Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.823
Filtrar
1.
Molecules ; 29(9)2024 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-38731629

RESUMEN

This work presents the design, synthesis and biological activity of novel N-substituted benzimidazole carboxamides bearing either a variable number of methoxy and/or hydroxy groups. The targeted carboxamides were designed to investigate the influence of the number of methoxy and/or hydroxy groups, the type of substituent placed on the N atom of the benzimidazole core and the type of substituent placed on the benzimidazole core on biological activity. The most promising derivatives with pronounced antiproliferative activity proved to be N-methyl-substituted derivatives with hydroxyl and methoxy groups at the phenyl ring and cyano groups on the benzimidazole nuclei with selective activity against the MCF-7 cell line (IC50 = 3.1 µM). In addition, the cyano-substituted derivatives 10 and 11 showed strong antiproliferative activity against the tested cells (IC50 = 1.2-5.3 µM). Several tested compounds showed significantly improved antioxidative activity in all three methods compared to standard BHT. In addition, the antioxidative activity of 9, 10, 32 and 36 in the cells generally confirmed their antioxidant ability demonstrated in vitro. However, their antiproliferative activity was not related to their ability to inhibit oxidative stress nor to their ability to induce it. Compound 8 with two hydroxy and one methoxy group on the phenyl ring showed the strongest antibacterial activity against the Gram-positive strain E. faecalis (MIC = 8 µM).


Asunto(s)
Antineoplásicos , Antioxidantes , Bencimidazoles , Proliferación Celular , Diseño de Fármacos , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Humanos , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Células MCF-7 , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Relación Estructura-Actividad , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Estructura Molecular , Pruebas de Sensibilidad Microbiana , Estrés Oxidativo/efectos de los fármacos
2.
Bioorg Med Chem ; 105: 117725, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38640588

RESUMEN

Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50 = 0.32 nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50 = 1.20 nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC50 = 0.03 nM; EZH2 Y641N, IC50 = 0.08 nM), which were approximately 10-fold more active than those of 1 (EZH2 Y641F, IC50 = 0.37 nM; EZH2 Y641N, IC50 = 0.85 nM). Furthermore, compound N40 (IC50 = 3.52 ±â€¯1.23 nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than 1 (IC50 = 35.01 ±â€¯1.28 nM). Further cellular experiments showed that N40 arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, N40 inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.


Asunto(s)
Antineoplásicos , Benzamidas , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Proteína Potenciadora del Homólogo Zeste 2 , Piridonas , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Humanos , Relación Estructura-Actividad , Benzamidas/química , Benzamidas/farmacología , Benzamidas/síntesis química , Piridonas/farmacología , Piridonas/química , Piridonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Relación Dosis-Respuesta a Droga , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Descubrimiento de Drogas , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química
3.
J Agric Food Chem ; 72(19): 11185-11194, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38687832

RESUMEN

Aspergillus flavus contamination in agriculture and food industries poses threats to human health, leading to a requirement of a safe and effective method to control fungal contamination. Chitosan-based nitrogen-containing derivatives have attracted much attention due to their safety and enhanced antimicrobial applications. Herein, a new benzimidazole-grafted chitosan (BAC) was synthesized by linking the chitosan (CS) with a simple benzimidazole compound, 2-benzimidazolepropionic acid (BA). The characterization of BAC was confirmed by Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance spectroscopy (1H and 13C NMR). Then, the efficiency of BAC against A. flavus ACCC 32656 was investigated in terms of spore germination, mycelial growth, and aflatoxin production. BAC showed a much better antifungal effect than CS and BA. The minimum inhibitory concentration (MIC) value was 1.25 mg/mL for BAC, while the highest solubility of CS (16.0 mg/mL) or BA (4.0 mg/mL) could not completely inhibit the growth of A. flavus. Furthermore, results showed that BAC inhibited spore germination and elongation by affecting ergosterol biosynthesis and the cell membrane integrity, leading to the permeabilization of the plasma membrane and leakage of intracellular content. The production of aflatoxin was also inhibited when treated with BAC. These findings indicate that benzimidazole-derived natural CS has the potential to be used as an ideal antifungal agent for food preservation.


