- Expression, Purification, and Comparative Inhibition of Helicobacter pylori Urease by Regio‐Selectively Alkylated Benzimidazole 2‐Thione Derivatives
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The urease enzyme has been an important target for the discovery of effective pharmacological and agricultural products. Thirteen regio‐selectively alkylated benzimidazole‐2‐thione derivatives have been designed to carry the essential features of urease i
- Amer, Mohamed R.,Eissa, Ibrahim H.,El Ashry, El Sayed H.,Elkaeed, Eslam B.,Elshobaky, Ahmed,Hafez, Elsayed E.,Khalid, Asaad,Metwaly, Ahmed M.,Mohammed, Salih Osman
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- Head-to-head bisbenzazole derivatives as antiproliferative agents: design, synthesis, in vitro activity, and SAR analysis
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Abstract: In the present work, a series of bisbenzazole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of these compounds was investigated using MTT assay. Bisbenzazole derivatives showed significant antiproliferative activity against all the four tested cancer cell lines. Among the various bisbenzazole derivatives, bisbenzoxazole derivatives exhibited the most promising anticancer activity followed by bisbenzimidazole and bisbenzothiazole derivatives. All the derivatives were found to be less toxic as compared to methotrexate (positive control) in normal human cells, indicating selective and efficient antiproliferative activity of these bisbenzazole derivatives. The structure–activity relationships of heteroaromatic systems and linkers present in bisbenzazole derivatives were analyzed in detail. In silico ADMET prediction revealed that bisbenzazole is a drug-like small molecule with a favorable safety profile. Compound 31 is a potential antiproliferative hit compound that exhibits unique cytotoxic activity distinct from methotrexate. Graphic abstract: Twenty-one bisbenzoxazole derivatives have been designed synthesized and evaluated to be an antiproliferative activity against four human tumor cell lines.[Figure not available: see fulltext.]
- Ersan, Ronak Haj,Alagoz, Mehmet Abdullah,Ertan-Bolelli, Tugba,Duran, Nizami,Burmaoglu, Serdar,Algul, Oztekin
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p. 2247 - 2259
(2020/06/27)
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- Bisbenzimidazole Derivatives as Potential Antimicrobial Agents: Design, Synthesis, Biological Evaluation and Pharmacophore Analysis
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In an attempt to design and synthesize a potent class of antimicrobials, 1,2-phenylenediamine derivatives were reacted with various aliphatic and heteroaliphatic dicarboxylic acids to generate a small library of 26 head-to-head bisbenzimidazole compounds (16 – 42) using the polyphosphoric acid method. These compounds were screened for their antibacterial activity and their antifungal activity. Compound 25 showed maximum potency against both Gram-positive and Gram-negative bacterial strains with minimum inhibitory concentration (MIC) values in the range of 7.81 – 31.25 μg/mL. In particular, it showed the maximum MIC values of 7.81 μg/mL against Gram-negative bacteria, which was four-fold more active than the standard drug ampicillin (MIC = 32.25 μg/mL). Compound 19 was found to be the most active against S. aureus with a MIC value of 3.90 μg/mL, whereas the remaining compounds showed only low-to-moderate activity. Furthermore, all compounds exhibited low activity against all fungal strains in comparison to the standard drug fluconazole. I addition, pharmacophore hypotheses were generated to analyze structure–activity relationships between the molecular structures and antimicrobial activities on E. coli. This pharmacophore model can be useful in order to design new antimicrobial drugs. It can be suggested that the substitution of a phenyl ring at the 5/6 and 5′/6′ positions in symmetric bisbenzimidazole derivatives produces compounds with promising antimicrobial activity.
- Ersan, Ronak Haj,Bolelli, Kayhan,Gonca, Serpil,Dogen, Aylin,Burmaoglu, Serdar,Algul, Oztekin
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p. 149 - 158
(2021/05/13)
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- Amino acid conjugates of 2-mercaptobenzimidazole provide better anti-inflammatory pharmacology and improved toxicity profile
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Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant analgesic/anti-inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2-mercaptobenzimidazole amino acid conjugates (4a–4o) and screened them for analgesic, anti-inflammatory and gastro-protective effects. The synthesized 2-mercaptbenzimidazole derivatives were characterized for their structure using FTIR, 1H NMR and 13C NMR spectroscopic techniques. The 2-mercaptobenzimidazole amino acid conjugates have found to possess potent analgesic, anti-inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti-ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX-2 (PDB ID: 3LN1) and H+/K+-ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2-mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation.
