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1.
J Enzyme Inhib Med Chem ; 35(1): 330-343, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31856607

RESUMO

Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer's disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 ± 0.11 µM; 15j, eqBChE IC50 = 0.16 ± 0.04 µM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Benzimidazóis/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Benzimidazóis/síntese química , Benzimidazóis/química , Butirilcolinesterase/metabolismo , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Células Hep G2 , Cavalos , Humanos , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Células PC12 , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
2.
Chem Pharm Bull (Tokyo) ; 67(12): 1293-1300, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787656

RESUMO

Based on our previous research on cysticidal drugs, we report the synthesis and evaluation of three new benzimidazole derivatives. In these compounds, the amido group was used as a bioisosteric replacement of the ester group. The molecular docking on ß-tubulin revealed that the derivatives interacted through hydrogen bonding with N165, E198 and V236. All compounds showed in vitro activity against Taenia crassiceps cysts. Among them, benzimidazole 3 was found to be the most potent of the series (EC50 0.86 µM). This compound also exhibited the highest probability of binding and the lowest binding free energy score and was therefore selected for in vivo evaluation. Results indicated that the efficacy of compound 3 was comparable to that of the reference drug, albendazole (50.39 vs. 47.16% parasite reduction). Animals treated with compound 3 seemed to tolerate this benzimidazole well, with no changes in behavior, or food and water consumption. These findings are consistent with the in silico prediction results, which indicated low toxicity risks. The pharmacokinetic study showed that the half-life and mean residence time (6.06 and 11.9 h, respectively) were long after oral administration. Together, these results indicate that this new benzimidazole derivative represents a promising structure with cysticidal activity.


Assuntos
Amebicidas/farmacologia , Benzimidazóis/farmacologia , Cisticercose/tratamento farmacológico , Simulação de Acoplamento Molecular , Taenia/efeitos dos fármacos , Amebicidas/síntese química , Amebicidas/química , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Relação Estrutura-Atividade
3.
SAR QSAR Environ Res ; 30(12): 919-933, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31702401

RESUMO

Folates are essential biomolecules required to carry out many crucial processes in leishmania parasite. Dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) involved in folate biosynthesis in leishmania have been established as suitable targets for development of chemotherapy against leishmaniasis. In the present study, various computational tools such as homology modelling, pharmacophore modelling, docking, molecular dynamics and molecular mechanics have been employed to design dual DHFR-TS and PTR1 inhibitors. Two designed molecules, i.e. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were synthesized. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to evaluate in vitro activity of molecules against promastigote form of Leishmania donovani using Miltefosine as standard. 2-(4-((4-nitrobenzyl)oxy)phenyl)-1H-benzo[d]imidazole and 2-(4-((2,4-dichlorobenzyl)oxy)phenyl)-1H-benzo[d]oxazolemolecules were found to be moderately active with showed IC50 = 68 ± 2.8 µM and 57 ± 4.2 µM, respectively.


Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Complexos Multienzimáticos/química , Oxirredutases/química , Proteínas de Protozoários/química , Tetra-Hidrofolato Desidrogenase/química , Timidilato Sintase/química , Antiprotozoários/síntese química , Antiprotozoários/química , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Descoberta de Drogas , Concentração Inibidora 50 , Leishmania donovani/metabolismo , Modelos Moleculares , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Relação Estrutura-Atividade
4.
Eur J Med Chem ; 183: 111731, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31577977

RESUMO

With the expectation to find out new anti-gastric cancer agents with high efficacy and selectivity, a series of novel tertiary sulfonamide derivatives were synthesized and the anti-cancer activity was studied in three selected cancer cell lines (MGC-803, PC-3, MCF-7) in vitro. Some of the synthesized compounds could significantly inhibit the proliferation of these tested cancer cells and were more potent than the positive control (5-Fu). The structure-activity relationship of tertiary sulfonamide derivatives was explored in this report. Among the tested compounds, compound 13g containing benzimidazole moiety showed the best anti-proliferation activities against MGC-803 cells (IC50 = 1.02 µM), HGC-27 cells (IC50 = 1.61 µM), SGC-7901 (IC50 = 2.30 µM) cells as well as the good selectivity between the cancer and normal cells. Cellular mechanism studies elucidated compound 13g inhibited the colony formation of gastric cancer cell lines. Meanwhile, compound 13g arrested cell cycle at G2/M phase and induced cell apoptosis. Mechanistically, compound 13g markedly decreased p-Akt and p-c-Raf expression, which revealed that compound 13g targeted gastric cancer cell lines via interfering with AKT/mTOR and RAS/Raf/MEK/ERK pathways. All the findings suggest that compound 13g might be a valuable lead compound for the anti-gastric cancer agents.


