- Discovery of novel rivastigmine-hydroxycinnamic acid hybrids as multi-targeted agents for Alzheimer's disease
-
A series of rivastigmine-caffeic acid and rivastigmine-ferulic acid hybrids were designed, synthesized, and evaluated as multifunctional agents for Alzheimer's disease (AD) in?vitro. The new compounds exerted antioxidant neuroprotective properties and good cholinesterases (ChE) inhibitory activities. Some of them also inhibited amyloid protein (Aβ) aggregation. In particular, compound 5 emerged as promising drug candidates endowed with neuroprotective potential, ChE inhibitory, Aβ self-aggregation inhibitory and copper chelation properties. These data suggest that compound 5 offers an attractive starting point for further lead optimization in the drug-discovery process against AD.
- Chen, Ziwei,Digiacomo, Maria,Tu, Yalin,Gu, Qiong,Wang, Shengnan,Yang, Xiaohong,Chu, Jiaqi,Chen, Qiuhe,Han, Yifan,Chen, Jingkao,Nesi, Giulia,Sestito, Simona,Macchia, Marco,Rapposelli, Simona,Pi, Rongbiao
-
-
Read Online
- Design, synthesis and structure-activity relationship study of novel urea compounds as FGFR1 inhibitors to treat metastatic triple-negative breast cancer
-
Triple-negative breast cancer (TNBC) is an aggressive type of cancer characterized by higher metastatic and reoccurrence rates, where approximately one-third of TNBC patients suffer from the metastasis in the brain. At the same time, TNBC shows good responses to chemotherapy, a feature that fuels the search for novel compounds with therapeutic potential in this area. Recently, we have identified novel urea-based compounds with cytotoxicity against selected cell lines and with the ability to cross the blood-brain barrier in vivo. We have synthesized and analyzed a library of more than 40 compounds to elucidate the key features responsible for the observed activity. We have also identified FGFR1 as a molecular target that is affected by the presence of these compounds, confirming our data using in silico model. Overall, we envision that these compounds can be further developed for the potential treatment of metastatic breast cancer.
- Akwii, Racheal,Alvina, Karina,Ashraf-Uz-Zaman, Md,Farshbaf, Mohammad Jodeiri,German, Nadezhda A.,Kallem, Raja Reddy,Mikelis, Constantinos M.,Putnam, William,Sajib, Md Sanaullah,Shahi, Sadisna,Trippier, Paul C.,Wang, Wei,Zhang, Ruiwen
-
-
- Synthesis and biological evaluation of novel 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives as potential antitumor agents
-
A novel series of 4-(4-formamidophenylamino)-N-methylpicolinamide derivatives were synthesized and evaluated against different tumor cell lines. Experiments in vitro showed that these derivatives could inhibit the proliferation of two kinds of human cancer cell lines (HepG2, HCT116) at low micromolar concentrations and the most potent analog 5q possessed broad-spectrum antiproliferative activity. Experiments in vivo demonstrated that 5q could effectively prolong the longevity of colon carcinoma-burdened mice and slow down the progression of cancer cells by suppression of angiogenesis and the induction of apoptosis and necrosis.
- Hu, Min,Meng, Nana,Xia, Yong,Xu, Youzhi,Yu, Luoting,Zeng, Xiuxiu,Zhou, Shuyan
-
-
- Design, synthesis and anticancer activity of a new series of n-aryl-n′-[4-(Pyridin-2-ylmethoxy)benzyl]urea derivatives
-
The development of cancer treatments requires continuous exploration and improvement, in which the discovery of new drugs for the treatment of cancer is still an important pathway. In this study, based on the molecular hybridization strategy, a new structural framework with an N-aryl-N’-arylmethylurea scaffold was designed, and 16 new target compounds were synthesized and evaluated for their antiproliferative activities against four different cancer cell lines A549, MCF7, HCT116, PC3, and human liver normal cell line HL7702. The results have shown seven compounds with 1-methylpiperidin-4-yl groups having excellent activities against all four cancer cell lines, and they exhibited scarcely any activities against HL7702. Among them, compound 9b and 9d showed greatly excellent activity against the four kinds of cells, and the IC50 for MCF7 and PC3 cell lines were even less than 3μM.
