- Design, Synthesis, Cytotoxicity, and Molecular Docking Studies of New Benzimidazole Hybrids as Possible Anticancer Agents
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In the course of efforts to develop new anticancer agents, benzimidazole-based morpholine, thiomorpholine, and piperazine hybrid compounds were designed and synthesized. The structures of the synthesized compounds were confirmed by Proton nuclear magnetic resonance, Carbon-13 NMR, and mass spectroscopy. The title compounds were screened for cytotoxicity against breast and lung cancer cell lines. Compound 6c was found most active against lung cancer cell line with IC50 value of 2.11 μM and compound 10c was found most active against breast cancer cell line with IC50 of 2.23 μM. The molecular docking analysis was also carried out to explore binding pattern of compound with the target protein. All synthesized compounds showed excellent binding affinity toward target protein. Therefore, these findings will be helpful in future drug design of more potent anticancer agents.
- Mishra, Shashank Shekher,Sharma, C. S.
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- Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity
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Poly(adenosine 5′-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 ((Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC50 = 434 nM) led to a tetrazolyl analogue (51, IC50 = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC50 = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC50 values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC50 values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC50 = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 (BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.
- Velagapudi, Uday Kiran,Langelier, Marie-France,Delgado-Martin, Cristina,Diolaiti, Morgan E.,Bakker, Sietske,Ashworth, Alan,Patel, Bhargav A.,Shao, Xuwei,Pascal, John M.,Talele, Tanaji T.
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p. 5330 - 5357
(2019/06/07)
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- Substituted benzimidazoles as modulators of Ras signaling
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Benzimidazole compounds that increase the rate of SOS-mediated nucleotide exchange on Ras by binding to a functionally relevant, chemically tractable pocket on the SOS protein, as part of the Ras:SOS:Ras complex.
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- Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS
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Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ~30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.
- Hodges, Timothy R.,Abbott, Jason R.,Little, Andrew J.,Sarkar, Dhruba,Salovich, James M.,Howes, Jennifer E.,Akan, Denis T.,Sai, Jiqing,Arnold, Allison L.,Browning, Carrie,Burns, Michael C.,Sobolik, Tammy,Sun, Qi,Beesetty, Yugandhar,Coker, Jesse A.,Scharn, Dirk,Stadtmueller, Heinz,Rossanese, Olivia W.,Phan, Jason,Waterson, Alex G.,McConnell, Darryl B.,Fesik, Stephen W.
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p. 8875 - 8894
(2018/10/09)
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- From Cells to Mice to Target: Characterization of NEU-1053 (SB-443342) and Its Analogues for Treatment of Human African Trypanosomiasis
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Human African trypanosomiasis is a neglected tropical disease that is lethal if left untreated. Existing therapeutics have limited efficacy and severe associated toxicities. 2-(2-(((3-((1H-Benzo[d]imidazol-2-yl)amino)propyl)amino)methyl)-4,6-dichloro-1H-indol-1-yl)ethan-1-ol (NEU-1053) has recently been identified from a high-throughput screen of >42,000 compounds as a highly potent and fast-acting trypanocidal agent capable of curing a bloodstream infection of Trypanosoma brucei in mice. We have designed a library of analogues to probe the structure-activity relationship and improve the predicted central nervous system (CNS) exposure of NEU-1053. We report the activity of these inhibitors of T. brucei, the efficacy of NEU-1053 in a murine CNS model of infection, and identification of the target of NEU-1053 via X-ray crystallography.
- Devine, William G.,Diaz-Gonzalez, Rosario,Ceballos-Perez, Gloria,Rojas, Domingo,Satoh, Takashi,Tear, Westley,Ranade, Ranae M.,Barros-álvarez, Ximena,Hol, Wim G. J.,Buckner, Frederick S.,Navarro, Miguel,Pollastri, Michael P.
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p. 225 - 236
(2017/04/21)
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- Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening
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Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC50 = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.
- Kilchmann, Falco,Marcaida, Maria J.,Kotak, Sachin,Schick, Thomas,Boss, Silvan D.,Awale, Mahendra,G?nczy, Pierre,Reymond, Jean-Louis
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p. 7188 - 7211
(2016/09/09)
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- Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs
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A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5- methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.2% in rats after oral administration. As expected, continuously administering 35 significantly suppressed the growth of DU145 cells, which are human hormone-independent prostate cancer cells, in a mouse xenograft model without untoward effects.
