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1.
Proc Natl Acad Sci U S A ; 117(24): 13261-13266, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32482866

RESUMO

Modern organic reaction discovery and development relies on the rapid assessment of large arrays of hypothesis-driven experiments. The time-intensive nature of reaction analysis presents the greatest practical barrier for the execution of this iterative process that underpins the development of new bioactive agents. Toward addressing this critical bottleneck, we report herein a high-throughput analysis (HTA) method of reaction mixtures by photocapture on a 384-spot diazirine-terminated self-assembled monolayer, and self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry (SAMDI-MS) analysis. This analytical platform has been applied to the identification of a single-electron-promoted reductive coupling of acyl azolium species.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Benzimidazóis/síntese química , Benzimidazóis/química , Diazometano/química , Oxirredução , Raios Ultravioleta
2.
Chem Biol Interact ; 327: 109163, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32534988

RESUMO

The aim of the study was to synthesize a new series of benzimidazole derivatives and to investigate the underlying molecular mechanisms of the potential cell cycle inhibition and apoptotic effects against a panel of selected human cancer cell lines along with HEK-293 human embryonic kidney cells. MTT assay was used to evaluate cytotoxic effects. Muse™ Cell Analyzer was used to assess cell cycle progression. Annexin-V/PI staining assay was used for detecting apoptosis. All the synthesized compounds showed a significant cytotoxic effect against cancer cells with the IC50 values between 9.2 and 166.1 µg/mL. Among the tested derivatives, compound 5 showed significant cytotoxic activity against MCF-7, DU-145 and H69AR cancer cells with the IC50 values of 17.8 ± 0.24, 10.2 ± 1.4 and 49.9 ± 0.22 µg/mL respectively. The compounds 5 was also tested on HEK-293 human embryonic kidney cells and found to be safer with lesser cytotoxicity. The results revealed that compound 5 significantly increased cell population in the G2/M-phase which is modulated by a p53 independent mechanism. Compound 5 caused an increase in the percentage of late apoptotic cells in all tested cancer cells in a concentration-dependent manner. Among all synthesized derivatives, compound 5 the bromo-derivative, showed the highest cytotoxic potential, induced G2/M cell cycle arrest and apoptotic cell death in genotypically different human cancer cells. These results suggest that compound 5 might be a promising agent for cancer therapy and further structural modifications of benzimidazole derivatives may create promising anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Antineoplásicos/síntese química , Benzimidazóis/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos
3.
Inorg Chem ; 59(7): 4961-4971, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32182052

RESUMO

A new family of neutral chiral cyclometalated platinum(II) complexes with formula [Pt(κ2-(C^N))Cl(κ1-(L))], where (C^N) = 2-phenylpyridinate and (L) = 2-(2-pyridyl)benzimidazole (L1) or (N-(CH2)-Ar-(2-(2-pyridyl)benzimidazole) ligands; (Ar = phenyl (L2), naphthyl (L3), pyrenyl (L4)), have been synthesized and completely characterized. The unexpected κ1 coordination mode of the 2-(2-pyridyl)benzimidazole-derived ligands has been confirmed by spectroscopic techniques and X-ray diffraction. The aromatic moieties on the ligands in the new platinum(II) complexes have a remarkable influence on the cytotoxicity and in the binding mode to DNA. [Pt-L1]-[Pt-L4] complexes internalized more than cisplatin in the SW480 cancer cells even though only [Pt-L1] and [Pt-L2] display high cytotoxicity. 1H NMR and 13P{1H}NMR pointed out that [Pt-L1] and [Pt-L2] complexes bind covalently to dGMP, while the electrophoresis assays and CD experiments indicate that only [Pt-L2] is able to covalently interact with DNA, inducing the same conformational changes in the plasmid DNA as cisplatin. Although the complex [Pt-L4] intercalates into DNA, probably through the pyrenyl moiety, no biological activity is observed.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Complexos de Coordenação/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Benzimidazóis/síntese química , Benzimidazóis/metabolismo , Bovinos , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , DNA/química , DNA/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Enterococcus faecium/efeitos dos fármacos , Humanos , Ligantes , Platina/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
4.
PLoS One ; 15(3): e0229801, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163428

