adamantane moiety
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Six diphenolic compounds containing adamantane moiety were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in melan-a cells. The inhibitory activity of 4-adamantyl resorcinol 1 was similar to that of 4-n-butyl resorcinol in both assays. However, dihydroxyl benzamide derivatives 6a-e showed different inhibitory patterns. All derivatives significantly suppressed the cellular melanin formation without tyrosinase inhibitory activities. These behaviors indicated that the introduction of amide bond changes the binding mode of dihydroxyl groups to tyrosinase. Among derivatives, 6d (3,4-dihydroxyl compound) and 6e (2,3-dihydroxyl compound) showed stronger inhibitory activities (IC50 = 1.25 μM and 0.73 μM, respectively) as compared to 4-n-butyl resorcinol (IC50 = 21.64 μM) and hydroquinone (IC50 = 3.97 μM). This study showed that the position of dihydroxyl substituent at aromatic ring is important for the intercellular inhibition of melanin formation, and also amide linkage and adamantane moiety enhance the inhibition.
- Rho, Ho Sik,Baek, Heung Soo,Ahn, Soo Mi,Yoo, Jae Won,Kim, Duck Hee,Kim, Han Gon
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scheme or table
p. 1532 - 1533
(2009/12/01)
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- Design and synthesis of novel nitrogen-containing polyhydroxylated aromatics as HIV-1 integrase inhibitors from caffeic acid phenethyl ester
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A series of nitrogen-containing polyhydroxylated aromatics from caffeic acid phenethyl ester were designed and synthesized as HIV-1 integrase inhibitors. Most of these compounds exhibited potent inhibitory activities at micromolar concentrations against HIV-1 integrase in the 3′-end processing and the strand transfer. Their key structure-activity relationship was also discussed.
- Wang, Peng,Liu, Chuan,Sanches, Tino,Zhong, Yuan,Liu, Bo,Xiong, Junlong,Neamati, Nouri,Zhao, Guisen
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supporting information; experimental part
p. 4574 - 4578
(2010/04/24)
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- HIV-1 integrase inhibition of biscoumarin analogues
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Nineteen biscoumarins bearing free and modified hydroxyl substituents at benzoyloxyphenyl linker have been synthesized by multiple step synthesis. Among these biscoumarins, thirteen were found to be active molecules against HIV-1 integrase (HIV-1 IN). The structure-activity relationship of the nineteen compounds on HIV IN may be useful for the design of potent therapeutic agents.
- Chang-Xiao,Mouscadet, Jean-Francois,Chiang, Chih-Chia,Tsai, Hou-Jen,Hsu, Ling-Yih
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p. 682 - 686
(2007/10/03)
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- Synthesis of selenium-containing polyphenolic acid esters and evaluation of their effects on antioxidation and 5-lipoxygenase inhibition
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Six novel selenium-containing polyphenolic acid esters were synthesized and evaluated as antioxidants and 5-lipoxygenase inhibitors. Synthesis of the title compounds involved the Mitsunobu reaction of polyphenolic acids (4-8, 14) with 2-phenylselenoethanol (3). Compounds 22, 23, and 25 were found to be very effective antioxidants and 5-lipoxygenase inhibitors with activity comparable to or better than caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE).
- Lin, Chi-Fu,Chang, Tsu-Chung,Chiang, Chih-Chia,Tsai, Hou-Jen,Hsu, Ling-Yih
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p. 1402 - 1407
(2007/10/03)
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- Synthesis and structure-activity relationship of diarylamide derivatives as selective inhibitors of the proliferation of human coronary artery smooth muscle cells
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A series of diarylamide derivatives were synthesized and evaluated for their inhibitory activities against human coronary artery smooth muscle cells (SMCs) and human coronary artery endothelial cells (ECs). Compound 2w was superior to the lead compound, Tranilast, in terms of the potency of the activity and cell selectivity.
- Gita, Haruhisa,Sobe, Yoshiaki,Akaku, Haruo,Ekine, Rena,Oto, Yuso,Isawa, Satoru,Hayashi, Hideya
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p. 549 - 551
(2007/10/03)
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- Synthesis and conformational property of tannin-like p-tert-butylcalix[4]arene 1,3-diesters stabilized by intramolecular hydrogen bonds
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Tannin-like p-tert-butylcalix[4]arene 1,3-digallate was synthesized, and its conformational property was investigated by dynamic 1H NMR and X-ray crystallography. It was found that the 3-OH (or 5-OH) group of the galloyl group in p-tert-butylcalix[4]arene 1,3-digallate is placed at the position where an unusual nonbonded close contact is observed between the OH group and the aromatic ring of the galloyl group facing each other. The calixarene 1,3-diesters of various hydroxybenzoic acids were also prepared, and the conformational properties of those calixarenes were compared with that of p-tert-butylcalix[4]arene 1,3-digallate. A significant contribution of the 3- and 5-OH groups in pendant groups toward the close contact was found. It was suggested that the conformation of p-tert-butylcalix[4]arene 1,3-digallate was stabilized by intramolecular hydrogen bonds including OH···O and OH-π interactions.
