- Identification and development of non-cytotoxic cell death modulators: Impact of sartans and derivatives on PPARγ activation and on growth of imatinib-resistant chronic myelogenous leukemia cells
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4’-((2-Propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid derived from telmisartan was identified as lead for the design of cell death modulators. In this study, we evaluated the efficacy of telmisartan itself and other sartans in combination with imatinib against K562-resistant cells. The findings were directly used to further optimize the lead structure. Telmisartan and candesartan cilexetil represented the most effective sartans, thus the influence of carboxyl/methyl carboxylate groups at positions 7 (compounds 6, 7) or 4 (compounds 12–14) at the benzimidazole core was studied. Additionally, according to the results of a former structure-activity study, telmisartan was transformed to the related amide (1). Telmisartan amide 1, as well as the esters 6 and 12 markedly sensitized the resistant CML cells to imatinib treatment. Correlation with their potency to activate PPARγ is not given. Candesartan cilexetil, telmisartan and 1 showed the profile of partial agonists at PPARγ with EC50 values of 4.2, 4.3 and 9.1 μM, respectively, while 6 and 12 caused only marginal intrinsic activation at 10 μM (Amax = 22% and 13%). However, the repression of the STAT5 phosphorylation relates with the possibility to sensitize K562-resistant CML cells to imatinib treatment. It is worth mentioning that all compounds were per se non-cytotoxic at relevant concentrations.
- Gust, Ronald,Obexer, Petra,Salcher, Stefan,Schoepf, Anna M.
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supporting information
(2020/04/08)
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- Synthesis and Antifungal Activity of Substituted 2-Aryl Benzimidazoles Derivatives
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Benzimidazole fungicides were among the early systemic fungicides developed and used for controlling a wide variety of plant diseases. During the course of our screening process for active compounds, two 2-aryl benzimidazoles derivatives bearing sulfoxide group (6b and 6c) have been demonstrated to exhibit good inhibition activity against high-resistant isolate of Botrytis cinerea compared with carbendazim, and the inhibition rates are up to 46.67% and 51.11% at the concentration of 10 μg/mL, which might be considered as the active framework for the discovery of novel fungicide to high-resistant isolate of B. cinerea.
- Huang, Daye,Qiu, Fang,Zhang, Zhigang,Shi, Liqiao,Cao, Chunxia,Ke, Shaoyong
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supporting information
p. 2494 - 2498
(2019/08/12)
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- MUSCARINIC M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
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The present invention relates to compounds of formula (I), or their isotopic forms, stereoisomers, tautomers or pharmaceutically acceptable salt (s) thereof as muscarinic M1 receptor positive allosteric modulators (M1 PAMs). The present invention describes the preparation, pharmaceutical composition and the use of compound formula (I).
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Page/Page column 50
(2018/03/25)
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- Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists
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N-Benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2′ and 3′-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2′-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2′-benzyl substituent were also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines.
- Hansen, Martin,Jacobsen, Stine Engesgaard,Plunkett, Shane,Liebscher, Gudrun Eckhard,McCorvy, John D.,Br?uner-Osborne, Hans,Kristensen, Jesper Langgaard
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p. 3933 - 3937
(2015/01/30)
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- Benzimidazole-4-Carboxamide Derivatives, Their Preparation Methods, Pharmaceutical Compositions And Their Uses
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The present invention relates to the benzimidazole-4-carboxamide derivatives, their preparation methods, pharmaceutical compositions and their uses; wherein X represents monosubstituted or bissubstituted or polysubstitued C1-C14 alkoxy, monosubstituted or bisubstituted or polysubstitued C1-C14 alkyl, monosubstituted or bisubstituted or polysubstitued C2-C14 alkenyl, monosubstituted or bisubstituted or polysubstitued C6-C14 aryl, or monosubstituted or bisubstituted or polysubstitued 5 to 6 membered heterocyclic group, or monosubstituted or bisubstituted or polysubstitued fused ring group containing nitrogen heteroatom; Y represents hydrogen, monosubstituted or bisubstituted or polysubstitued C1-C16 alkyl, monosubstituted or bisubstituted or polysubstitued C6-C12 aryl, or monosubstituted or bisubstituted or polysubstitued 5 to 6 membered heterocyclic group, or monosubstituted or bisubstituted or polysubstitued fused ring group containing nitrogen heteroatom. The derivatives of the present invention have the functions of antiviral medicine.