RESUMO

We report the synthesis and preliminary characterization of IODVA1, a potent small molecule that is active in xenograft mouse models of Ras-driven lung and breast cancers. In an effort to inhibit oncogenic Ras signaling, we combined in silico screening with inhibition of proliferation and colony formation of Ras-driven cells. NSC124205 fulfilled all criteria. HPLC analysis revealed that NSC124205 was a mixture of at least three compounds, from which IODVA1 was determined to be the active component. IODVA1 decreased 2D and 3D cell proliferation, cell spreading and ruffle and lamellipodia formation through downregulation of Rac activity. IODVA1 significantly impaired xenograft tumor growth of Ras-driven cancer cells with no observable toxicity. Immuno-histochemistry analysis of tumor sections suggests that cell death occurs by increased apoptosis. Our data suggest that IODVA1 targets Rac signaling to induce death of Ras-transformed cells. Therefore, IODVA1 holds promise as an anti-tumor therapeutic agent.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas ras/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Células NIH 3T3 , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Molecules ; 25(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32013037

RESUMO

An unsubstituted 2-hydroxyphenylbenzimidazole has recently been included as a scaffold in a series of hybrids (including the hit compound PZ1) based on the framework of the acetylcholinesterase (AChE) inhibitor Donepezil, which is a new promising multi-target ligand in Alzheimer's disease (AD) treatment. Building upon these findings, we have now designed and completed the whole synthesis of PZ1 in the so-called deep eutectic solvents (DESs), which have emerged as an unconventional class of bio-renewable reaction media in green synthesis. Under optimized reaction conditions, the preparation of a series of 2-hydroxyphenylbenzimidazole-based nuclei has also been perfected in DESs, and comparison with other routes which employ toxic and volatile organic solvents (VOCs) provided. The functionalization of the aromatic ring can have implications on some important biological properties of the described derivatives and will be the subject of future studies of structure-activity relationships (SARs).


Assuntos
Benzimidazóis/síntese química , Donepezila/química , Solventes/síntese química , Benzimidazóis/química , Química Verde , Solventes/química , Relação Estrutura-Atividade
6.
Molecules ; 25(4)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32053964

RESUMO

In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 µM in comparison to sorafenib (IC50 = 10.99 µM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Benzimidazóis/síntese química , Sítios de Ligação , Carcinoma Hepatocelular , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
7.
Org Lett ; 22(4): 1290-1294, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-31999466

RESUMO

2-Aminobenzimidazole cores are among the most common structural components in medicinal chemistry and can be found in many biologically active molecules. Herein, we report a mild protocol for the synthesis of multifunctional 2-aminobenzimidazoles on-DNA with broad substrate scopes. The reaction conditions expand our ability to design and synthesize 2-aminobenzimidazole core-focused DNA-encoded libraries.


Assuntos
Benzimidazóis/síntese química , DNA/química , Iodo/química , Benzimidazóis/química , Ciclização , Estrutura Molecular , Estereoisomerismo
8.
Eur J Med Chem ; 186: 111850, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31735572

RESUMO

Gram-negative bacteria pose a distinctive risk worldwide, especially with the evolution of major resistance to carbapenems, fluoroquinolones and colistin. Therefore, development of new antibacterial agents to target Gram-negative infections is of utmost importance. Using phenotypic screening, we synthesized and tested thirty-one benzimidazole derivatives against E. coli JW55031 (TolC mutant strain). Compound 6c showed potent activity with MIC value of 2 µg/ml, however, it lacked activity against several Gram-negative microbes with intact efflux systems, including E. coli BW25113 (wild-type strain). Combination of 6c with colistin partially restored its antibacterial activity against wild strains (MIC range, 8-16 µg/ml against E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa). 6c exhibited no cytotoxicity against two mammalian cell lines. Therefore, compound 6c represents a promising lead for further optimization to overcome Gram-negative resistance alone or in combination therapy.


Assuntos
Antibacterianos/farmacologia , Benzimidazóis/farmacologia , Colistina/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Colistina/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
9.
ACS Comb Sci ; 22(1): 42-48, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31756080

RESUMO

A one-pot, three-component synthesis of benzimidazole-linked thiazolidines from 2-cyanomethyl benzimidazole, iso-, isothio-, or isoselenocyanates and 1,2-dichloroethane is reported. Isolation of the key intermediate formed during the course of the reaction validates its mechanistic pathway. Under the same reaction conditions, benzimidazole-linked/fused thiazinanes were obtained when 1,3-dichloropropane or diiodomethane was used.