- Khan, Muhammad T.,Nadeem, Humaira,Khan, Arif-ullah,Abbas, Muzaffar,Arif, Muazzam,Malik, Nadia Shamshad,Malik, Zulkifal,Javed, Ibrahim
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p. 1057 - 1072
(2020/08/13)
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- Novel bisphosphonates with antiresorptive effect in bone mineralization and osteoclastogenesis
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Bisphosphonates such as zoledronic, alendronic and risedronic acids are a class of drugs clinically used to prevent bone density loss and osteoporosis. Novel P-C-P bisphosphonates were synthesized for targeting human farnesyl pyrophosphate synthase (hFPPS) and human geranylgeranyl pyrophosphate synthase (hGGPPS), key enzymes of the mevalonate pathway, and capable of anti-proliferative action on a number of cell lines (PC3, MG63, MC3T3, RAW 264.7, J774A.1, bone marrow cells and their co-colture with PC3) involved in bone homeostasis, bone formation and death. Among sixteen compounds, [1-hydroxy-2-(pyrimidin-2-ylamino)ethane-1,1-diyl]bis(phosphonic acid) (10) was effective in reducing PC3 and RAW 264.7 cell number in crystal-violet and cell-dehydrogenase activity assays at 100 μM concentration. 10 reduced differentiated osteoclasts number similarly with zoledronic acid in osteoclastogenesis assay. At nanomolar concentrations, 10 was more effective than zoledronic acid in inducing mineralization in MC3T3 and murine bone marrow cells. Further, 10 significantly inhibited the activity of hFPPS showing an IC50 of 0.31 μM and a remarkable hydroxyapatite binding of 90%. Docking calculations were performed identifying putative interactions between some representative novel bisphosphonates and both hFPPS and hGGPPS. Then, 10 was found to behave similarly or even better than zoledronic acid as a anti-resorptive agent.
- Savino, Salvatore,Toscano, Annamaria,Purgatorio, Rosa,Profilo, Emanuela,Laghezza, Antonio,Tortorella, Paolo,Angelelli, Mariacristina,Cellamarea, Saverio,Scala, Rosa,Tricarico, Domenico,Thomas Marobbio, Carlo Marya,Perna, Filippo,Vitale, Paola,Agamennone, Mariangela,Dimiccoli, Vincenzo,Tolomeo, Anna,Scilimati, Antonio
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p. 184 - 200
(2018/09/18)
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- Novel thiazolidinone/thiazolo[3,2-a] benzimidazolone-isatin conjugates as apoptotic anti-proliferative agents towards breast cancer: One-pot synthesis and in vitro biological evaluation
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In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (4a–n) and thiazolo[3,2-a]benzimidazolone-isatin conjugates (7a–d), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC50 = 7.6 ± 0.5 and 13.2 ± 1.1 μM, respectively). Compounds 4m and 7b were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid 4m induced a fourfold increase in the percentage of cells at Sub-G1, with concurrent arrest in G2-M phase by 2.5-folds. Furthermore, hybrid 4m resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates 4m and 7b displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study.
- El-Naggar, Mohamed,Eldehna, Wagdy M.,Almahli, Hadia,Elgez, Amr,Fares, Mohamed,Elaasser, Mahmoud M.,Abdel-Aziz, Hatem A.
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- Design, synthesis, molecular docking, and in vitro antidiabetic activity of novel PPARγ agonist
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Abstract: The present work describes the design, synthesis, molecular docking, biological evaluation, and assessment of structure–activity relationship of new derivatives based upon the molecular skeleton of the drug pioglitazone, a compound which is currently used for the management of type 2 diabetes mellitus. Pioglitazone has several side effects such as weight gain, edema, congestive heart failure, and bladder cancer. Therefore, there is a strong demand for identification of new lead candidates in the treatment of type 2 diabetes mellitus. A series of 24 compounds were prepared and evaluated for their peroxisome proliferator-activated receptor-γ (PPARγ) binding affinity assay and the IC50 values were determined. Among these compounds, six compounds exhibited promising IC50 values as compared to standard drugs pioglitazone and rosiglitazone. Furthermore, in order to confirm the target of these molecules, molecular docking study was carried out with peroxisome proliferator-activated receptor-γ (PPARγ) protein. Molecular modeling studies suggested that these compounds appropriately interact in the active sites of receptor. Graphical abstract: [Figure not available: see fulltext.].
