- Cyano-and ketone-containing selenoesters as multi-target compounds against resistant cancers
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Fifteen selenocompounds, comprising of eight ketone-containing selenoesters (K1–K8, also known as oxoselenoesters) and seven cyano-containing selenoesters (N1–N7, known also as cyanoselenoesters), have been designed, synthesized, and evaluated as novel anticancer agents. These compounds are derivatives of previously reported active selenoesters and were prepared following a three-step one-pot synthetic route. The following evaluations were performed in their biological assessment: cytotoxicity determination, selectivity towards cancer cells in respect to non-cancer cells, checkerboard combination assay, ABCB1 inhibition and inhibition of ABCB1 ATPase activity, apoptosis induction, and wound healing assay. As key results, all the compounds showed cytotoxicity against cancer cells at low micromolar concentrations, with cyanoselenoesters being strongly selective. All of the oxoselenoesters, except K4, were potent ABCB1 inhibitors, and two of them, namely K5 and K6, enhanced the activity of doxorubicin in a synergistic manner. The majority of these ketone derivatives modulated the ATPase activity, showed wound healing activity, and induced apoptosis, with K3 being the most potent, with a potency close to that of the reference compound. To summarize, these novel derivatives have promising multi-target activity, and are worthy to be studied more in-depth in future works to gain a greater understanding of their potential applications against cancer.
- Alonso-Martínez, Francisco-Javier,Benito-Lama, Miguel,Dobiasová, Simona,Domínguez-álvarez, Enrique,Habibullah, Giyaullah,Kincses, Annamária,Nové, Márta,Salardón-Jiménez, Noemi,Sevilla-Hernández, Clotilde,Spengler, Gabriella,Szemerédi, Nikoletta,Viktorová, Jitka
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- Discovery of methoxy-naphthyl linked N-(1-benzylpiperidine) benzamide as a blood-brain permeable dual inhibitor of acetylcholinesterase and butyrylcholinesterase
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The cholinesterase enzymes play a vital role in maintaining balanced levels of the neurotransmitter acetylcholine in the central nervous system. However, the overexpression of these enzymes results in hampered neurotransmission. Both the major forms of cholinesterase enzymes viz. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play a crucial role in blocking neurotransmission; therefore, in recent years, a strategy of dual cholinesterase inhibition is being explored. Herein, we developed an energy-optimized e-pharmacophore hypothesis AHHPRR from AChE-donepezil complex and screened a set of 15 scaffolds that were designed imaginarily. The ligand with N-(1-benzylpyridinium) benzamide framework has shown the highest fitness and volume score, which was chosen for synthesis and validation. A series of pyridinium benzamides were synthesized and screened for cholinesterase inhibition that led to the identification of 7b, a naphthalene containing N-(1-benzylpiperidine) benzamide as a potent dual AChE and BChE inhibitor with IC50 values of 0.176, and 0.47 μM, respectively. The kinetic study indicated that 7b inhibits AChE in a non-competitive manner with Ki value of 0.21 μM, and BChE in a mixed-fashion with Ki of 0.15 μM. The observed mode of inhibition was corroborated with molecular docking studies. The MD simulation studies pointed out that both AChE and BChE undergo low conformational changes in complex with 7b. The benzamide 7b displayed high BBB permeability in PAMPA assay, which indicates its potential for further exploration in preclinical studies for Alzheimer's disease.
- Abdullaha, Mohd,Bharate, Sandip B.,Nuthakki, Vijay K.
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- Deuterium-Substituted Pyridin- And Pyrimidin-2-yl-Methylamine Compounds
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Described are deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine compounds of structural Formula (I), which are agonists of 5-hydroxytryptamine receptors. Also described are pharmaceutical compositions comprising the deuterium-substituted pyridin- and pyrimidin-2-yl-methylamine compounds, and methods of use thereof.