Assuntos
Benzimidazóis/síntese química , Benzotiazóis/síntese química , Tiazolidinas/síntese química , Dicloretos de Etileno/química , Hidrocarbonetos Iodados/química , Compostos Organosselênicos/química , Propano/análogos & derivados , Propano/química
10.
J Med Chem ; 63(2): 601-612, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31859507

RESUMO

The serine/threonine kinase TBK1 (TANK-binding kinase 1) and its homologue IKKε are noncanonical members of the inhibitor of the nuclear factor κB (IκB) kinase family. These kinases play important roles in multiple cellular pathways and, in particular, in inflammation. Herein, we describe our investigations on a family of benzimidazoles and the identification of the potent and highly selective TBK1/IKKε inhibitor BAY-985. BAY-985 inhibits the cellular phosphorylation of interferon regulatory factor 3 and displays antiproliferative efficacy in the melanoma cell line SK-MEL-2 but showed only weak antitumor activity in the SK-MEL-2 human melanoma xenograft model.


Assuntos
Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Modelos Moleculares , Fosforilação , Relação Estrutura-Atividade , Especificidade por Substrato
11.
ACS Comb Sci ; 22(1): 1-5, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31860283

RESUMO

An efficient approach to the parallel synthesis of benzimidazoles from anilines is described. Library approaches to vary the N1 and C2 vectors of benzimidazoles are well established; however, C4-C7 variation has traditionally relied on 1,2-dianiline building blocks, providing limited chemical space coverage. We have developed an amidine formation/oxidative cyclization sequence that enables anilines as a diversity set for benzimidazole C4-C7 SAR generation in parallel format. The amidine annulation was achieved using PIDA or Cu-mediated oxidation to access both N-H and N-alkyl benzimidazoles. This library protocol has now been utilized for analog production in four medicinal chemistry projects. Additionally, the synthesis of aza-benzimidazoles from aminopyridines was achieved via an analogous sequence.


Assuntos
Benzimidazóis/síntese química , Compostos de Anilina/química , Benzimidazóis/química , Química Farmacêutica/métodos , Ciclização , Oxirredução , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade
12.
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 Fármacos , 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
13.
J Med Chem ; 63(1): 260-282, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31820985

RESUMO

Stimulator of interferon genes (STING) is an endoplasmic reticulum-localized adaptor protein (STING receptor) that has been shown to be activated by binding to natural cyclic dinucleotide (CDN) ligands and plays a vital role in innate immune sensing of exogenous or endogenous DNA, which then induces type I interferons and other cytokines. In this paper, we described a series of amidobenzimidazole STING agonists with high potency for the STING receptor and presented the relevant structure-activity relationships (SARs). The relative potencies of compounds 16g, 24b, and 24e were measured by a STING competition binding assay. A more thorough study of the effect on the STING signaling pathway demonstrated that three compounds, 16g, 24b, and 24e, significantly increased the protein levels and mRNA levels of IFN-ß, CXCL10, and IL-6, and 24b as a representative compound effectively triggered the phosphorylation of STING, TBK1, and IRF3 in both human peripheral blood mononuclear cells (hPBMCs) and WT THP-1 cells. In addition, compound 24b demonstrated impressive antitumor efficacy in mice with established syngeneic colon tumors by intravenous administration. Furthermore, the pharmacokinetic profile of compound 24b was fully evaluated.


Assuntos
Benzimidazóis/uso terapêutico , Proteínas de Membrana/agonistas , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 185: 111845, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718941