- Nakao, Syuhei,Mabuchi, Miyuki,Shimizu, Tadashi,Itoh, Yoshihiro,Takeuchi, Yuko,Ueda, Masahiro,Mizuno, Hiroaki,Shigi, Naoko,Ohshio, Ikumi,Jinguji, Kentaro,Ueda, Yuko,Yamamoto, Masatatsu,Furukawa, Tatsuhiko,Aoki, Shunji,Tsujikawa, Kazutake,Tanaka, Akito
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p. 1071 - 1074
(2014/03/21)
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- Trimethylsilyl chloride catalyzed synthesis of substituted benzimidazoles using two phase system under microwave conditions, and their antimicrobial studies
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A convenient method using TMSCl (20 mol%) and microwave-induced technique for the synthesis of various benzimidazole is described. This has reduced the reaction time drastically as well as improved the yield when compared to conventional heating. The synthesized compounds were evaluated for their in vitro antibacterial and antifungal activities against four strains each. Preliminary results indicated that, compounds 3e, 3f, 3g, 3k, 3m, 3n and 3o demonstrated very good antimicrobial activity, comparable to the first line standard drugs. The most effective compounds have exhibited activity at MIC of 6.25 μg/mL.
- Karuvalam, Ranjith P.,Haridas, Karickal R.,Shetty, Suchetha N.
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p. 1122 - 1125,4
(2020/08/24)
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- Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping
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By virtual screening, compound 1 was found to be active against NS2B-NS3 protease (IC50 = 13.12 ± 1.03 μM). Fourteen derivatives (22) of compound 1 were synthesized, leading to the discovery of four new inhibitors with biological activity. In order to expand the chemical diversity of the inhibitors, small-molecule-based scaffold hopping was performed on the basis of the common scaffold of compounds 1 and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized. Protease inhibition assays revealed that 12 compounds with the new scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new compounds were discovered as NS2B-NS3 protease inhibitors with IC50 values of 7.46 ± 1.15 to 48.59 ± 3.46 μM, and 8 compounds belonging to two different scaffolds are active to some extent against DENV based on luciferase reporter replicon-based assays. These novel chemical entities could serve as lead structures for discovering therapies against DENV.
- Deng, Jing,Li, Ning,Liu, Hongchuan,Zuo, Zhili,Liew, Oi Wah,Xu, Weijun,Chen, Gang,Tong, Xiankun,Tang, Wei,Zhu, Jin,Zuo, Jianping,Jiang, Hualiang,Yang, Cai-Guang,Li, Jian,Zhu, Weiliang
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supporting information; experimental part
p. 6278 - 6293
(2012/09/07)
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- Design and synthesis of small molecule RhoA inhibitors: A new promising therapy for cardiovascular diseases?
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RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as an important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of ~200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1-3). Compound 1 was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a-v, 13a-h, and 14a-j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC50 values of 1.24 to 3.00 μM. A pharmacological assay indicated that two compounds (14g and 14 h) demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents.
- Deng, Jing,Feng, Enguang,Ma, Sheng,Zhang, Yan,Liu, Xiaofeng,Li, Honglin,Huang, Huang,Zhu, Jin,Zhu, Weiliang,Shen, Xu,Miao, Liyan,Liu, Hong,Jiang, Hualiang,Li, Jian
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experimental part
p. 4508 - 4522
(2011/09/14)
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- Tetra butyl ammonium chloride catalyzed synthesis of substituted benzimidazoles under microwave conditions
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TBACl (10 mol %) was found to be a useful catalyst for the synthesis of substituted benzimidazoles. The method was proved to be simple, convenient and the product was isolated with good yield.
- Ranjith, P. Karuvalam,Siji,Divia,Karickal, R. Haridas
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experimental part
p. 589 - 593
(2011/01/12)
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- Direct conversion of thiols to sulfonyl chlorides and sulfonamides
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(Chemical Equation Presented) H2O2 in combination with SOCl2 proved to be a highly reactive reagent for the direct oxidative conversion of thiol derivatives to the corresponding sulfonyl chlorides with high purity through oxidative chlorination. Upon reaction with amines, the corresponding sulfonamides were obtained in excellent yields and in very short reaction times.