Assuntos
Antineoplásicos , Benzimidazóis/química , Neoplasias Gástricas/tratamento farmacológico , Sulfonamidas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Drogas , Humanos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
5.
J Enzyme Inhib Med Chem ; 34(1): 1716-1721, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31571509

RESUMO

A series of 4-arylamido 5-methylisoxazole derivatives incorporating benzimidazole was designed and synthesised by conformational restriction of an in-house type II FMS inhibitor. Kinase profiling of one compound revealed interesting features, with increased inhibitory potency towards FLT3 and concomitant loss of potency towards FMS. Several benzimidazole derivatives 5a-5g and 6a-6c containing various hydrophobic moieties were synthesised, and their inhibitory activity against FLT3 was evaluated. Specifically, 5a, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-5-yl) isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC50 = 495 nM), with excellent selectivity profiles.


Assuntos
Benzimidazóis/química , Isoxazóis/química , Inibidores de Proteínas Quinases/química , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Descoberta de Drogas , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Isoxazóis/síntese química , Isoxazóis/farmacologia , Conformação Molecular , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
6.
J Enzyme Inhib Med Chem ; 34(1): 1697-1710, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31537132

RESUMO

Inhibition of Carbonic Anhydrases (CAs) has been clinically exploited for many decades for a variety of therapeutic applications. Within a research project aimed at developing novel classes of CA inhibitors (CAIs) with a proper selectivity for certain isoforms, a series of derivatives featuring the 2-substituted-benzimidazole-6-sulfonamide scaffold, conceived as frozen analogs of Schiff bases and secondary amines previously reported in the literature as CAIs, were investigated. Enzyme inhibition assays on physiologically relevant human CA I, II, IX and XII isoforms revealed a number of potent CAIs, showing promising selectivity profiles towards the transmembrane tumor-associated CA IX and XII enzymes. Computational studies were attained to clarify the structural determinants behind the activities and selectivity profiles of the novel inhibitors.


Assuntos
Benzimidazóis/química , Inibidores da Anidrase Carbônica/síntese química , Sulfonamidas/síntese química , Aminas/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Humanos , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Bases de Schiff/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
7.
Eur J Med Chem ; 183: 111703, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31550661

RESUMO

Heme oxygenase (HO) enzymes are involved in heme catabolism and several physiological functions. Among the different HO isoforms, HO-2 stands out for its neuroprotective properties and modulatory activity in male reproduction. However, unlike the HO-1 ligands, the potential therapeutic applications of HO-2 inhibitors/activators have not been extensively explored yet. Moreover, the physiological role of HO-2 is still unclear, mostly due to the lack of highly selective HO-2 chemical probes. To boost the interest on this intriguing target, the present review updates the knowledge on the structure-activity relationships of HO-2 inhibitors and activators, as well as their potential therapeutic applications. To the best of our knowledge, among HO-2 inhibitors, clemizole derivatives are the most selective HO-2 inhibitors reported so far (IC50 HO-1 >100 µM, IC50 HO-2 = 3.4 µM), while the HO-2 nonselective inhibitors described herein possess IC50 HO-2 values ≤ 10 µM. Furthermore, the development of HO-2 activators, such as menadione analogues, helped to understand the critical moieties required for HO-2 activation. Recent advances in the potential therapeutic applications of HO-2 inhibitors/activators cover the fields of neurodegenerative, cardiovascular, inflammatory, and reproductive diseases further stimulating the interest towards this target.