- Nomura, Eisaku,Hosoda, Asao,Taniguchi, Hisaji
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p. 8030 - 8036
(2007/10/03)
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- Synthesis and biological evaluation of CX-659S and its related compounds for their inhibitory effects on the delayed-type hypersensitivity reaction
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In order to find novel nonsteroidal compounds possessing an inhibitory activity against delayed-type hypersensitivity (DTH) reactions, we conducted random screening using a picryl chloride (PC)-induced contact hypersensitivity reaction (CHR) in mice, and found compound 1 as a lead compound. Then we synthesized and evaluated an extensive series of 5-carboxamidouracil derivatives focused on both the uracil and the antioxidative moieties. Among them, we found that the hindered phenol moiety was necessary to exhibit the activities; especially, compounds 28a-28c having the partial structure of vitamin E were found to exert potent activities against the DTH reaction by both oral and topical administration. And compound 28c showed antioxidative activity against lipid peroxidation with an IC50 of 5.9μM. Compound 28c (CX-659S) was chosen as a candidate drug for the treatment of cutaneous disorders such as atopic dermatitis and allergic contact dermatitis. Copyright (C) 2000 Elsevier Science Ltd.
- Tobe, Masanori,Isobe, Yoshiaki,Goto, Yuso,Obara, Fumihiro,Tsuchiya, Masami,Matsui, Junko,Hirota, Kosaku,Hayashi, Hideya
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p. 2037 - 2047
(2007/10/03)
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- Derivative of dihydroxybenzamide and a pharmaceutical composition having an anti-inflammatory activity
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Disclosed herein are a derivative of dihydroxybenzamide represented by the formula(I): STR1 wherein (1) R1 represents a hydrogen atom or a lower alkyl group and R2 represents a straight chain-alkyl group of 4 to 12 carbon atoms, a branched chain-alkyl group of 4 to 12 carbon atoms, a cyclo-alkyl group of 4 to 12 carbon atoms, STR2 wherein n is an integer of 1 to 6, or a pyridyl group which is substituted or unsubstituted, or (2) R1 and R2 are cyclized to make a heterocycle containing amino group represented by the formula STR3 wherein X represents a nitrogen atom or a methine and Y represents a hydrogen atom, an alkyl group of 1 to 6 carbon atoms or a phenyl group, and a pharmaceutical composition containing the same.
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- Syntheses of Peptide Alkaloids, 11. - Amino Acids and Peptides, 51. - Dehydroamino Acids, 19. - Total Synthesis of Hexaacetylcelenamide A
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The total synthesis of the linear peptide alkaloid hexaacetylcelenamide A (7) is described.Key steps are two condensation reactions with α-dialkylphosphoryl amino acid derivatives 10 to obtain the dehydroamino acid and dehydro peptide derivatives 14 and 17, respectively.
- Schmidt, Ulrich,Wild, Jochen
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p. 1882 - 1894
(2007/10/02)
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- A New Method for the Degradation of Anthocyanidins, Flavones, Chalcones, and Coumarins
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After transformation into the corresponding chalcone or flavenol acetates anthocyanidins are oxidatively cleaved with ruthenium tetroxide to yield benzoic acid derivatives of the rings A and B.Flavones, chalcones, and coumarins are degradated by the same method.
- Mentlein, Rolf,Vowinkel, Erich,Wolf, Bernd
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p. 401 - 406
(2007/10/02)
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- The Red Membrane Pigments of the Peat Moss Sphagnum rubellum
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The red colour of the peat moss Sphagnum rubellum results from three membrane pigments, the sphagnorubins A, B, and C; they have been isolated and their structures elucidated.Sphagnorubin A (1) is identical with the formerly known sphagnorubin obtained from Sphagnum magellanicum.Sphagnorubin B (3) was identificated as 2-(3',4'-dihydroxyphenyl)-8,9-dihydroxy-11-methoxyphenanthropyrylium chloride.Sphagnorubin C (7) is the 3'-methyl ether of sphagnorubin B.
- Mentlein, Rolf,Vowinkel, Erich
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p. 1024 - 1035
(2007/10/02)
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