RESUMO

The three series of 5-mono- and 2,5-bis-1,2,3-triazolyl-substituted benzimidazo[1,2-a]quinolines as potential antitumor agents were synthesized. Their growth-inhibitory activity is influenced by the introduction of fluorine at C-2 and the mono-triazolyl nuclei at C-5 of the tetracyclic skeleton, particularly if the 1,2,3-triazole moiety contains a short aliphatic side-chain. Thus, the chloropropyl side-chain in all three series had the highest impact on the inhibitory effect. 1,2,3-Triazolyl-2-fluorobenzimidazo[1,2-a]quinoline conjugates 8a and 8b with 3-chloropropyl and 2-hydroxyethyl substituents, respectively, exhibited the most pronounced cytostatic effect on colon cancer (HCT116) cells in the submicromolar range. The compound 8a emerged as the most promising candidate because of its higher potency and some selectivity in the non-tumor aneuploid immortal keratinocyte (HaCaT) cells. Fluorescence and CD spectroscopy, as well as the thermal denaturation assays, revealed moderate to high DNA/RNA binding affinities of the selected compounds and identified intercalation as a dominant binding mode to both polynucleotides. However, results of intracellular distribution assay in human lung carcinoma (H460) cells suggest that both 8a and 8b do not target nuclear DNA and that their non-specific cytotoxic effect may be attributed to the damage of intercellular membranes.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , DNA/química , Quinolonas/farmacologia , RNA/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Sítios de Ligação/efeitos dos fármacos , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade
15.
Biomolecules ; 9(12)2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842463

RESUMO

In the present study, new 4-(1H-benzimidazol-2-yl)-benzene-1,3-diols, modified in both rings, have been synthesized and their efficacies as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been determined. The modified Ellman's spectrophotometric method was applied for the biological evaluation. The compounds showed strong (IC50 80-90 nM) AChE and moderate (IC50 5-0.2 µM) BuChE inhibition in vitro. Some compounds were effective toward AChE/BuChE, exhibiting high selectivity ratios versus BuChE, while the other compounds were active against both enzymes. The structure-activity relationships were discussed. The compounds inhibited also in vitro self-induced Aß(1-42) aggregation and exhibited antioxidant properties. The docking simulations showed that the benzimidazoles under consideration interact mainly with the catalytic site of AChE and mimic the binding mode of tacrine.


Assuntos
Acetilcolinesterase/metabolismo , Antioxidantes/farmacologia , Benzimidazóis/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Simulação de Acoplamento Molecular , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Benzimidazóis/síntese química , Benzimidazóis/química , Compostos de Bifenilo/antagonistas & inibidores , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Cavalos , Humanos , Cinética , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Picratos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade
16.
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
17.
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
18.
Molecules ; 24(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600970

RESUMO

A methodology is reported for the preparation of 2-aryl-benzimidazole-3-oxide derivatives. By means of a one-pot two-step protocol, a library of 42 new compounds has been prepared. Reactions were performed in a total time of 40 min using microwave heating as a tool. A streamlined work-up process was also developed, allowing for facile isolation of the products. The methodology offers a more sustainable approach than previous routes, with only water and ethanol being used as solvents, and the products being isolated by means of a simple filtration without the need for any further purification.


Assuntos
Benzimidazóis/química , Técnicas de Química Sintética , Química Verde , Calefação , Micro-Ondas , Óxidos/química , Benzimidazóis/síntese química , Estrutura Molecular
19.
Eur J Med Chem ; 184: 111746, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610373

RESUMO

Presequence protease (PreP) is a proteostatic enzyme that plays a key role in the maintenance of mitochondrial health. Defects in PreP stability are associated with neurological disorders in humans, and altered activity of this enzyme modulates the progress of Alzheimer's disease-like pathology in mice. As agonists that boost PreP proteolytic activity represent a promising therapeutic avenue, we sought to determine the structural basis for the action of benzimidazole derivatives (3c and 4c), first reported by Vangavaragu et al. (Eur. J. Med. Chem. 76 (2014) 506-516) that enhance the activity of PreP. However, we found the published procedure for the synthesis of 3c yielded aldimine A instead. We then developed an alternative synthesis and obtained 3c, termed compound C, and an alternative benzimidazole derivative, termed compound B. We tested compounds A, B and C for their ability to enhance the activities of human PreP. In contrast to the previous report, we observed that none of the compounds A, B, or C (3c) modulated the catalytic activity of human PreP. Here we report our findings on the mis-identification of the reported benzimidazoles and the lack of biological activity of such compounds on human PreP. Thus, PreP modulators for PreP-based therapies remain to be discovered.


Assuntos
Benzimidazóis/farmacologia , Proteínas Mitocondriais/metabolismo , Serina Endopeptidases/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Humanos , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/isolamento & purificação , Estrutura Molecular , Serina Endopeptidases/genética , Serina Endopeptidases/isolamento & purificação , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
20.
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
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