Assuntos
Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/metabolismo , Vitamina K 3/farmacologia , Animais , Benzimidazóis/química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Vitamina K 3/química
8.
Int J Mol Sci ; 20(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487790

RESUMO

Benzimidazole derivatives have a diverse range of biological activities, including antiulcer, antihypertensive, antiviral, antifungal, anti-inflammatory, and anticancer. Despite these activities, previous studies have revealed that some of the derivatives can induce mutations. This study aimed to screen for potential mutagenic activities of novel benzimidazole derivatives 1-4 using the Ames test and to study their structure-activity relationship (SAR). An Ames test was carried out on two strains of Salmonella typhimurium (TA98 and TA100) in the absence and presence of metabolic activation. Genetic analysis was performed prior to the Ames test to determine the genotypes of the bacterial tester strains. Both bacterial strains showed dependency on histidine with the presence of rfa mutation, uvrB deletion, and plasmid pKM101. Further, all derivatives tested showed no mutagenic activity in the absence of metabolic activation in both tester strains. However, in the presence of metabolic activation, compound 1 appeared to induce mutation at 2.5 µg/plate when tested against the TA98 strain. These results suggest that the absence of the -OH group at the ortho-position over the phenyl ring might be the cause of increased mutagenic activity in compound 1. Additionally, the presence of mutagenic activity in compound 1 when it was metabolically activated indicates that this compound is a promutagen.


Assuntos
Benzimidazóis/química , Resistência Microbiana a Medicamentos/genética , Mutagênicos/química , Ativação Metabólica , Benzimidazóis/metabolismo , Benzimidazóis/toxicidade , Genótipo , Mutagênicos/metabolismo , Mutagênicos/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Relação Estrutura-Atividade
9.
Molecules ; 24(17)2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31480486

RESUMO

Elucidation of the structure and function of biomolecules provides us knowledge that can be transferred into the generation of new materials and eventually applications in e.g., catalysis or bioassays. The main problems, however, concern the complexity of the natural systems and their limited availability, which necessitates utilization of simple biomimetic analogues that are, to a certain degree, similar in terms of structure and thus behaviour. We have, therefore, devised a small library of six tridentate N-heterocyclic coordinating agents (L1-L6), which, upon complexation, form two groups of artificial, monometallic non-heme iron species. Utilization of iron(III) chloride leads to the formation of the 1:1 (Fe:Ln) 'open' complexes, whereas iron(II) trifluoromethanosulfonate allows for the synthesis of 1:2 (M:Ln) 'closed' systems. The structural differences between the individual complexes are a result of the information encoded within the metallic centre and the chosen counterion, whereas the organic scaffold influences the observed properties. Indeed, the number and nature of the external hydrogen bond donors coming from the presence of (benz)imidazole moieties in the ligand framework are responsible for the observed biological behaviour in terms of mimicking phenoxazinone synthase activity and interaction with DNA.


Assuntos
Benzimidazóis/química , Materiais Biomiméticos/química , DNA/metabolismo , Ferro/química , Oxirredutases/metabolismo , Bases de Schiff/química , Aminofenóis/metabolismo , Animais , Ligação Competitiva , Catálise , Bovinos , Fluorescência , Imidazóis , Cinética , Ligantes , Oxazinas , Oxirredução , Bases de Schiff/síntese química , Elementos de Transição/metabolismo
10.
Eur J Med Chem ; 181: 111574, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400705

RESUMO

A series of novel hydroxyethylaminomethylbenzimidazole analogs 5a-y were synthesized and evaluated for their IL-5 inhibitory activity using pro-B Y16 cell line. Among them, 2-(((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)amino)butan-1-ol (5e, 94.3% inhibition at 30 µM, IC50 = 3.5 µM, cLogP = 4.132) and 3-cyclohexyl-2-(((4-(cyclohexylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)amino) propan-1-ol (5k, 94.7% inhibition at 30 µM, IC50 = 5.0 µM, cLogP = 6.253) showed the most potent inhibitory activity. The essential feature of SAR (Fig. 5) indicated that the chromenone ring can be replaced by a benzimidazole ring to maintain the inhibitory activity. In addition, the hydroxyethylaminomethyl group was suitable for the IL-5 inhibitory activity. Moreover, the hydrophobic substituents on carbon play an important role in the IL-5 inhibitory activity of these analogs. However, N-substituted analogs did not improve inhibitory activity. In addition, MTT assay of 5e and 5k with normal B lymphoblasts revealed that they had no significant effects on cell viability.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Interleucina-5/antagonistas & inibidores , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos , Modelos Moleculares , Relação Estrutura-Atividade
11.
Molecules ; 24(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398916