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Paragraph 0306; 0307
(2018/04/14)
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- Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors
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We have previously described the identification of indolin-2-one-5-carboxamides as potent PAK4 inhibitors. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds, 2 and 3. A series of novel derivatives was designed, synthesized, and evaluated in biochemical and cellular assay. Most of this series displayed nanomolar biochemical activity and potent antiproliferative activity against A549 and HCT116 cells. The representative compound 10a exhibited excellent enzyme inhibition (PAK4 IC50 = 25 nM) and cellular potency (A549 IC50 = 0.58 μM, HCT116 IC50 = 0.095 μM). An X-ray structure of compound 10a bound to PAK4 was obtained. Crystallographic analysis confirmed predictions from molecular modeling and helped refine SAR results. In addition, Compound 10a displayed focused multi-targeted kinase inhibition, good calculated drug-likeness properties. Further profiling of compound 10a revealed it showed weak inhibitory activity against various isoforms of human cytochrome P450.
- Guo, Jing,Zhao, Fan,Yin, Wenbo,Zhu, Mingyue,Hao, Chenzhou,Pang, Yu,Wu, Tianxiao,Wang, Jian,Zhao, Dongmei,Li, Haitao,Cheng, Maosheng
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p. 197 - 209
(2018/06/12)
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- Studies on phenothiazines: New microtubule-interacting compounds with phenothiazine A-ring as potent antineoplastic agents
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New phenothiazine derivatives 6-20 have been designed, synthesized and evaluated in vitro for their ability to inhibit tubulin polymerization and antiproliferative activity against 60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. The phenothiazine unit may successfully replace the classical 3,4,5-trimethoxyphenyle A ring of parent combretastatin A-4 or phenstatin, confirming previous studies. The most promising structural modulations have been realized on the B ring, the 2′-fluoro-4′-methoxy substitution in compound 6 and the 2′-trifluoromethyl-4′-methoxy substitution in compound 7 providing the best antitubulin and antitumor activity in the current study. Compounds 6-8 and 16 exhibited more important cell growth inhibition than parent phenstatin 2 on human colon Duke's type D, colorectal adenocarcinoma COLO 205 and on human kidney adenocarcinoma A498 cell lines. 10-Methylphenothiazine derivatives 19 and 20 did not show biological activity but exerted bright fluorescence and solvatochromism effects. These molecules deserve further chemical efforts in order to provide valuable tools for biophysical studies.
- Ghinet, Alina,Moise, Iuliana-Monica,Rigo, Beno?t,Homerin, Germain,Farce, Amaury,Dubois, Jo?lle,B?cu, Elena
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p. 2307 - 2317
(2016/04/26)
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- Synthesis and anti-cancer, anti-metastatic evaluation of some new fluorinated isocoumarins and 3,4-dihydroisocoumarins
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Synthesis of some fluorinated isocoumarins and 3,4-dihydroisocoumarins is reported. Structures of the synthesized compounds were confirmed by spectral and elemental analysis. All the synthesized compounds were evaluated for their antimetastatic activity and anti-cancer activity against breast cell line (MCF-7). Among all the tested compounds 3h [3-(3′,4′-difluorophenyl) isocoumarin] has shown excellent antimetastatic activity, however the growth inhibitory response of the tested compounds [3a-h, 4a-h, 5e-h, 6a-h and 7a, c, d] for MCF-7 human breast carcinoma cell line was moderate at higher concentrations (100-400 μM) and negligible at lower concentrations.
- Abid, Obaid-Ur-Rahman,Khalid, Muhammad,Hussain, Muhammad T.,Hanif, Muhammad,Qadeer, Ghulam,Rama, Nasim H.,Kornienko, Alexander,Khan, Khalid M.