Asunto(s)
Aspergillus flavus , Bencimidazoles , Quitosano , Fungicidas Industriales , Pruebas de Sensibilidad Microbiana , Aspergillus flavus/efectos de los fármacos , Aspergillus flavus/crecimiento & desarrollo , Bencimidazoles/farmacología , Bencimidazoles/química , Bencimidazoles/síntesis química , Quitosano/farmacología , Quitosano/química , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Aflatoxinas , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Esporas Fúngicas/efectos de los fármacos , Esporas Fúngicas/crecimiento & desarrollo
4.
Eur J Med Chem ; 271: 116402, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38636128

RESUMEN

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, the hit compound CDI (IC50 = 2.46 ± 0.33 µM) was identified by screening of an in-house compound library. And then novel potent benzimidazole derivatives were designed and synthesized as core assembly modulators, and their antiviral effects were evaluated in vitro and in vivo biological experiments. The results indicated that compound 26f displayed the most optimized modulator of HBV capsid assembly (IC50 = 0.51 ± 0.20 µM, EC50 = 2.24 ± 0.43 µM, CC50 = 84.29 µM) and high selectivity index. Moreover, treatment with compound 26f for 14 days significantly decreased serum levels of HBV DNA levels in the Hydrodynamic-Injection (HDI) mouse model. Therefore, compound 26f could be considered as a promising candidate drug for further development of novel HBV CAMs with the desired potency and safety.


Asunto(s)
Antivirales , Bencimidazoles , Virus de la Hepatitis B , Hepatitis B , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Virus de la Hepatitis B/efectos de los fármacos , Animales , Ratones , Humanos , Hepatitis B/tratamiento farmacológico , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Cápside/efectos de los fármacos , Cápside/metabolismo , Pruebas de Sensibilidad Microbiana , Células Hep G2 , Desarrollo de Medicamentos
5.
Eur J Med Chem ; 271: 116425, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38636129

RESUMEN

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 µM and 23.96 µM respectively). Its IC50 value was at 3.38 µM to the SiHa cells. Further mechanistic studies revealed that 4r induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.


Asunto(s)
Antineoplásicos , Bencimidazoles , Proliferación Celular , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TOR , Moduladores de Tubulina , Tubulina (Proteína) , Neoplasias del Cuello Uterino , Pez Cebra , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Bencimidazoles/farmacología , Bencimidazoles/química , Bencimidazoles/síntesis química , Tubulina (Proteína)/metabolismo , Proliferación Celular/efectos de los fármacos , Animales , Relación Estructura-Actividad , Fosfatidilinositol 3-Quinasas/metabolismo , Femenino , Estructura Molecular , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos
6.
Eur J Med Chem ; 271: 116405, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38678823

RESUMEN

PARPi have been explored and applied in the treatment of various cancers with remarkable efficacy, especially BRCA1/2 mutated ovarian, breast, prostate, and pancreatic cancers. However, PARPi renders inevitable drug resistance and showed high toxicity because of PARP-Trapping with long-term clinic tracking. To overcome the drug resistance and the high toxicity of PARPi, many novel methods have been developed including PROTACs. Being an event-driven technology, PROTACs needs a high affinity, low toxicity warhead with no steric hindrance in binding process. Veliparib shows the lowest PARP-Trapping effect but could hardly to be the warhead of PROTACs because of the strong steric hindrance. Other PARP1 inhibitors showed less steric hindrance but owns high PARP-Trapping effect. Thus, the development of novel warhead with high PARP1 affinity, low PARP1-Trapping, and no steric hindrance would be valuable. In this work, we reserved benzimidazole as the motif to reserve the low PARP1-Trapping effect and substituted the pyrrole by aromatic ring to avoiding the steric hindrance in PARP1 binding cave. Thus, a series of benzimidazole derivates were designed and synthesized, and some biological activities in vitro were evaluated including the inhibition for PARP1 enzyme and the PARP-Trapping effect using MDA-MB-436 cell line. Results showed that the compound 19A10 has higher PARP1 affinity(IC50 = 4.62 nM)) and similar low PARP-Trapping effect compared with Veliparib(IC50 (MDA-MB-436) >100 µM). Docking study showed that the compound 19A10 could avoiding the steric hindrance which was much better than Veliparib. So, the compound 19A10 could potentially be a perfect warhead for PARP1 degraders. Besides, because of the depletion of the PARP1 and the decreasing of the binding capability, we suppose that the PROTACs using 19A10 as the warhead would be no-PARP-Trapping effect. Furthermore, QSAR study showed that to develop novel compounds with high PARP1 binding affinity and low PARP-Trapping, we can choose the skeleton with substituent R1H, R2 = piperiazine, and R3 with large tPSA. And, if we want to develop the compounds with high PARP1 binding affinity and high PARP-Trapping which can possibly improve the lethality against tumor cells, we can choose the skeleton with substituent R1F, R2 = 3-methy-piperiazine, and R3 with large tPSA.