- Chaturvedi, Radha Nandan,Pendem, Krishnaiah,Patel, Vipul P.,Sharma, Mukta,Malhotra, Sunita
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p. 2069 - 2084
(2018/08/22)
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- Synthesis of novel benzimidazole and benzothiazole derivatives bearing a 1,2,3-triazole ring system and their acetylcholinesterase inhibitory activity
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A series of 20 novel benzimidazole and benzothiazole derivatives linked to a 1,2,3-triazole ring system was synthesised, characterised and evaluated for in vitro acetylcholinesterase (AChE) inhibitory activity. Several copper catalysts and solvents were screened to establish the optimal conditions for the preparation of the target compounds. Three different linkers were used to optimise the enzyme inhibitory effect. Out of the 20 compounds, 13 showed some AChE inhibition. The most potent compound, which showed 84% inhibition at 100 μM, contained a 1-(2-fluorobenzyl)-1,2,3-triazole linked to a benzimidazole group. A docking simulation study showed that the most active compound bound preferentially to the catalytic anionic subsite of the AChE enzyme.
- Faraji, Laleh,Shahkarami, Shiva,Nadri, Hamid,Moradi, Alireza,Saeedi, Mina,Foroumadi, Alireza,Ramazani, Ali,Haririan, Ismaeil,Ganjali, Mohammad Reza,Shafiee, Abbas,Khoobi, Mehdi
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- Tautomerism and isomerism in some antitrichinellosis active benzimidazoles: Morphological study in polarized light, quantum chemical computations
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The morphology of the crystal structure of some antitrichinellosis active benzimidazole derivatives including (1H-benzimidazol-2-ylthio)acetic acids, [1,3]thiazolo[3,2-a]benzimidazol-3(2H)-ones, 1H-benzimidazol-2-ylthioacetylpiperazines and starting 2-mercapto benzimidazoles, was studied by the use of Polarized Light Microscopy (PLM). Characterization of the crystal phase was complimented by Differential scanning calorimetry analysis (DSC) and spectroscopic data. DFT computations were performed in order to investigate the prototropic tautomerism and the geometry of the molecule of the synthesized compounds. One distinct type of crystal structure for each one of 5 or 6-methyl-(1H-benzimidazol-2-ylthio)acetic acid 6 was observed by PLM – dendritic and needle-shaped formations. Compound 14, containing a methyl substituent in the benzimidazole ring crystallized also into two phases; while for the unsubstituted compound 13 a separation of phases does not take place. The influence of the both solvents - chloroform and ethanol on the phase separation and the formation of the crystalline structure of compound 14 was investigated. The morphological study showed that the cyclization of 6 in the presence of acetic anhydride in pyridine medium led to a mixture of 6-methyl-[1,3]tiazolo[3,2-a]benzimidazol-3(2H)-one (10a) and 7-methyl-[1,3]thiazolo[3,2-a]-benzimidazole-3(2H)-one (10b), which crystallized in the form of fibrils and spherulites respectively. It was found that a difference in the crystal structures of substituted and unsubstituted benzimidazol-2-thiones, respectively benzimidazol-2-thiol derivatives exists, which may be due not only to the thiol-thione tautomerism but to the prototropic properties of the hydrogen atom in first position of the ring. The calculation results indicated that the thione form is more stable than the thiol tautomer by 51–55 kJ mol?1. But at the same time ΔG for the two thiol tautomers is below 0.5 kJ mol?1. In solid phase the 5(6)-substituted-1H-benzimidazol-2-thiols crystallized in two different crystal structures while the unsubstituted 1H-benzimidazol-2-thiol possess one type of crystal structure.
- Anichina, Kameliya,Mavrova, Anelia,Yancheva, Denitsa,Tsenov, Jordan,Dimitrov, Rasho
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p. 179 - 187
(2017/09/05)
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- Synthesis and antibacterial evaluation of some novel mannich bases of benzimidazole derivatives
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Substituted benzimidazoles are known for their chemotherapeutic importance and many pharmacological properties. In this paper, we synthesized some novel Mannich bases of benzimidazole derivatives. The synthesized compounds were characterized by their physical and spectral data and in vitro antibacterial activity of these compounds tested against Bacillus subtilis, Bacillus pumilus, Escherichia coli and Pseudomonas aeruginosa organisms. The potency of the synthesized compounds was determined against standard drug Ciprofloxacin by measuring the zone of inhibition.