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- Inhibitory properties of 2-substituent-1H-benzimidazole-4-carboxamide derivatives against enteroviruses
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A series of novel benzimidazole derivatives were designed, synthesized, and evaluated for their activities against four kinds of enteroviruses, that is, Coxsackie virus A16, B3, B6 and Enterovirus 71 in VERO cells. Strong activities against enterovirus replication and low cytotoxicities were observed in these benzimidazoles generally. The most promising compound was (l)-2-(pyridin-2-yl)- N-(2-(4-nitrophenyl)pentan-3-yl)-1H-benzimidazole-4-carboxamide (16), with a high antiviral potency (IC50 = 1.76 μg/mL) and a remarkable selectivity index (328). These compounds were selected for further evaluation as novel enterovirus inhibitors.
- Xue, Fei,Luo, Xianjin,Ye, Chenghao,Ye, Weidong,Wang, Yue
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p. 2641 - 2649
(2011/06/11)
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- Synthesis and antiviral activity against Coxsackie virus B3 of some novel benzimidazole derivatives
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Some benzimidazole derivatives were synthesized and the antiviral evaluation against Coxsackie virus B3 is reported. These compounds are proved to be excellent inhibitors of CVB3. Some benzimidazole derivatives were synthesized and evaluated for their antiviral properties. Compounds 20 and 21 showed potent selective activity against Coxsackie virus B3 in VERO cells. Some structure-activity relationships were discussed.
- Cheng, Jun,Xie, Jiangtao,Luo, Xianjin
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p. 267 - 269
(2007/10/03)
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- On benzo[b][1,4]diazepinium-olates, -thiolates and -carboxylates as anti-Hueckel mesomeric betaines
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2,3-Diaminophenol 4, 3,4-diaminophenol 5, 4-methoxy-1,2-diaminobenzene 6, 3,4-diaminobenzenthiol 7, 2,3-diaminobenzoic acid 8, and 3,4-diaminobenzoic acid 9 were reacted with 2,4-pentanedione to yield the corresponding benzo[b][1,4]diazepinium salts, respectively. The hydroxy-benzo[b][1,4]diazepinium salts 17 and 18 do not form mesomeric betaines (MB) on deprotonation. Instead, they are converted into the diimines 24 and 25. By contrast, the 7-mercaptobenzo[b][1,4]diazepinium salt 20 yields the corresponding thiolate on increasing the pH of the solution. This MB, which possesses 4n π-electrons, does not fit into the classification system of heterocyclic mesomeric betaines accepted today. Deprotonation of the betaine results in the formation of an instable anionic thiolate 31 which oxidizes immediately to the disulfide 32. The carboxy derivatives 21 and 22 readily form cross-conjugated mesomeric betaines. Whereas the diimine 34 proved to be instable, the sodium salt of the diimine 36 was unambiguously characterized. An X-ray single crystal analysis of 22 as its picrate is presented in order to gain additional insights into these 4n π-electron systems.
- Schmidt, Andreas,Gholipour Shilabin, Abbas,Nieger, Martin
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p. 4342 - 4350
(2007/10/03)
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- Substituted benzimidazoles
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Compounds of formula I are suitable for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of NFκB is involved.
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- 3-thienyl and 3-furanyl pyrrolidine modulators of chemokine receptor activity
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The present invention is directed to pyrrolidine compounds of the formula I: (wherein R1, R2, R3, R4c, R4d, and R4fare defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-3 and/or CCR-5.
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- Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase
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The nuclear enzyme poly(ADP-ribose) polymerase (PARP) facilitates the repair of DNA strand breaks and is implicated in the resistance of cancer cells to certain DNA-damaging agents. Inhibitors of PARP have clinical potential as resistance-modifying agents capable of potentiating radiotherapy and the cytotoxicity of some forms of cancer chemotherapy. The preclinical development of 2-aryl-1H-benzimidazole-4-carboxamides as resistance-modifying agents in cancer chemotherapy is described. 1H-Benzimidazole-4-carboxamides, particularly 2-aryl derivatives, are identified as a class of potent PARP inhibitors. Derivatives of 2-phenyl-1H-benzimidazole-4-carboxamide (23, K(i) = 15 nM), in which the phenyl ring contains substituents, have been synthesized. Many of these derivatives exhibit K(i) values for PARP inhibition 10 nM, with 2-(4-hydroxymethylphenyl)-1H-benzimidazole-4-carboxamide (78, K(i) = 1.6 nM) being one of the most potent. Insight into structure-activity relationships (SAR) for 2-aryl-1H-benzimidazole-4-carboxamides has been enhanced by studying the complex formed between 2-(3-methoxyphenyl)-1H-benzimidazole-4-carboxamide (44, K(i) = 6 nM) and the catalytic domain of chicken PARP. Important hydrogen-bonding and hydrophobic interactions with the protein have been identified for this inhibitor. 2-(4-Hydroxyphenyl)-1H-benzimidazole-4-carboxamide (45, K(i) = 6 nM) potentiates the cytotoxicity of both temozolomide and topotecan against A2780 cells in vitro (by 2.8- and 2.9-fold, respectively).