- Hou, Shicheng,Liang, Shishao,Zhang, Chao,Han, Yingmei,Liang, Jianhui,Hu, Hongyu,Zhang, Xingeng,Hu, Chun,Liu, Xiaoping,Zhang, Hong
-
-
- Discovery of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido) phenylurea-based thymidylate synthase (TS) inhibitor as a novel multi-effects antitumor drugs with minimal toxicity
-
Thymidylate synthase (TS) is a hot target for tumor chemotherapy, and its inhibitors are an essential direction for anti-tumor drug research. To our knowledge, currently, there are no reported thymidylate synthase inhibitors that could inhibit cancer cell migration. Therefore, for optimal therapeutic purposes, combines our previous reports and findings, we hope to obtain a multi-effects inhibitor. This study according to the principle of flattening we designed and synthesized 18 of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)phenyl urea derivatives as multi-effects inhibitors. The biological evaluation results showed that target compounds could significantly inhibit the hTS enzyme, BRaf kinase and EGFR kinase activity in vitro, and most of the compounds had excellent anti-cell viability for six cancer cell lines. Notably, the candidate compound L14e (IC50 = 0.67 μM) had the superior anti-cell viability and safety to A549 and H460 cells compared with pemetrexed. Further studies had shown that L14e could cause G1/S phase arrest then induce intrinsic apoptosis. Transwell, western blot, and tube formation results proved that L14e could inhibit the activation of the EGFR signaling pathway, then ultimately achieve the purpose of inhibiting cancer cell migration and angiogenesis in cancer tissues. Furthermore, in vivo pharmacology evaluations of L14e showed significant antitumor activity in A549 cells xenografts with minimal toxicity. All of these results demonstrated that the L14e has the potential for drug discovery as a multi-effects inhibitor and provides a new reference for clinical treatment of non-small cell lung cancer.
- Li, Xin-yang,Zhang, Ting-jian,Kamara, Mohamed Olounfeh,Lu, Guo-qing,Xu, Hai-li,Wang, De-pu,Meng, Fan-hao
-
-
- A simple and efficient synthesis of diaryl ureas with reduction of the intermediate isocyanate by triethylamine
-
Thirty symmetrical diaryl urea derivatives were synthesised in moderate to excellent yields from arylamine and triphosgene with triethylamine as a reducing agent for the intermediate, isocyanate. It was significant that part of the products could be collected in almost quantitative yield without column chromatography. The procedure under mild reaction conditions was tolerant of a wide range of functional groups. The structures of the compounds were determined by NMR, MS and X-ray crystallographic analyses.
- Zhou, Shuguang,Yao, Ting,Yi, Jicheng,Li, Dashuai,Xiong, Jing
-
p. 315 - 319
(2013/07/27)
-
- Mechanism of sulfur transfer from 1,2,4-dithiazolidine-3,5-diones to triphenylphosphines
-
The mechanism of sulfurization of substituted triphenylphosphines with 4-(3- and 4-substituted)-1,2,4-dithiazolidine-3,5-diones in acetonitrile, dichloromethane, tetrahydrofuran and toluene at 25°C was studied. The reaction pathway involves rate-limiting initial nucleophilic attack of the phosphorus at sulfur followed by fast decomposition of the phosphonium intermediate to the corresponding phosphine sulfide, phenylisocyanate and carbonylsulfide. From the Hammett correlations and from the solvent dependency, it was concluded that the transition-state structure is very polar and resembles the zwitter-ionic intermediate. The extent of P-S bond formation and S-S bond cleavage is very similar in the solvents series, but the latter gradually decreases with the decreasing polarity of the solvent. Copyright 2013 John Wiley & Sons, Ltd. The mechanism of sulfurization of substituted triphenylphosphines with 4-(3- and 4-substituted)-1,2,4-dithiazolidine-3,5- diones in acetonitrile, dichloromethane, tetrahydrofuran and toluene at 25°C was studied. The reaction pathway involves rate-limiting initial nucleophilic attack of the phosphorus at sulfur followed by fast decomposition of the phosphonium intermediate to the corresponding phosphine sulfide, phenylisocyanate and carbonylsulfide. The transition-state structure is very polar and resembles the zwitter-ionic phosphonium intermediate. Copyright
- Ponomarov, Oleksandr,Padelkova, Zdenka,Hanusek, Jiri
-
p. 560 - 564
(2013/07/26)
-
- Discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using common-feature pharmacophore model based virtual screening and hit-to-lead optimization
-
Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H- pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d] pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4- fluorophenyl)urea) that potently inhibits CK1 with an IC50 value of 78 nM.
- Yang, Ling-Ling,Li, Guo-Bo,Yan, Heng-Xiu,Sun, Qi-Zheng,Ma, Shuang,Ji, Pan,Wang, Ze-Rong,Feng, Shan,Zou, Jun,Yang, Sheng-Yong
-
-
- Synthesis of aryl urea derivatives from aryl amines and aryl isocyanates
-
The present study describes the synthesis of novel diaryl urea derivatives derived from aryl amine and aryl isocyanates. The synthesized compounds are analogs of sorafenib [4-[4-[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]phenoxy]-N-methylpyridine-2- carboxamide] having potential antiproliferative activity.