- Ahmadi
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p. 421 - 425
(2017/03/11)
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- Alkylation and Aminomethylation of 1,3-Dihydro-2H-Benzimidazole-2-Thione
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Alkylation of 1,3-dihydro-2H-benzimidazole-2-thione (2-mercaptobenzimidazole) with bromoethane and chloroacetic acid derivatives occurrs at the sulfur atom, leading to the corresponding 2-sulfanylbenz-imidazole derivatives. Aminomethylation of 1,3-dihydro-2H-benzimidazole-2-thione with piperidine and 4-methylpiperidine gives reaction products at both nitrogen atoms, while reaction with morpholine gives derivative at only one nitrogen atom, which is in an equilibrium with the starting compound and bis-adduct in DMSO solution.
- Bespalov,Gorchakova,Ivanov,Kuznetsov,Kuznetsova,Pankova,Prokopenko,Avdontceva
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p. 1547 - 1558
(2015/02/19)
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- Synthesis and antimicrobial activity of a new class of sulfonylmethane linked bisheterocycles
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A new class of sulfonylmethane linked bisheterocycles were prepared and studied their antimicrobial activity.
- Venkatapuram, Padmavathi,Dandu, Seenaiah,Chokkappagari, Premakumari,Adivireddy, Padmaja
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p. 1757 - 1763
(2015/01/09)
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- Synthesis and biological evaluation of novel thiazolidinone derivatives as potential anti-inflammatory agents
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The modulation of pro-inflammatory cytokines provides a target for controlling inflammatory diseases and attracts much attention in current anti-inflammatory drug development. Here, four series of thiazolidinone derivatives were synthesized and screened for anti-inflammatory activities. A majority of these compounds showed excellent inhibition on the expression of TNF-α and IL-6 in LPS-stimulated macrophages. Discussions are given regarding the structure-activity relationships. Compounds 12d and 12h inhibited LPS-induced TNF-α and IL-6 release in a dose-dependent manner. Furthermore, 12d exhibited a significant protection against LPS-induced septic death in mouse model. Together, these data present a series of new thiazolidinones with potential therapeutic effects in acute inflammatory diseases and they could be important leads in the continuing anti-inflammatory drug research.
- Hu, Jie,Wang, Yi,Wei, Xiaoyan,Wu, Xixi,Chen, Gaozhi,Cao, Gaozhong,Shen, Xueqian,Zhang, Xiuhua,Tang, Qinqin,Liang, Guang,Li, Xiaokun
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p. 292 - 301
(2013/07/11)
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- Synthesis and Structural studies of Pd (II) and Pt (II) complexes with 2-thiobenzimidazolyl acetic acid
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The complexes of Pd(II) and Pt(II) with 2-thiobenzimidazolyl acetic acid have been prepared and characterized.The bonding of ligand and geometry of complexes have been suggested by UV,IR, Spectroscopic methods and resembles with square planar geometry of Pd(II) & Pt(II) Complexes.
- Irshad,Kumari, Jyotsana
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body text
p. 1529 - 1532
(2011/10/13)
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- Phenylimidazole derivatives as new inhibitors of bacterial enoyl-ACP reductase FabK
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Novel FabK inhibitors with antibacterial activity against Streptococcus pneumoniae were synthesized and evaluated. Through SAR studies of our initial hit compound 2-(1H-benz[d]imidazol-2-ylthio)-N-(6-methoxycarbonylbenzo[d]thiazol-2-yl)acetamide, a series of novel phenylimidazole derivatives were discovered as potent FabK inhibitors.
- Kitagawa, Hideo,Ozawa, Tomohiro,Takahata, Sho,Iida, Maiko
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p. 4982 - 4986
(2008/03/13)
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- Antihelminthic activity of some newly synthesized 5(6)-(un)substituted-1H-benzimidazol-2-ylthioacetylpiperazine derivatives
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Piperazine derivatives of 5(6)-substituted-(1H-benzimidazol-2-ylthio)acetic acids were synthesized by using two methods and studied for antihelminthic activity. The antiparasitic screening showed that compounds 18-24 exhibited higher activity against Trichinella spiralis in vitro in comparison to methyl 5-(propylthio)-1H-benzimidazol-2-yl-carbamate (albendazole). Most active were compounds 2-({2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}thio)-1H-benzimidazo le 21 and 2-{[2-oxo-2-(4-benzhydrylpiperazin-1-yl)ethyl]thio}-5(6)-methyl-1(H)-ben zimidazole 19 as well as 2-({2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}thio)-5(6)-methyl-1( H)-benzimidazole 23 with efficacy of 96.0%, 98.4% and 100%, respectively. The tested derivatives 15-19 and 20-23 were less active against Syphacia obvelata in vivo than albendazole and exhibited the same efficacy as piperazine, but in twice lower concentration.Compounds 2-({2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}thio)-1H-benzimidazo le 21, 1,4-bis[(5(6)-methyl-1(H)-benzimidazol-2-ylthio)acetyl]piperazine 17 and 2-({2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}thio)-5(6)-methyl-1( H)-benzimidazole 23 had higher efficacies of 73%, 76%, and 77%, respectively.