- White,Almassy,Calvert,Curtin,Griffin,Hostomsky,Maegley,Newell,Srinivasan,Golding
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p. 4084 - 4097
(2007/10/03)
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- Benzimidazole compounds
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Benzimidazole-4-carboxamide compounds (I) which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. In formula (I), R and R' may each be selected independently from hydrogen, alkyl, hydroxyalkyl (e.g. CH2CH2OH), acyl (e.g. acetyl or benzoyl) or an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl or carboxybenzyl) group. R is generally a substituted phenyl group in the most preferred compounds. The compounds may also be used in the form of pharmaceutically acceptable salts or pro-drugs.
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- Synthesis and evaluation of heterocyclic carboxamides as potential antipsychotic agents
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Heterocyclic analogues of 1192U90, 2-amino-N-(4-(4-(1,2-benzisothiazol- 3-yl)-1-piperazinyl)-butyl)benzamide hydrochloride (1), were prepared and evaluated as potential antipsychotic agents. These analogues were evaluated in vitro for their binding to the dopamine D2, serotonin 5-HT2, and serotonin 5-HT(1a) receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Nine different types of heterocyclic carboxamides were studied in this investigation (i.e., pyridine- , thiophene-, benzothiophene-, quinoline-, 1,2,3,4-tetrahydroquinoline-, 2,3- dihydroindole-, indole-, benzimidazole-, and indazolecarbox-amides). Two derivatives exhibited potent in vivo activities comparable to 1: 3-amino-N- (4(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2-pyridinecarboxamide (16) and 3-amino-N-(4(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2- thiophenecarboxamide (29). Furthermore, these derivatives were found to be much less active in behavioral models predictive of extrapyramidal side effects than in the mouse climbing assay, which predicts antipsychotic activity. Carboxamides 16 and 29 were selected for further evaluation as potential backup compounds to 1.
- Norman, Mark H.,Navas III, Frank,Thompson, James B.,Rigdon, Greg C.
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p. 4692 - 4703
(2007/10/03)
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- Structure-activity relationships of imidazo[4,5-f]quinoline partial structures and analogs. Discovery of pyrazolo[3,4-f]quinoline derivatives as potent immunostimulants
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Structure-activity studies have been carried out on a series of imidazo[4,5-f]quinoline derivatives reported to have potent in vivo immunostimulatory activity. This activity has been confirmed, and subtle structure-activity relationships have been uncovered which resulted in the identification of novel analogs (pyrazolo[3,4-f]quinoline derivatives, 7a,b) with potent in vivo effects in a mouse protection model. Regioisomeric pyrazolo[4,3-f]quinoline derivatives (6a,b) were shown to be inactive. Data are presented which support the notion that the in vivo activity is mediated by an immunostimulatory mechanism.
- Moyer,Weber,Gross
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p. 4595 - 4601
(2007/10/02)
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- Potential Antitumor Agents. 59. Structure-Activity Relationships for 2-Phenylbenzimidazole-4-carboxamides, a New Class of "Minimal" DNA-Intercalating Agents Which May Not Act via Topoisomerase II
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A series of substituted 2-phenylbenzimidazole-4-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity.These compounds represent the logical conclusion to our search for "minimal" DNA-intercalating agents with the lowest possible DNA-binding constants.Such "2-1" tricyclic chromophores, of lower aromaticity than the structurally similar 2-phenylquinolines, have the lowest DNA binding affinity yet seen in the broad series of tricyclic carboxamide intercalating agents.Despite very low in vitro cytotoxicities, several of the compoundshad moderate levels of in vivo antileukemic effects.However, the most interesting aspect of their biological activity was the lack of cross-resistance shown to an amsacrine-resistant P388 cell line, suggesting that these compounds may not express their cytotoxicity via interaction with topoisomerase II.
- Denny, William A.,Rewcastle, Gordon W.,Baguley, Bruce C.
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p. 814 - 819
(2007/10/02)
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