RESUMO

The exploitation and use of alternative synthetic methods, in the face of classical procedures that do not conform to the ethics of green chemistry, represent an ever-present problem in the pharmaceutical industry. The procedures for the synthesis of benzimidazoles have become a focus in synthetic organic chemistry, as they are building blocks of strong interest for the development of compounds with pharmacological activity. Various benzimidazole derivatives exhibit important activities such as antimicrobial, antiviral, anti-inflammatory, and analgesic activities, and some of the already synthesized compounds have found very strong applications in medicine praxis. Here we report a selective and sustainable method for the synthesis of 1,2-disubstituted or 2-substituted benzimidazoles, starting from o-phenylenediamine in the presence of different aldehydes. The use of deep eutectic solvent (DES), both as reaction medium and reagent without any external solvent, provides advantages in terms of yields as well as in the work up procedure of the reaction.


Assuntos
Benzimidazóis/síntese química , Química Verde , Solventes/química , Benzimidazóis/química , Estrutura Molecular , Análise Espectral
12.
Eur J Med Chem ; 181: 111553, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369932

RESUMO

A series of new 6-substituted aminocarbonyl benzimidazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole moiety and benzoic acid moiety were designed, synthesized and pharmacologically evaluated. Most of the synthesized compounds could bind to the AT1 receptor and decrease blood pressure significantly. Notably, 2e and 1h could obviously decrease MBP in a dose dependent manner. The maximal response lowered 57.9 ±â€¯2.3 mmHg (2e) and 57.6 ±â€¯1.9 mmHg (1h) of MBP at 10 mg/kg after oral administration, and the antihypertensive effect lasted beyond 24 h, which performed better than Losartan (Fig. 1). These results indicate that 2e and 1h are effective and long-lasting anti-hypertension drug candidates and deserve further investigation for therapeutic application.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Desenho de Drogas , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 181: 111541, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31382120

RESUMO

Based on the significantly synergistic effects of CDK4 and VEGFR2 inhibitors on growth of cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2 with half-maximal inhibitory concentration at the nanomolar level. It effectively induced breast and cervical cancer cell cycle arrest and cell apoptosis. Roxyl-ZV-5J also inhibited the proliferation, tube formation and VEGFR2 downstream signaling pathways of HUVECs. Oral administration of Roxyl-ZV-5J led to significant tumor regression and anti-angiogenesis without obvious toxicity in SiHa xenograft mouse model. In addition, this compound showed good pharmacokinetics. This study confirmed a new tool for dual CDK-VEGFR2 pathways inhibition achieved with a single molecule, which provided valuable leads for further structural optimization and anti-angiogenesis and anti-tumor mechanism study.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Aminopiridinas/síntese química , Aminopiridinas/química , Anilidas/síntese química , Anilidas/química , Anilidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
14.
Eur J Med Chem ; 180: 546-561, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31344614

RESUMO

A novel series of 6-substituted-8-(1-cyclohexyl-1H-benzo[d]imidazole-6-yl)imidazo[1,2-a]pyrazine and 6-substituted-8-(1-benzyl-1H-benzo[d]imidazole-6-yl)imidazo[1,2-a]pyrazine is first time synthesized and screen in vitro biological activity for 60 human cancer cell lines representing nine different cancer types. Derivatives 10 and 36 show antitumor activity for all tested cell lines, display comparable full panel mean-graph midpoint growth inhibition (MG_MID GI50) values of 2.10 and 2.23 µM, respectively. Furthermore, these derivatives show strong binding interactions with DNA and bovine serum albumin (BSA), studied through absorption, emission, and circular dichroism techniques. These spectroscopic studies reveal that imidazo[1,2-a]pyrazine-benzimidazoles 10 and 36, intercalate with ct-DNA as a leading interaction for fundamental biologically significant effects, with monobenzimidazole show better activity than bisbenzimidazole. These experiments have confirmed that the imidazo[1,2-a]pyrazine and benzimidazole moieties are efficient pharmacophores to trigger binding to DNA. These compounds have also interacted with bovine serum albumin protein that demonstrating high values of binding constant.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Imidazóis/farmacologia , Pirazinas/farmacologia , Animais , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Relação Estrutura-Atividade
15.
Inorg Chem ; 58(15): 9773-9784, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31318533