Asunto(s)
Antineoplásicos , Bencimidazoles , Ensayos de Selección de Medicamentos Antitumorales , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis química , Humanos , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Estructura Molecular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular
7.
J Med Chem ; 67(8): 6673-6686, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38569098

RESUMEN

The use of benzimidazole-based trinuclear ruthenium(II)-arene complexes (1-3) to selectively target the rare cancer rhabdomyosarcoma is reported. Preliminary cytotoxic evaluations of the ruthenium complexes in an eight-cancer cell line panel revealed enhanced, selective cytotoxicity toward rhabdomyosarcoma cells (RMS). The trinuclear complex 1 was noted to show superior short- and long-term cytotoxicity in RMS cell lines and enhanced selectivity relative to cisplatin. Remarkably, 1 inhibits the migration of metastatic RMS cells and maintains superior activity in a 3D multicellular spheroid model in comparison to that of the clinically used cisplatin. Mechanistic insights reveal that 1 effectively induces genomic DNA damage, initiates autophagy, and prompts the intrinsic and extrinsic apoptotic pathways in RMS cells. To the best of our knowledge, 1 is the first trinuclear ruthenium(II) arene complex to selectively kill RMS cells in 2D and 3D cell cultures.


Asunto(s)
Antineoplásicos , Apoptosis , Complejos de Coordinación , Rabdomiosarcoma , Rutenio , Humanos , Rabdomiosarcoma/tratamiento farmacológico , Rabdomiosarcoma/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Rutenio/química , Rutenio/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Apoptosis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Daño del ADN/efectos de los fármacos , Bencimidazoles/farmacología , Bencimidazoles/química , Bencimidazoles/síntesis química , Autofagia/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos
8.
Molecules ; 28(14)2023 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-37513362

RESUMEN

Heterocyclic compounds are significant lead drug candidates based on their various structure-activity relationships (SAR), and their use in pharmaceutics is constantly developing. Benzimidazole (BnZ) is synthesized by a condensation reaction between benzene and imidazole. The BnZ structure consists of two nitrogen atoms embedded in a five-membered imide ring which is fused with a benzene ring. This review examines the conventional and green synthesis of metallic and non-metallic BnZ and their derivatives, which have several potential SARs, along with a wide range of pharmacological properties, including anti-cancer, anti-inflammatory, anti-microbial, anti-tubercular, and anti-protozoal properties. These compounds have been proven by pharmacological investigations to be efficient against different strains of microbes. Therefore, in this review, the structural variations of BnZ are listed along with various applications, predominantly related to their biological activities.


Asunto(s)
Antiinfecciosos , Antiinflamatorios , Bencimidazoles , Bencimidazoles/síntesis química , Bencimidazoles/química , Bencimidazoles/farmacología , Relación Estructura-Actividad , Benceno/química , Imidazoles/química , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Catálisis , Metales/química
9.
Molecules ; 27(4)2022 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-35209126