- Bahrami, Kiumars,Khodaei, Mohammad M.,Soheilizad, Mehdi
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supporting information; experimental part
p. 9287 - 9291
(2010/03/04)
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- Thietane ring as a novel protecting group
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A novel protecting group for NH functionality of heterocycles, a thietane ring, was proposed. It can be readily introduced by alkylation of NH-heterocycles with 2-chloromethylthiirane. Removal of the thietane protecting group is performed via oxidation to thietane 1,1-dioxide with hydrogen peroxide in acetic acid and subsequent treatment with sodium alkoxide.
- Khaliullin,Klen
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experimental part
p. 135 - 138
(2009/09/06)
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- Design, syntheses, and structure-activity relationships of novel NPY Y5 receptor antagonists: 2-{3-Oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl}benzimidazole derivatives
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Design, syntheses, and structure-activity relationships of a novel class of 2-{3-oxospiro[isobenzofuran-1(3H),4′-piperidin]-1′-yl}benzimidazole NPY Y5 receptor antagonists are described. The benzimidazole structures were newly designed based on the urea linkage of our prototype Y5 receptor antagonists (2 and 3). By optimizing substituents on the benzimidazole core part of the lead compound 5a, we were able to develop a potent, orally available, and brain-penetrable Y5 selective antagonist (5k). Crown Copyright
- Ogino, Yoshio,Ohtake, Norikazu,Nagae, Yoshikazu,Matsuda, Kenji,Moriya, Minoru,Suga, Takuya,Ishikawa, Makoto,Kanesaka, Maki,Mitobe, Yuko,Ito, Junko,Kanno, Tetsuya,Ishihara, Akane,Iwaasa, Hisashi,Ohe, Tomoyuki,Kanatani, Akio,Fukami, Takehiro
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scheme or table
p. 5010 - 5014
(2009/05/07)
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- Synthesis of 1-(n-hexyl-5-one)-2-chlorobenzimidazole
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o-Phenylenediamine on condensation with urea gives the known benzimidazolin-2-one, which on reaction with phosphoryl chloride in the presence of catalytic amount of phenol yields the already reported 2- chlorobenzimidazole. The latter on alkylation with 6-chloro-2-hexanone in the presence of K2CO3 in DMF medium, gives the title compound.
- Dubey,Naidu,Anandam,Hemasunder
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p. 1239 - 1242
(2007/10/03)
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- Amide substituted imidazoquinolines
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Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain amide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.
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- Amide substituted imidazoquinolines
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Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain amide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.
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- An improved large-scale preparation of benzimidazole-2-sulfonic acids and 2-chlorobenzimidazoles
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An improved method for the preparation of benzimidazole-2-sulfonic acids from 2-mercaptobenzimidazoles has been developed which utilizes aqueous sodium percarbonate. 2-chlorobenzimidazoles were obtained in high yield from the corresponding sulfonic acids upon reaction with PCl5 in POCl3 on a gram-mole scale.
- Hinkley, Jack M.,Porcari, Anthony R.,Walker II, John A.,Swayze, Eric E.,Townsend, Leroy B.
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p. 1703 - 1712
(2007/10/03)
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- A short synthesis of astemizole
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The synthesis of astemizole 6, a potent H1-antihistaminic agent, was achieved in 20% overall yield. Compound 6 was obtained in high purity and on a multigram scale starting from 2-hydroxybenzimidazole.
- De Parrodi, Cecilia Anaya,Quintero-Cortes, Leticia,Sandoval-Ramirez, Jesus
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p. 3323 - 3329
(2007/10/03)
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- Synthesis and structure-activity relationship of new piperidinyl and piperazinyl derivatives as antiallergics
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A series of piperazinebenzothiazoles 3-5, piperazinebenzimidazoles 6-12, piperidinobenzothiazoles 14-45, piperidinobenzoxazoles 46-52 and piperidinobenzimidazoles 53-129 has been synthesized and their antiallergic activity evaluated by means of the passive cutaneous anaphylaxis (PCA) assay. Structure-activity relationships are discussed and related to classical antihistaminics. Piperidino derivatives with an aryl group linked to the nitrogen atom by an ethyl chain are the most active compounds, with ID50 1 mg/kg po. Some of these compounds are more potent antiallergics than astemizole and terfenadine.