- Mavrova, Anelia Ts.,Anichina, Kamelya K.,Vuchev, Dimitar I.,Tsenov, Jordan A.,Denkova, Pavletta S.,Kondeva, Magdalena S.,Micheva, Mitka K.
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p. 1412 - 1420
(2007/10/03)
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- Synthesis and antitrichinellosis activity of some 2-substituted-[1,3] thiazolo[3,2-a]benzimidazol-3(2H)-ones
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Some new thiazolo[3,2-a]benzimidazolone derivatives were synthesized using two methods. The structures of the synthesized compounds were proved by means of IR, 1H NMR and mass spectral data. Ab initio computations were performed in order to determine the electronic structure and geometry of the investigated molecules and to compare it to the geometry of albendazole. Biologically, experiments in vitro and in vivo were accomplished in order to identify the efficacy of the obtained thiazolobenzimidazolones against Trichinella spiralis. The effectiveness of compounds 4a-c in the intestinal phase of trichinellosis was 100% and in the muscle phase were 88% and 80% at a concentration of 100 mg/kg mw for the compounds 4a and 4c. The results of the hepatotoxicity test showed that the compounds 4a and 4b possess hepatotoxicity comparable to that of albendazole.
- Mavrova, Anelia Ts.,Anichina, Kamelya K.,Vuchev, Dimitar I.,Tsenov, Jordan A.,Kondeva, Magdalena S.,Micheva, Mitka K.
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p. 5550 - 5559
(2007/10/03)
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- Synthesis and Reactions of 3-Aminothiazolobenzimidazole-2-carbonitrile
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3-Aminothiazolobenzimidazole-2-carbonitrile was prepared and allowed to react with aromatic aldehydes, formamide and formic acid to give the corresponding arylmethylidenes 4a-d, pyrimidine 5 and pyrimidinone 6 respectively. 6 was alkylated with alkyl halides and the N-alkyl derivatives 9a-b were obtained.Acetylation of 3 afforded the N-acetyl derivative 10, which cyclized to the pyrimidinone 11.Compound 11 was also prepared independently by several methods.On alkylation of 11 by using EtOH/ AcONa or EtOH/KOH the N-alkyl derivatives 12a-d were obtained.Hydrolysis of 3 with EtOH/KOH or EtOH/NH2NH2 gave the benzimidazole-2-thiol 1.Furthermore, condensation of 3 with triethylorthoformate gave the ethoxymethylideneamino derivative 14.Interaction of 14 with different amines afforded the derivatives 15, 16 and 17a-c in good yield.Reaction of 3 with H3PO4 or H2SO4 afforded the corresponding amide derivative 18. - Keywords: Thiazolobenzimidazole; alkylation; acetylation; cyclization; condensation; hydrolysis
- Sarhan, A. A. O.,El-Shenef, H. A. H.,Mahmoud, A. M.
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p. 116 - 135
(2007/10/03)
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- 1,3-thiazoles and their use as immunomodulators
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Heterocyclic sulfides of the general formula heterocycle-S-R, a process for their preparation and, in particular, their use for immunostimulation, immunorestoration and cytostatic treatment, and pharmaceutical agents, which contain a sulfide of this type, for these indications.
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- Synthesis of New 2-Substituted Benzylidenethiazolobenzimidazol-3(2H)-ones and Their Biological Activity
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2-Substituted benzylidenethiazolobenzimidazol-3(2H)-ones (I-XIV) have been synthesized and found to possess anticonvulsant activity (0-60percent).These compounds also inhibit rat brain monoamine oxidase (MAO) (33.70-98.30percent) and succinate dehydrogenase (SDH) (25.72-78.95percent) in vitro of concentrations 4E-4 M and 6E-4 M, respectively.Structure-activity relationship has been dicussed.
- Soni, Namita,Barthwal, J. P.,Gupta, T. K.,Bhalla, T. N.,Parmar, S. S.,Bhargava, K. P.
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p. 785 - 788
(2007/10/02)
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