RESUMEN

P2X3 receptors (P2X3R) are ATP-gated ion channels predominantly expressed in C- and Aδ-fiber primary afferent neurons and have been introduced as a novel therapeutic target for neurological disorders, including neuropathic pain and chronic cough. Because of its localized distribution, antagonism of P2X3R has been thoroughly considered, and the avoidance of issues related to CNS side effects has been proven in clinical trials. In this article, benzimidazole-4,7-dione-based derivatives were introduced as a new chemical entity for the development of P2X3R antagonists. Starting from the discovery of a hit compound from the screening of 8364 random library compounds in the Korea Chemical Bank, which had an IC50 value of 1030 nM, studies of structure-activity and structure-property relationships enabled further optimization toward improving the antagonistic activities as well as the drug's physicochemical properties, including metabolic stability. As for the results, the final optimized compound 14h was developed with an IC50 value of 375 nM at P2X3R with more than 23-fold selectivity versus P2X2/3R, along with properties of metabolic stability and improved solubility. In neuropathic pain animal models evoked by either nerve ligation or chemotherapeutics in male Sprague-Dawley rats, compound 14h showed anti-nociceptive effects through an increase in the mechanical withdrawal threshold as measured by von Frey filament following intravenous administration.


Asunto(s)
Analgésicos/química , Analgésicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Antagonistas del Receptor Purinérgico P2X/química , Antagonistas del Receptor Purinérgico P2X/farmacología , Analgésicos/síntesis química , Animales , Bencimidazoles/síntesis química , Técnicas de Química Sintética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Monitoreo de Drogas , Humanos , Ratones , Estructura Molecular , Antagonistas del Receptor Purinérgico P2X/síntesis química , Ratas , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad
10.
Bioorg Med Chem ; 58: 116656, 2022 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-35183028

RESUMEN

We report the synthesis of a range of symmetrical bis-benzimidazoles (BBZ) which possess anticancer and antibacterial activities. One of these BBZs has specific activity against Clostridium difficile and is currently in a phase 3 clinical evaluation as the drug ridinilazole. X-ray and computer modelling studies showed that BBZs typically exhibit high specificity for oligonucleotide sequences that occur in the minor groove of DNA.


Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Infecciones por Clostridium/tratamiento farmacológico , ADN/química , Piridinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Piridinas/química
11.
Bioorg Med Chem Lett ; 60: 128604, 2022 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-35123004

RESUMEN

To explore effective antituberculosis agents, a new class of imidazoles and benzimidazoles linked ethionamide analogs were designed and synthesized. The elemental analysis, 1H NMR, 13C NMR and mass spectral data were used to characterize all of the novel analogs. In vitro activity against Mycobacterium tuberculosis (Mtb) H37Rv was assessed for all of the target compounds. The hydroxy and nitrile moieties on the imidazole ring, as well as the hydroxy and methoxy groups on the benzimidazole ring connected to the ethionamide side chain, were shown to be advantageous. In our cell viability experiment against the Vero cell line, all of the compounds were non-cytotoxic even at 100 µM. To confirm the powerful analogs target identification, we investigated their in vitro inhibitory action on an M. tuberculosis InhA over-expressing (Mtb InhA-OE) strain, which yielded MICs nearly twice those of the Mtb H37Rv strain. Furthermore, the results of molecular docking confirmed the experimental findings. Additionally, the molecules were evaluated in silico for ADMET and drug similarity features. The experimental observation enables the newly generated ethionamide derivatives to be attractive candidates for the creation of newer and better anti-TB agents.


Asunto(s)
Antituberculosos/farmacología , Bencimidazoles/farmacología , Etionamida/farmacología , Imidazoles/farmacología , Inhibinas/antagonistas & inhibidores , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/síntesis química , Antituberculosos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Etionamida/síntesis química , Etionamida/química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Inhibinas/metabolismo , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad
12.
J Med Chem ; 65(4): 3667-3683, 2022 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-35152694

RESUMEN

We observed a synergistic antiproliferation effect with combined use of a DNA minor groove binder and a histone deacetylase (HDAC) inhibitor. Inspired by this result, a new series of benzimidazole-hydroxamate hybrids were designed and synthesized to target both DNA minor groove and HDAC. The most active compounds 9k and 9l not only exhibited improved HDAC inhibitory activities compared to SAHA but also possessed potent antiproliferation activities against tumor cells. Importantly, compounds 9k and 9l showed good in vivo antitumor efficacies in both HEL xenograft model and murine melanoma model. We also found that 9k and 9l promote the antigen presentation and activate T cells, thereby triggering antitumor immunity. Moreover, these inhibitors reshaped the tumor immune microenvironment by inhibiting the recruitment of Treg cells and promoting the polarization of tumor-infiltrating macrophages to M2 type with antitumor activity. Our study validated the effectiveness of incorporating a DNA-binding fragment in HDAC inhibitors as novel multitargeting antitumor agents.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , ADN/efectos de los fármacos , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Inmunoterapia/métodos , Neoplasias/terapia , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ácidos Hidroxámicos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Simulación del Acoplamiento Molecular , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
13.
J Enzyme Inhib Med Chem ; 37(1): 472-486, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35067150