RESUMO

In recent years, transition metal complexes have been developed for catalytical degradation of a phosphate ester bond, particularly in RNA and DNA; however, less consideration has been given for development of complexes for the degradation of a phosphorothioate bond, as they are the foremost used pesticides in the environment and are toxic to human beings. In this context, we have developed copper complexes of benzimidazolium based ligands for catalytical degradation of a series of organophosphates (parathion, paraoxon, methyl-parathion) at ambient conditions. The copper complexes (assigned as N1-N3) were characterized using single X-ray crystallography which revealed that all three complexes are mononuclear and distorted square planner in geometry. Further, the solution state studies of the prepared complexes were carried out using UV-visible absorption, fluorescence spectroscopy, and cyclic voltametry. The complexes N1 and N2 have benzimidazolium ionic liquid as base attached with two 2-mercapto-benzimidazole pods, whereas complex N3 contains a nonionic ligand. The synthesized copper complexes were evaluated for their catalytic activity for degradation of organophosphates. It is interesting that the complex containing the ionic ligand efficiently degrades phosphorothioate pesticides, whereas complex N3 was not found to be appropriate for degradation due to a weaker conversion rate. The organophosphate degradation studies were monitored by recording absorbance spectra of parathion in the presence of catalyst, i.e., copper complexes with respect to time. The parathion was hydrolyzed into para-nitrophenol and diethyl thiophosphate. Moreover, to analyze the inhibition activity of the pesticides toward acetylcholine esterase enzyme in the presence of prepared metal complexes, Ellman's assay was performed and revealed that, within 20 min, the inhibition of acetylcholine esterase enzyme decreases by up to 13%.


Assuntos
Acetilcolina/metabolismo , Esterases/metabolismo , Estruturas Metalorgânicas/química , Praguicidas/química , Praguicidas/toxicidade , Fosfatos/química , Acetilcolina/análise , Benzimidazóis/química , Catálise , Cobre/química , Cristalografia por Raios X , Esterases/análise , Estruturas Metalorgânicas/síntese química , Modelos Moleculares , Estrutura Molecular , Fosfatos/toxicidade
16.
Eur J Med Chem ; 180: 121-133, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301563

RESUMO

Phenyl- and bioisosteric ferrocenyl-derived aminoquinoline-benzimidazole hybrid compounds were synthesised and evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive NF54 and multi-drug resistant K1 strains of the human malaria parasite, Plasmodium falciparum. All compounds were active against the two strains, generally showing enhanced activity in the K1 strain, with resistance indices less than 1. Cytotoxicity studies using Chinese hamster ovarian cells revealed that the hybrids were relatively non-cytotoxic and demonstrated selective killing of the parasite. Based on favourable in vitro antiplasmodial and cytotoxicity data, the most active phenyl (4c) and ferrocenyl (5b) hybrids were tested in vivo against the rodent Plasmodium berghei mouse model. Both compounds caused a reduction in parasitemia relative to the control, with 5c displaying superior activity (92% reduction in parasitemia at 4 × 50 mg/kg oral doses). The most active phenyl and ferrocenyl derivatives showed inhibition of ß-haematin formation in a NP-40 detergent-mediated assay, indicating a possible contributing mechanism of antiplasmodial action. The most active ferrocenyl hybrid did not display appreciable reactive oxygen species (ROS) generation in a ROS-induced DNA cleavage gel electrophoresis study. The compounds were also screened for their in vitro activity against Mycobacterium tuberculosis. The hybrids containing a more hydrophobic substituent had enhanced activity (<32.7 µM) compared to those with a less hydrophobic substituent (>62.5 µM).


