- Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and in Vivo Oral Efficacy Studies
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A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.
- Dziwornu, Godwin Akpeko,Coertzen, Dina,Leshabane, Meta,Korkor, Constance M.,Cloete, Cleavon K.,Njoroge, Mathew,Gibhard, Liezl,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Wittlin, Sergio,Birkholtz, Lyn-Marie,Chibale, Kelly
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supporting information
p. 5198 - 5215
(2021/05/06)
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- Astemizole-based turn-on fluorescent probes for imaging hERG potassium channel
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Based on the scaffold of astemizole, three novel turn-on fluorescent probes (N1-N3) for human ether-a-go-go-related gene (hERG) potassium channel were developed herein. These probes have reasonable fluorescence properties, acceptable cell toxicity, and potent inhibitory activity, all of which contribute to cell imaging at the nanomolar level. Overall, these probes have the potential for setting up a screening system for hERG channels.
- Zhang, Xiaomeng,Liu, Tingting,Wang, Beilei,Gao, Yuqi,Liu, Pan,Li, Minyong,Du, Lupei
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supporting information
p. 513 - 516
(2019/04/30)
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- Design, synthesis and characterization of novel N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors leading to the identification of the selective compound, AC1903
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The transient receptor potential cation channel 5 (TRPC5) has been previously shown to affect podocyte survival in the kidney. As such, inhibitors of TRPC5 are interesting candidates for the treatment of chronic kidney disease (CKD). Herein, we report the synthesis and biological characterization of a series of N-heterocyclic-1-benzyl-1H-benzo[d]imidazole-2-amines as selective TRPC5 inhibitors. Work reported here evaluates the benzimidazole scaffold and substituents resulting in the discovery of AC1903, a TRPC5 inhibitor that is active in multiple animal models of CKD.
- Sharma, Swagat H.,Pablo, Juan Lorenzo,Montesinos, Monica Suarez,Greka, Anna,Hopkins, Corey R.
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supporting information
p. 155 - 159
(2018/12/11)
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- Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action
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A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver, and sexual gametocytic stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the 17 derivatives showed half-maximal inhibitory concentrations (IC50s) of 50 100). Screening of AST and its analogues against gametocytes revealed their moderate activity (IC50: 1-5 μM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.
- Kumar, Malkeet,Okombo, John,Mambwe, Dickson,Taylor, Dale,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Fontinha, Diana,Sanches-Vaz, Margarida,Bezuidenhout, Belinda C.,Lauterbach, Sonja B.,Liebenberg, Dale,Birkholtz, Lyn-Marie,Coetzer, Theresa L.,Prudêncio, Miguel,Egan, Timothy J.,Wittlin, Sergio,Chibale, Kelly
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p. 303 - 315
(2019/01/15)
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- Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds
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Astemizole is a H1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.
- Tian, Junjun,Vandermosten, Leen,Peigneur, Steve,Moreels, Lien,Rozenski, Jef,Tytgat, Jan,Herdewijn, Piet,Van den Steen, Philippe E.,De Jonghe, Steven
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p. 6332 - 6344
(2017/10/23)
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- A benzimidazole hERG potassium ion channel of small molecule fluorescent probe and its preparation method and application
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The invention relates to a benzimidazole hERG potassium ion channel small-molecular fluorescent probe and a preparation method and applications thereof; the fluorescent probe has the structural general formula represented by the formula (I), wherein in the formula, R1 is hydroxyl, halogen, alkyl or alkoxy monosubstituent or polysubstituent, R2 is fluorophore, n is 1-6, particularly, R1 is p-halogen, and R2 is coumarin, naphthalene diimide, NBD, Cy5 or fluorescein isothiocyanate fluorophore. The invention discloses the applications of the probe in marking of hERG potassium ion channels and high-expression tumor cells or tissues, high-throughput screening of hERG potassium ion channel inhibitors, evaluation of new drug cardiotoxicity, use as a probe for identification of the hERG potassium ion channels and studies on hERG potassium ion channel physiological, pathological and related diseases.