RESUMEN

Fms-like tyrosine kinase 3 (FLT3) has been verified as a therapeutic target for acute myeloid leukaemia (AML). In this study, we report a series of 2-(1H-indazol-6-yl)-1H-benzo[d]imidazol-5-yl benzamide and phenyl urea derivatives as potent FLT3 inhibitors based on the structural optimisation of previous FLT3 inhibitors. Derivatives were synthesised as benzamide 8a-k, 8n-z, and phenyl urea 8l-m, with various substituents. The most potent inhibitor, 8r, demonstrated strong inhibitory activity against FLT3 and FLT3 mutants with a nanomolar IC50 and high selectivity profiles over 42 protein kinases. In addition, these type II FLT3 inhibitors were more potent against FLT3 mutants correlated with drug resistance. Overall, we provide a theoretical basis for the structural optimisation of novel benzimidazole analogues to develop strong inhibitors against FLT3 mutants for AML therapeutics.


Asunto(s)
Bencimidazoles/farmacología , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Bencimidazoles/síntesis química , Bencimidazoles/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Mutación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo
14.
J Med Chem ; 65(3): 2522-2531, 2022 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-34994550

RESUMEN

New psychoactive substance (NPS) opioids have proliferated within the international drug market. While synthetic opioids are traditionally composed of fentanyl analogues, benzimidazole-derived isotonitazene and its derivatives are the current NPS opioids of concern. Hence, in this study, we implement immunopharmacotherapy wherein antibodies are produced with high titers and nanomolar affinity to multiple benzimidazole-derived NPS opioids (BNO). Notably, these antibodies blunt psychoactive and physiological repercussions from BNO exposure, which was observed through antinociception, whole-body plethysmography, and blood-brain biodistribution studies. Moreover, we detail previously unreported pharmacokinetics of these drugs, which explains the struggle of traditional pharmaceutical opioid antagonists against BNO substances. These findings provide further insight into the in vivo effects of BNO drugs and the development of effective broad-spectrum therapeutics against NPS opioids.


Asunto(s)
Analgésicos Opioides/inmunología , Bencimidazoles/inmunología , Drogas Ilícitas/inmunología , Vacunas Conjugadas/inmunología , Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacocinética , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Femenino , Haptenos/química , Haptenos/inmunología , Hemocianinas/química , Hemocianinas/inmunología , Drogas Ilícitas/síntesis química , Drogas Ilícitas/farmacocinética , Ratones Endogámicos BALB C , Nocicepción/efectos de los fármacos , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/prevención & control , Vacunas Conjugadas/química
15.
Bioorg Med Chem ; 56: 116596, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-35033885

RESUMEN

FMS-like tyrosine kinase 3 (FLT3) enzyme overexpression and mutations are the most common molecular abnormalities associated with acute myeloid leukemia (AML). In addition, recent studies investigated the role of tropomyosin receptor kinase A (TrKA) enzyme fusions in promoting AML growth and survival. Based on these premises, targeting both kinases using dual inhibitors would constitute a promising therapeutic approach to target resistant AML. Guided by ligand-based design and structure simplification of the FLT3 inhibitor, quizartinib, we developed a benzimidazole-based small molecule, 4ACP, that exhibited nanomolar activity against wild-type FLT3, FLT3-Internal tandem duplications (FLT3-ITD), and FLT3-D835Y (FLT3-TKD) mutation (IC50 = 43.8, 97.2, and 92.5 nM respectively). Additionally, 4ACP demonstrated potent activity against colon cancer KM12 cell line (IC50 = 358 nM) and subsequent mechanistic deconvolution identified TrKA enzyme as a second plausible target (IC50 = 23.6 nM) for our compound. 4ACP manifested preferential antiproliferative activity against FLT3-ITD positive AML cell lines (MV4-11 IC50 = 38.8 ± 10.7 nM and MOLM-13 IC50 = 54.9 ± 4.1 nM), while lacking activity against FLT3-ITD negative AML cell lines. Western blot analysis confirmed 4ACP ability to downregulate ERK1/2 and mTOR signaling downstream of FLT3-ITD in AML cells. Furthermore, 4ACP prompted apoptotic and necrotic cell death and G0/G1 cell cycle arrest as indicated by cell cycle analysis. 4ACP did not show cytotoxic effects on normal BNL and H9c2 cells and demonstrated decreased activity against c-Kit enzyme, hence, indicating lower probability of synthetic lethal toxicity and a relatively safer profile. In light of these data, 4ACP represents a novel FLT3/TrKA dual kinase inhibitor for targeted therapy of AML.


Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Bencimidazoles/síntesis química , Bencimidazoles/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Receptor trkA/metabolismo , Relación Estructura-Actividad , Tirosina Quinasa 3 Similar a fms/metabolismo
16.
Eur J Med Chem ; 227: 113953, 2022 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-34731760

RESUMEN

As epigenetic readers, bromodomain and extra-terminal domain (BET) family proteins bind to acetylated-lysine residues in histones and recruit protein complexes to promote transcription initiation and elongation. Inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for cancer. Herein, we describe our efforts toward the discovery of a novel series of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as BET inhibitors. Intensive structural modifications led to the identification of compound 35f as the most active inhibitor of BET BRD4 with selectivity against BET family proteins. Further biological studies revealed that compound 35f can arrest the cell cycle in G0/G1 phase and induce apoptosis via decreasing the expression of c-Myc and other proteins related to cell cycle and apoptosis. More importantly, compound 35f showed favorable pharmacokinetic properties and antitumor efficacy in MV4-11 mouse xenograft model with acceptable tolerability. These results indicated that BET inhibitors could be potentially used to treat hematologic malignancies and some solid tumors.


Asunto(s)
Alcoholes/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Descubrimiento de Drogas , Pirroles/farmacología , Factores de Transcripción/antagonistas & inhibidores , Alcoholes/síntesis química , Alcoholes/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Factores de Transcripción/metabolismo
17.
Bioorg Med Chem ; 49: 116424, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34626901

RESUMEN

Somatostatin receptors are members of G-protein coupled receptor superfamily. Receptors can be classified into five subtypes, SSTR1 to 5. The highly potent and orally active SSTR2 agonist 7, which had been identified by our group, was found out to have toxicological liabilities such as hERG inhibition and phospholipidosis (PLD). We investigated the relationship between in silico physicochemical properties and hERG and PLD, and explored well-balanced agonists to identify amide 19 and benzimidazole 30. As a result of this exploration, we found out that the value of (cLogP) [2] + (pKa) [2] needs to be less than 110 to mitigate the liabilities.


Asunto(s)
Amidas/farmacología , Bencimidazoles/farmacología , Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Fosfolípidos/antagonistas & inhibidores , Receptores de Somatostatina/agonistas , Amidas/síntesis química , Amidas/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Estructura Molecular , Fosfolípidos/metabolismo , Relación Estructura-Actividad
18.
Eur J Med Chem ; 226: 113819, 2021 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-34536669

RESUMEN

The inhibition of glutaminyl cyclase (QC) may provide a promising strategy for the treatment of early Alzheimer's disease (AD) by reducing the amount of the toxic pyroform of ß-amyloid (AßΝ3pE) in the brains of AD patients. In this work, we identified potent QC inhibitors with subnanomolar IC50 values that were up to 290-fold higher than that of PQ912, which is currently being tested in Phase II clinical trials. Among the tested compounds, the cyclopentylmethyl derivative (214) exhibited the most potent in vitro activity (IC50 = 0.1 nM), while benzimidazole (227) showed the most promising in vivo efficacy, selectivity and druggable profile. 227 significantly reduced the concentration of pyroform Aß and total Aß in the brain of an AD animal model and improved the alternation behavior of mice during Y-maze tests. The crystal structure of human QC (hQC) in complex with 214 indicated tight binding at the active site, supporting that the specific inhibition of QC results in potent in vitro and in vivo activity. Considering the recent clinical success of donanemab, which targets AßΝ3pE, small molecule-based QC inhibitors may also provide potential therapeutic options for early-stage AD treatment.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Aminoaciltransferasas/antagonistas & inhibidores , Bencimidazoles/farmacología , Ciclopentanos/farmacología , Inhibidores Enzimáticos/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/metabolismo , Aminoaciltransferasas/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Bencimidazoles/síntesis química , Bencimidazoles/química , Ciclopentanos/síntesis química , Ciclopentanos/química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Relación Estructura-Actividad
19.
Molecules ; 26(18)2021 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-34576932