- Usharani,Bhujanga Rao,Reddy,Dubey
-
experimental part
p. 1802 - 1806
(2011/12/22)
-
- An 'inside-out' approach to suramin analogues
-
An approach to the synthesis of suramin analogues has been realised, which avoids synthetic problems associated with conventional routes. The use of isobutyl ester protecting groups for sulfonic acids was crucial to the success of the strategy, because these were able to be cleanly deprotected with sodium iodide, yielding the sodium salts of the corresponding sulfonic acids.
- McGeary, Ross P.,Bennett, Andrew J.,Tran, Quoc B.,Prins, Johannes,Ross, Benjamin P.
-
experimental part
p. 3990 - 3997
(2009/10/09)
-
- A novel synthesis of chiral guanidinium receptors and their use in unfolding the energetics of enantiorecognition of chiral carboxylates
-
(Chemical Equation Presented) A novel synthetic route to the versatile chiral bicyclic guanidinium building block is described making use of L-methionine as a starting material from the natural chiral pool. Furthermore, the synthetic elaboration of this building block is shown in the construction of macrocyclic and open chain hosts, respectively. The host design employs urea functions as the connecting units and supplementary anchor groups for the complexation of anions. The binding studies of these hosts with various chiral and achiral oxoanions are performed by isothermal titration calorimetry. A trend analysis of the binding energetics in an ensemble of structurally similar guests discloses the importance of geometrical confinement of the guest. Association entropy rather than free energy (affinity) is identified as an indicator of structural uniqueness needed to distinguish configurational isomers in the recognition of enantiomeric carboxylates by the chiral guanidinium hosts.
- Jadhav, Vinod D.,Schmidtchen, Franz P.
-
p. 1077 - 1087
(2008/09/18)
-
- Novel and efficient synthesis of 4-substituted-1,2,4-triazolidine-3,5- diones from anilines
-
A simple and efficient three-step synthetic procedure for the preparation of 4-substituted phenyl derivatives of 1,2,4-triazolidindiones (urazoles), starting from anilines, has been developed. In this method, aniline derivatives were reacted with 4-nitrophenyl chloroformate to provide corresponding carbamate derivatives. In the second step, semicarbazide derivatives were prepared from these carbamates by reaction with ethyl carbazate. The cyclization reaction of corresponding semicarbazides furnished 1,2,4-triazolidindiones in high yields. Copyright Taylor & Francis Group, LLC.
- Mallakpour, Shadpour,Rafiee, Zahra
-
p. 1927 - 1934
(2008/02/04)
-
- New β-alanine derivatives are orally available glucagon receptor antagonists
-
A weak human glucagon receptor antagonist with an IC50 of 7 μM was initially found by screening of libraries originally targeted to mimic the binding of the glucagon-like peptide (GLP-1) hormone to its receptor. Optimization of this hit for binding affinity for the glucagon receptor led to ligands with affinity in the nanomolar range. In addition to receptor binding, optimization efforts were made to stabilize the molecules against fast metabolic turnover. A potent antagonist of the human human glucagon receptor was obtained that had 17% oral availability in rats with a plasma half-life of 90 min. The major metabolites of this lead were identified and used to further optimize this series with respect to pharmacokinetic properties. This final optimization led to a potent glucagon antagonist that was orally available in rats and dogs and was efficacious in lowering blood glucose levels in a diabetic animal model.
- Lau, Jesper,Behrens, Garsten,Sidelmann, Ulla G.,Knudsen, Lotte B.,Lundt, Behrend,Sams, Christian,Ynddal, Lars,Brand, Christian L.,Pridal, Lone,Ling, Anthony,Kiel, Dan,Plewe, Michael,Shi, Shengua,Madsen, Peter
-
p. 113 - 128
(2007/10/03)
-
- Arylcarbamate derivatives of 1-piperidineethanol as potent ligands for 5-HT4 receptors
-
A series of carbamate derivatives (7) of 2-(1-piperidinyl)ethyl 4- amino-5-chloro-2-methoxybenzoates, which have been described as potent agonists and antagonists of 5-HT4 receptors, were synthesized. They were evaluated using radioligand binding assays with [3H]GR 113808, a 5-HT4 receptor selective ligand, in the rat striatum and the electrically stimulated myenteric plexus longitudinal muscle of the guinea pig. In contrast to the previously described ester derivatives, a drop in the affinity for 5-HT4 receptors was observed and the compounds were inactive as agonists in the guinea pig ileum preparation. Unexpectedly, the ortho- substituted carbamates 8b,c (R' = H, RO = MeO or EtO, R'' = H) had nanomolar affinity for 5-HT4 receptors (K(i) = 8.9 ± 0.5 and 2.6 ± 0.4 nM, respectively). As reported previously, the cis- or trans-3,5-dimethyl substitution of piperidine (8n,o) was particularly favorable (K(i) = 1.1 ± 0.6 nM for both isomers). 8c is an antagonist equipotent to the 5-HT4 receptor antagonist SDZ 205-557 (1).