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Paragraph 0032; 0034; 0036; 0037; 0055
(2017/08/25)
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- Astemizole Derivatives as Fluorescent Probes for hERG Potassium Channel Imaging
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The detection and imaging of hERG potassium channels in living cells can provide useful information for hERG-correlation studies. Herein, three small-molecule fluorescent probes, based on the potent hERG channel inhibitor astemizole, for the imaging of hERG channels in hERG-transfected HEK293 cells (hERG-HEK293) and human colorectal cancer cells (HT-29), are described. These probes are expected to be applied in the physiological and pathological studies of hERG channels.
- Wang, Beilei,Liu, Zhenzhen,Ma, Zhao,Li, Minyong,Du, Lupei
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supporting information
p. 245 - 249
(2016/03/25)
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- Synthesis and Cytotoxic Evaluation of Pyrrole Hetarylazoles Containing Benzimidazole/Pyrazolone/1,3,4-Oxadiazole Motifs
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Azomethine-linked pyrrole bishetarylazoles containing benzimidazole/pyrazolone/1,3,4-oxadiazole were synthesized in satisfactory yields. Their structures were confirmed by IR,1H-NMR,13C-NMR, and elemental analysis. Evaluation for the cytotoxic activities in vitro against a panel of breast cancer cell lines (MDA-AB-231, BT-474, and Ishikawa cells) revealed that the pyrrole–benzimidazole hybrids are more potent than the pyrazolone and 1,3,4-oxadiazole hybrids in all cell lines. Compound 9 displayed promising cytotoxicity against BT-474 cell line with IC50values, 7.7 μM.
- Mochona, Bereket,Jackson, Timothy,McCauley, DeCoria,Mazzio, Elizabeth,Redda, Kinfe K.
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p. 1871 - 1877
(2016/11/23)
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- Synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-a] benzimidazole derivatives against Leishmania donovani and Trypanosoma cruzi
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A high-throughput (HTS) and high-content screening (HCS) campaign of a commercial library identified 2,3-dihydroimidazo[1,2-a]benzimidazole analogues as a novel class of anti-parasitic agents. A series of synthetic derivatives were evaluated for their in vitro anti-leishmanial and anti-trypanosomal activities against Leishmania donovani and Trypanosoma cruzi, which have been known as the causative parasites for visceral leishmaniasis and Chagas disease, respectively. In the case of Leishmania, the compounds were tested in both intracellular amastigote and extracellular promastigote assays. Compounds 4 and 24 showed promising anti-leishmanial activity against intracellular L. donovani (3.05 and 5.29 μM, respectively) and anti-trypanosomal activity against T. cruzi (1.10 and 2.10 μM, respectively) without serious cytotoxicity toward THP-1 and U2OS cell lines.
- Oh, Sangmi,Kim, Sungbum,Kong, Sunju,Yang, Gyongseon,Lee, Nakyung,Han, Dawoon,Goo, Junghyun,Siqueira-Neto, Jair L.,Freitas-Junior, Lucio H.,Song, Rita
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p. 395 - 403
(2014/08/05)
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- Synthesis and biological evaluation of 2,3-dihydroimidazo[1,2-a] benzimidazole derivatives against Leishmania donovani and Trypanosoma cruzi
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A high-throughput (HTS) and high-content screening (HCS) campaign of a commercial library identified 2,3-dihydroimidazo[1,2-a]benzimidazole analogues as a novel class of anti-parasitic agents. A series of synthetic derivatives were evaluated for their in vitro anti-leishmanial and anti-trypanosomal activities against Leishmania donovani and Trypanosoma cruzi, which have been known as the causative parasites for visceral leishmaniasis and Chagas disease, respectively. In the case of Leishmania, the compounds were tested in both intracellular amastigote and extracellular promastigote assays. Compounds 4 and 24 showed promising anti-leishmanial activity against intracellular L. donovani (3.05 and 5.29 μM, respectively) and anti-trypanosomal activity against T. cruzi (1.10 and 2.10 mM, respectively) without serious cytotoxicity toward THP-1 and U2OS cell lines.
- Oh, Sangmi,Kim, Sungbum,Kong, Sunju,Yang, Gyongseon,Lee, Nakyung,Han, Dawoon,Goo, Junghyun,Siqueira-Neto, Jair L.,Freitas-Junior, Lucio H.,Song, Rita
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p. 395 - 403
(2015/03/13)
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- Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists
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Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.