- Orjales,Bordell,Rubio
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p. 707 - 718
(2007/10/02)
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- Derivatives of terbutylphenyl-1-amino-4-hydroxybutane their preparation processes and the pharmaceutical compositions containing them
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STR1 The present invention concerns (4-substituted phenyl)4-oxy 1-aminobutane of the general formula (I) in which X is a nitrogen atom or >CH--CH, and R is a cyclic substituent chosen from the group comprising a) a xanthic substituent, b) a benzimidazolic substituent, as well as salts and optic isomers of the compounds of formula (I). The invention also concerns processes for obtaining the compounds of formula (I) and pharmaceutical compositions containing, as antihistamine ingredient, at least one compound of formula (I) or one of its salts with a mineral or organic acid.
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- N-(1-methyl-3-pyrrolidinyl)-1-(phenylmethyl)-1H-benzimidazol-2-amine and analogs as antiarrhythmic and muscle relaxing agents
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A method of treating cardiac arrhythmias and muscle tension and spasticity with N-(1-methyl-3-pyrrolidinyl)-1-(phenylmethyl)-1H-benzimidazol-2-amine and analogs and the pharmaceutical compositions are herein disclosed. Illustratively, the compound having the structure: STR1 corrects an induced arrhythmia in 7 out of 8 dogs at 7 mg/kg IV and has an ED50 of 21 mg/kg in the mouse Straub-tail test.
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- Substituted arylsulfonamides and benzamides
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This invention relates to substituted arylsulfonamides and benzamides possessing aniarrhythmic activity, to pharmaceutical compositions and to methods for production thereof.
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- OXIDATION OF SOME HETARYLHYDRAZINES WITH SELENIUM DIOXIDE
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The oxidation of 2-benzimidazolyl- and 2-quinoxalinylhydrazines with selenium dioxide in hydrochloric acid in the presence of cuprous chloride leads to the formation of 2-chloro derivatives of the heterocycles.When the reaction is carried out in ethanol, 2-benzimidazolylhydrazines give symmetrical formazans.In both cases oxidation proceeds through a step involving the formation of hetarenediazonium salts.
- Sedov, Yu. A.
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p. 217 - 220
(2007/10/02)
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- Photochemistry, of Heterocyclics. III. Photolysis of Various 2-Substituted Benzimidazoles
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A variety of 2-substituted benzimidazoles have been irradiated with ultraviolet light to determine the effects of substituents on the photochemical behaviour of the benzimidazole ring system.Benzimidazol-2-amine gave -2'amine and -2'-amine, showing that this derivative behaves in the same way as benzimidazole. 2-Chlorobenzimidazole loses chlorine forming a dimeric species and benzimidazol-2(3H)-one, which is itself inert to photolysis. 2-Trichloromethylbenzimidazole also loses chlorine to form a variety of products depending on the solvent. 2-Trifluoromethylbenzimidazole does not lose fluorine but forms a dimer and also undergoes imidazole ring cleavage.Benzimidazole-2-thiol also undergoes imidazole ring cleavage with loss of sulfur.The 2-phenyl group stabilizes the benzimidazole ring system to photolysis as does the 2-thiazolyl group; however, the latter suffers thiazole ring cleavage.
- Crank, George,Mursyidi, Achmad
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p. 775 - 784
(2007/10/02)
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- Phenylamine substituted on amine with a benzo(oxa, thia or di) azole group
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The invention concerns novel diarylamine derivatives of formula I STR1 wherein φ is chosen from STR2 The compounds are herbicides and in further embodiments the invention provides herbicidal compositions containing as active ingredient a compound of formula I, a process for severely damaging or killing unwanted plants by applying to the plants or to the growth medium of the plants an effective amount of a compound of formula I, processes for the preparation of compounds of formula I and intermediates useful in the preparation of compounds of formula I.
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- 1,2,3,4-Tetrahydroisoquinolines and the preparation thereof
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1,2,3,4-Tetrahydroisoquinolines of the formula STR1 wherein R is a heterocyclic group which may have appropriate substituent(s) and pharmaceutically acceptable salts thereof, which have relaxing activity on smooth muscle, are disclosed, together with a method for their preparation.
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