- Soulier, Jean-Louis,Yang, Donglai,Brémont, Béatrice,Croci, Tiziano,Guzzi, Umberto,Langlois, Michel
-
p. 1755 - 1761
(2007/10/03)
-
- Biological activity of analogues of YM022. Novel (3-amino substituted phenyl)urea derivatives of 1,4-benzodiazepin-2-one as gastrin/cholecystokinin-B receptor antagonists
-
A series of (3-substituted phenyl)urea analogues of the potent gastrin/cholecystokinin (CCK)-B receptor antagonist YM022 has been prepared. Structure activity relationship studies of this series suggested that a number of analogues retained good in vitro potency for gastrin/CCK-B receptor. In particular, the (3-amino substituted phenyl)urea derivatives (10-12) were more potent inhibitors of pentagastrin-induced gastric acid secretion in rats than YM022 on intraduodenal (i.d.) administration.
- Satoh, Masato,Okamoto, Yoshinori,Koshio, Hiroyuki,Ohta, Mitsuaki,Nishida, Akito,Akuzawa, Shinobu,Miyata, Keiji,Mase, Toshiyasu,Semple, Graeme
-
p. 1412 - 1414
(2007/10/03)
-
- Novel carbamates as potent histamine H3 receptor antagonists with high in vitro and oral in vivo activity
-
The known histamine H3 receptor antagonists burimamide, thioperamide, clobenpropit, and a related homohistamine thioamide derivative were taken as templates in search for new leads. Novel histamine H3 receptor antagonists structurally described as carbamate derivatives of 3-(1H-imidazol-4- yl)propanol were prepared in high yields by treatment of the alcohol with corresponding isocyanates or carbamoyl chlorides and investigated for their H3 receptor antagonist activity. Different chain lengths and various substituents possessing different electronic and steric parameters were introduced and structure-activity relationships established. In different functional tests, the new antagonists showed high H3 receptor antagonist potencies in vitro (-log K(i) values of 6.4-8.4) at synaptosomes of rat cerebral cortex and low activities at histamine H1 and H2 receptor subtypes. They were also screened for their central in vivo activity in mice after peroral administration. The most promising compounds (2, 16, 19) showed ED50 values of about 1-2 mg/kg and thus are potential drugs for the therapy of H3 receptor dependent diseases. Some of the novel carbamate derivatives are H3 receptor selective compounds with high in vitro and in vivo activity.
- Stark, Holger,Purand, Katja,Ligneau, Xavier,Rouleau, Agnès,Arrang, Jean-Michel,Garbarg, Monique,Schwartz, Jean-Charles,Schunack, Walter
-
p. 1157 - 1163
(2007/10/03)
-
- Herbicidally active methyl-substituted tetrahydro-2-pyrimidinone derivatives
-
Methyl-substituted tetrahydro-2-pyrimidinone derivatives of the general formula STR1 in which each Ar, independently of each other, represents an aryl group which is optionally mono- or poly-substituted by substituent(s) selected from halogen, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, nitro, phenoxy and trifluoromethyl, and R1, R2 and R3 independently represent a hydrogen atom or a methyl group, provided that at least one of R1, R2 and R3 represents a methyl group, are new and find use as herbicides, in particular as selective herbicides which may be used on weeds in crops such as cotton and rice. The N,N'-diaryl-N-haloalkyl-ureas which are starting materials for the production of compounds of formula (I) are also new.
- -
-
-
- Synthesis of isocyanates from nitroalkanes
-
A process for the preparation of aromatic isocyanates from nitroalkanes. A nitromethyl aromatic compound of the general formula: STR1 wherein R and R1 represent hydrogen, halogen, a C1 -C5 alkyl radical, a C1 -C4 alkoxy radical, nitro, isocyanato, an alkoxycarbonylamino, or nitromethyl radical, with R and R1 being the same or different, is heated in the presence of an effective amount of a Lewis acid or Bronsted acid substance to effect a dehydrogenation-isomerization reaction to yield an aromatic isocyanate of the general formula: STR2 The product of the reaction may be recovered as the aromatic isocyanate or the alcohol adduct, a carbamate.
- -
-
-