Assuntos
Antibacterianos/farmacologia , Antimaláricos/farmacologia , Benzimidazóis/farmacologia , Compostos Ferrosos/farmacologia , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antimaláricos/síntese química , Antimaláricos/química , Benzimidazóis/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Compostos Ferrosos/química , Camundongos , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Quinolinas/química , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 179: 483-492, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271960

RESUMO

Prostate cancer is one of the main causes of male cancer-related deaths worldwide and the suppression of androgen receptor signalling is established as an effective strategy for the treatment. A series of galeterone analogues including several steroid-fused azacycles, as well as 17-(benzimidazol-1-ylimino), 16α-(benzimidazol-2-ylamino), and 16α-(benzothiazol-2-ylamino) steroid derivatives, were synthesized and tested against prostate cancer cell lines. Candidate compound 3f was shown to reduce AR-regulated transcription in a dose-dependent manner in nanomolar ranges and suppress expression of AR-regulated proteins Nkx3.1 and PSA in 22Rv1-ARE14 and VCaP cancer cell lines. Flexible docking study revealed similar position of 3f within AR binding site in comparison of galeterone even with stronger binding energy.


Assuntos
Androstadienos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Androstadienos/síntese química , Androstadienos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Estrutura Molecular , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade
18.
Molecules ; 24(13)2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31277341

RESUMO

A novel flow-based approach for the preparation of benzimidazol-2-one (1) scaffold by the 1,1'-carbonyldiimidazole (CDI)-promoted cyclocarbonylation of o-phenylenediamine (2) is reported. Starting from a preliminary batch screening, the model reaction was successfully translated under flow conditions and optimised by means of design of experiment (DoE). The method allowed the efficient preparation of this privileged scaffold and to set up a general protocol for the multigram-scale preparation in high yield, purity, and productivity, and was successfully applied for the multigram flow synthesis of N-(2-chlorobenzyl)-5-cyano-benzimidazol-2-one, which is a key synthon for hit-to-lead explorations in our anti-inflammatory drug discovery program.


Assuntos
Benzimidazóis/química , Técnicas de Química Sintética , Desenho de Drogas , Benzimidazóis/síntese química , Modelos Teóricos , Estrutura Molecular
19.
Acta Pharm ; 69(1): 63-74, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259720

RESUMO

Development of safe and effective drugs requires complete impurity evaluation and, therefore, knowledge about the formation and elimination of impurities is necessary. During impurity profiling of a key intermediate during synthesis of candesartan cilexetil (1-(((cyclohexyloxy)carbonyl) oxy)ethyl 1-((2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate, TCV-116), a novel compound, which had not been reported previously, was observed. Structural elucidation of impurity was achieved by liquid chromatography hyphenated to different high resolution mass analyzers. Based on exact mass measurements and fragmentation pattern, a chloro alkyl carbonate ester analogue of the intermediate was identified. Structure of the impurity was confirmed by mass spectro-metric and NMR analyses of the target substance. Identified impurity could represent a hazard if it is transferred to the final API stage and its presence should be kept below allowed limits. Further investigation could reveal whether bis(1-chloroethyl) carbonate is a precursor to impurity formation. Therefore, synthesis should be regulated so as to minimize impurity production. Analysis of the final product indicated that the amount of impurity did not exceed 50 mg L-1, which represents the detection limit, determined according to the signal/noise ratio.


Assuntos
Benzimidazóis/química , Compostos de Bifenilo/química , Tetrazóis/química , Cromatografia Líquida/métodos , Contaminação de Medicamentos , Espectroscopia de Ressonância Magnética/métodos
20.
Molecules ; 24(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357480

RESUMO

We have previously shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cell cycle arrest and PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cancer cells and what is the exact molecular mechanism for its antiproliferation effect remained to be determined. In the present study, compound-7g exhibited strong activity in suppressing proliferation and growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression and upregulated cell cycle inhibitor p27, and then resulted in G1 cell cycle arrest. Mechanism analysis revealed that compound-7g also provokes the down-regulation of E2F-1, which acts as a transcriptional factor of SKP2. Further results indicated that compound-7g induced an increase of LC3B-II and p62, which causes a suppression of fusion between autophagosome and lysosome. Moreover, compound-7g mediated autophagic flux blockage promoted accumulation of ubiquitinated proteins and then led to endoplasmic reticulum stress. Our study thus demonstrated that pharmacological inactivation of E2F-1-SKP2-p27 axis is a promising target for restricting cancer progression.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/química , Isoquinolinas/química , Proteínas Quinases Associadas a Fase S/genética , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Fator de Transcrição E2F1/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Proteólise
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