- Sasmal, Pradip K.,Sasmal, Sanjita,Rao, P. Tirumala,Venkatesham,Roshaiah,Abbineni, Chandrasekhar,Khanna, Ish,Jadhav, Vikram P.,Suresh,Talwar, Rashmi,Muzeeb, Syed,Receveur, Jean-Marie,Frimurer, Thomas M.,Rist, ?ystein,Elster, Lisbeth,H?gberg, Thomas
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scheme or table
p. 5443 - 5448
(2011/01/03)
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- Discovery of the first nonpeptidic, Small-molecule, highly selective somatostatin receptor subtype 5 antagonists: A chemogenomics approach
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We disclose the first selective, nonpeptidic, small-molecule somatostatin receptor subtype 5 (SST5R) antagonists that were identified by a chemogenomics approach based on the analysis of the homology of amino acids defining the putative consensus drug binding site of SST5R. With this strategy, opioid, histamine, dopamine, and serotonine receptors were identified as the closest neighbors of SST5R. The H1 antagonist astemizole was chosen as a seed structure and subsequently transformed into a SST5 receptor antagonist with nanomolar binding affinity devoid of the original target activity.
- Martin, Rainer E.,Green, Luke G.,Guba, Wolfgang,Kratochwil, Nicole,Christ, Andreas
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p. 6291 - 6294
(2008/03/30)
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- 5-HT3R binding of lerisetron: An interdisciplinary approach to drug-receptor interactions
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The design, synthesis, and use of lerisetron-based molecular probes to investigate the 5-HT3R binding site are described. A SAR study, which involved distance and electronic parameter modifications of lerisetron's N-benzyl group, resulted in the discovery of a partial agonist.
- Parihar, Harish S.,Suryanarayanan, Asha,Ma, Chun,Joshi, Prasad,Venkataraman, Padma,Schulte, Marvin K.,Kirschbaum, Karen S.
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p. 2133 - 2136
(2007/10/03)
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- Substituted 4-(1H-benzimidazol-2-yl-amino)piperidines useful for the treatment of allergic diseases
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The present invention relates to novel substituted piperidine derivatives of formula (1), stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonist. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; asthma; bronchitis; and emesis.
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- Synthesis and antihistaminic H1 activity of 1,2,5(6)-trisubstituted benzimidazoles
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A number of benzimidazoles, having several substituents on the azole and benzene nuclei and C-2 (methylamino, ethylenediamine, morpholine, piperazine and piperidine) were prepared. Regioselective synthesis was designed for the N1-alkyl substituted benzimidazoles (14-15). X-Ray structure analysis of (14) was also revealed. Compounds were evaluated for their in vitro H1- antihistaminic activity in the isolated guinea-pig ileum method. The compound (11) exhibits best activity.
- Goeker, Hakan,Ayhan-Kilcigil, Guelguen,Tuncbilek, Meral,Kus, Canan,Ertan, Rahmiye,Kendi, Engin,Oezbey, Sueheyla,Fort, Merce,Garcia, Celia,Farre, Antonio J.
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p. 2561 - 2573
(2007/10/03)
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- SUBSTITUTED N-METHYL-N-(4-(4-(1H-BENZIMIDAZOL-2-YL-AMINO) PIPERIDIN-1-YL)-2-(ARLYL) BUTYL) BENZAMIDES USEFUL FOR THE TREATMENT OF ALLERGIC DISEASES
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The present invention relates to novel substituted N-methyl-N-(4-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)-2-(aryl)butyl) benzamide derivatives of the formula: STR1 stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; asthma; bronchitis; and emesis.
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- Method for synthesizing 2-substituted imidazoles
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The present invention is a method of preparing 2-substituted imidazoles from readily available imidazoles having a leaving group in the 2-position, by alkylating the imidazole under mild conditions to afford a 3-N-alkylated imidazolium salt; and coupling the imidazolium salt with a nucleophile also under mild conditions to afford a 2-substituted 3-N-alkylated imidazolium salt. The reaction product can optionally be isolated and purified. The 2-substituted 3-N-alkylated imidazolium salt is hydrolyzed to afford a 2-substituted imidazole. Alternatively, the imidazole is coupled with a nucleophile in the presence of fluoride ion to provide a 2-substituted imidazole.
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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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- 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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- 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines
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4-[(Bicyclic heterocyclyl)methyl and -hetero]-piperidines having antihistaminic and serotonin-antagonistic properties which compounds are useful agents in the treatment of allergic diseases.
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