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experimental part
p. 240 - 245
(2012/05/04)
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- N -pyridyl and pyrimidine benzamides as KCNQ2/Q3 potassium channel openers for the treatment of epilepsy
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A series of N-pyridyl benzamide KCNQ2/Q3 potassium channel openers were identified and found to be active in animal models of epilepsy and pain. The best compound 12 [ICA-027243, N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide] has an EC50 of 0.38 μM and is selective for KCNQ2/Q3 channels. This compound was active in several rodent models of epilepsy and pain but upon repeated dosing had a number of unacceptable toxicities that prevented further development. On the basis of the structure-activity relationships developed around 12, a second compound, 51, [N-(2-chloro-pyrimidin-5-yl)-3,4-difluoro- benzamide, ICA-069673], was prepared and advanced into a phase 1 clinical study. Herein, we describe the structure-activity relationships that led to the identification of compound 12 and to the corresponding pyrimidine 51.
- Amato, George,Roeloffs, Rosemarie,Rigdon, Greg C.,Antonio, Brett,Mersch, Theresa,McNaughton-Smith, Grant,Wickenden, Alan D.,Fritch, Paul,Suto, Mark J.
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supporting information; experimental part
p. 481 - 484
(2011/08/22)
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- HETEROARYL BENZAMIDE DERIVATIVES FOR USE AS GLK ACTIVATORS IN THE TREATMENT OF DIABETES
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Compounds of formula (I) wherein R1, R2, R3, and HET-1 are as described in the specification, and their salts, are activators of glucokinase (GLK) and are thereby useful in the treatment of, for example, type 2 diabetes. P
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Page/Page column 40-41
(2008/06/13)
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- COMPOUNDS
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Compounds of Formula (I) wherein: R1 is methyl; R2 is selected from -C (O) NR4R5, SO2NR4R5, S (O) pR4 and HET-2; HET-1 is a 5- or 6-membered, optionally substituted C-linked heteroaryl ring; HET-2 is a 4-, 5- or 6-membered, C- or N-linked optionally substituted heterocyclyl ring; R3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R4 is selected from for example hydrogen, optionally substituted (1-4C) alkyl and HET-2; R5 is hydrogen or (1-4C) alkyl; or R4 and R5 together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3; HET-3 is for example an optionally substituted N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring; p is (independently at each occurrence) 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro drug or solvate thereof, are described. Their use as GLK activators, pharmaceutical compositions containing them and processes for their preparation are also described.
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Page/Page column 95
(2008/06/13)
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- HETROARYL BENZAMIDE DERIVATIVES FOR USE AS GLK ACTIVATORS IN THE TREATMENT OF DIABETES
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Compounds of Formula (I) wherein: R1 is hydroxymethyl; R2 is selected from -C(O)NR4R5, SO2NR4R5, S(O)pR4 and HET-2; HET-1 is a 5- or 6-membered, optionally substituted C-linked heteroaryl ring; HET-2 is a 4-, 5- or 6-membered, C- or N-linked optionally substituted heterocyclyl ring; R3 is selected from halo, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, methoxy and cyano; R4 is selected from for example hydrogen, optionally substituted (1-4C)alkyl and HET-2; R5 is hydrogen or (1-4C)alkyl; or R4 and R5 together with the nitrogen atom to which they are attached may form a heterocyclyl ring system as defined by HET-3; HET-3 is for example an optionally substituted N-linked, 4, 5 or 6 membered, saturated or partially unsaturated heterocyclyl ring; p is (independently at each occurrence) 0, 1 or 2; m is 0 or 1; n is 0, 1 or 2; provided that when m is 0, then n is 1 or 2; or a salt, pro drug or solvate thereof, are described. Their use as GLK activators, pharmaceutical compositions containing them, and processes for their preparation are also described.
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Page/Page column 107
(2008/06/13)
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- Production of 3-chloro-4-fluoro-benzoyl chloride by Lewis-acid catalyzed chlorination of the aromatic ring
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The present invention relates to halogenated aromatic derivatives, in particular 3-chloro-4-fluoro-benzoyl chloride having the following formula: The aforesaid derivative is advantageously used as base product for the preparation of fluorinated compounds
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- Halogenated aromatic derivatives and process for the preparation thereof
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The present invention relates to halogenated aromatic derivatives, in particular 3-chloro-4-fluoro-benzoyl chloride having the following formula: The aforesaid derivative is advantageously used as base product for the preparation of fluorinated compounds
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