RESUMEN

Our study aimed to characterise the action mode of N-phenacyldibromobenzimidazoles against C. albicans and C. neoformans. Firstly, we selected the non-cytotoxic most active benzimidazoles based on the structure-activity relationships showing that the group of 5,6-dibromobenzimidazole derivatives are less active against C. albicans vs. 4,6-dibromobenzimidazole analogues (5e-f and 5h). The substitution of chlorine atoms to the benzene ring of the N-phenacyl substituent extended the anti-C. albicans action (5e with 2,4-Cl2 or 5f with 3,4-Cl2). The excellent results for N-phenacyldibromobenzimidazole 5h against the C. albicans reference and clinical isolate showed IC50 = 8 µg/mL and %I = 100 ± 3, respectively. Compound 5h was fungicidal against the C. neoformans isolate. Compound 5h at 160-4 µg/mL caused irreversible damage of the fungal cell membrane and accidental cell death (ACD). We reported on chitinolytic activity of 5h, in accordance with the patterns observed for the following substrates: 4-nitrophenyl-N-acetyl-ß-d-glucosaminide and 4-nitrophenyl-ß-d-N,N',N″-triacetylchitothiose. Derivative 5h at 16 µg/mL: (1) it affected cell wall by inducing ß-d-glucanase, (2) it caused morphological distortions and (3) osmotic instability in the C. albicans biofilm-treated. Compound 5h exerted Candida-dependent inhibition of virulence factors.


Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Bencimidazoles/química , Animales , Antifúngicos/síntesis química , Antifúngicos/toxicidad , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Bencimidazoles/toxicidad , Biopelículas/efectos de los fármacos , Candida albicans/citología , Candida albicans/efectos de los fármacos , Pared Celular/efectos de los fármacos , Quitina/metabolismo , Chlorocebus aethiops , Cryptococcus neoformans/citología , Cryptococcus neoformans/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Pruebas de Sensibilidad Microbiana , Microscopía Confocal , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Células Vero
20.
Bioorg Med Chem ; 48: 116418, 2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34563877

RESUMEN

Protein-tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling pathway and has been validated as a therapeutic target for type 2 diabetes. A wide variety of scaffolds have been included in the structure of PTP1B inhibitors, one of them is the benzimidazole nucleus. Here, we report the design and synthesis of a new series of di- and tri- substituted benzimidazole derivatives including their kinetic and structural characterization as PTP1B inhibitors and hypoglycemic activity. Results show that compounds 43, 44, 45, and 46 are complete mixed type inhibitors with a Ki of 12.6 µM for the most potent (46). SAR type analysis indicates that a chloro substituent at position 6(5), a ß-naphthyloxy at position 5(6), and a p-benzoic acid attached to the linker 2-thioacetamido at position 2 of the benzimidazole nucleus, was the best combination for PTP1B inhibition and hypoglycemic activity. In addition, molecular dynamics studies suggest that these compounds could be potential selective inhibitors from other PTPs such as its closest homologous TCPTP, SHP-1, SHP-2 and CDC25B. Therefore, the compounds reported here are good hits that provide structural, kinetic, and biological information that can be used to develop novel and selective PTP1B inhibitors based on benzimidazole scaffold.


Asunto(s)
Bencimidazoles/farmacología , Glucemia/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Simulación de Dinámica Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Animales , Bencimidazoles/síntesis química , Bencimidazoles/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Femenino , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Estructura Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Ratas , Ratas Wistar , Relación Estructura-Actividad
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA