RESUMO
Four new series 7a-e, 8a-e, 9a-e, and 10a-e of 7-aryl-3-substituted pyrazolo[1,5-a]pyrimidines were synthesized and tested for their RTK and STK inhibitory activity. Compound 7d demonstrated potent enzymatic inhibitory activity against TrkA and ALK2 with IC50 0.087and 0.105 µM, respectively, and potent antiproliferative activity against KM12 and EKVX cell lines with IC50 0.82 and 4.13 µM, respectively. Compound 10e showed good enzyme inhibitory activity against TrkA, ALK2, c-KIT, EGFR, PIM1, CK2α, CHK1, and CDK2 in submicromolar values. Additionally 10e revealed antiproliferative activity against MCF7, HCT116 and EKVX with IC50 3.36, 1.40 and 3.49 µM, respectively; with good safety profile. Moreover, 10e showed cell cycle arrest at the G1/S phase and G1 phase in MCF7 and HCT116 cells with good apoptotic effect. Molecular docking studies were fulfilled for compound 10e and illustrated good interaction with the hot spots of the active site of the tested enzymes.
Assuntos
Antineoplásicos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Antineoplásicos/química , Proliferação de Células , Pirimidinas/química , Simulação de Acoplamento Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina QuinasesRESUMO
In the title compound, C24H23FN4O4S·0.25H2O, the di-hydro-pyrimidine ring is distinctly non-planar, with the flap C atom deviating by 0.297â (2)â Å from the least-squares plane. In the crystal, zigzag chains are formed by N-Hâ¯N hydrogen bonds parallel to [010] and are connected into layers parallel to (100) by O-Hâ¯O, O-Hâ¯F, C-Hâ¯O, C-Hâ¯F and C-Hâ¯N hydrogen bonds. Additional C-Hâ¯O hydrogen bonds connect the layers into a three-dimensional network. A Hirshfeld surface analysis indicates that the most significant contributions to the crystal packing are from Hâ¯H (42.6%), Oâ¯H/Hâ¯O (16.8%) and Câ¯H/Hâ¯C (15.5%) contacts.
RESUMO
Sphingosine kinase 1 (SphK1) has emerged as an attractive drug target for different diseases. Recently, discovered SphK1 inhibitors have been recommended in cancer therapeutics; however, selectivity and potency are great challenges. In this study, a novel series of benzimidazoles was synthesized and evaluated as SphK1 inhibitors. Our design strategy is twofold: It aimed first to study the effect of replacing the 5-position of the benzimidazole ring with a polar carboxylic acid group on the SphK1-inhibitory activity and cytotoxicity. Our second aim was to optimize the structures of the benzimidazoles through the elongation of the chain. The enzyme inhibition potentials against all the synthesized compounds toward SphK1 were evaluated, and the results revealed that most of the studied compounds inhibited SphK1 effectively. The binding affinity of the benzimidazole derivatives toward SphK1 was measured by fluorescence binding and molecular docking. Compounds 33, 37, 39, 41, 42, 43, and 45 showed an appreciable binding affinity. Therefore, the SphK1-inhibitory potentials of compounds 33, 37, 39, 41, 42, 43, and 45 were studied and IC50 values were determined, to reveal high potency. The study showed that these compounds inhibited SphK1 with effective IC50 values. Among the studied compounds, compound 41 was the most effective one with the lowest IC50 value and a high cytotoxicity on a wide spectrum of cell lines. Molecular docking revealed that most of these compounds fit well into the ATP-binding site of SphK1 and form hydrogen bond interactions with catalytically important residues. Overall, the findings suggest the therapeutic potential of benzimidazoles in the clinical management of SphK1-associated diseases.
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Neoplasias/tratamento farmacológico , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Relação Estrutura-AtividadeRESUMO
Two new series of 1,3,4-oxadiazole and coumarin derivatives based on pyrimidine-5-carbonitrile scaffold have been synthesized and evaluated for their COX-1/COX-2 inhibitory activity. Compounds 10c, 10e, 10h-j, 14e-f, 14i and 16 were found to be the most potent and selective inhibitors of COX-2 (IC50 0.041-0.081 µM, SI 139.74-321.95). Eight compounds were further investigated for their in vivo anti-inflammatory activity. The most active derivatives 10c, 10j and 14e displayed superior in vivo anti-inflammatory activity (% edema inhibition 39.3-48.3, 1 h; 58.4-60.5, 2 h; 70.8-83.2, 3 h; 78.9-89.5, 4 h) to the reference drug celecoxib (% edema inhibition 38.0, 1 h; 48.8, 2 h; 58.4, 3 h; 65.4, 4 h). These derivatives were also tested for their ulcerogenic liability, compound 10j showed better safety profile with reference to celecoxib while 10c and 14e exhibited mild lesions. Molecular docking studies of 10c, 10j, and 14e in the COX-2 active site revealed similar orientation and binding interactions as selective COX-2 inhibitors with a higher liability to access the selectivity side pocket.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Simulação de Acoplamento Molecular , Pirimidinas/farmacologia , Úlcera/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Ovinos , Relação Estrutura-Atividade , Úlcera/metabolismo , Úlcera/patologiaRESUMO
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 & inibidoresRESUMO
New 1,3,4-thiadiazine-thiourea derivatives have been synthesized. All the synthesized compounds were examined for in vitro cytotoxic activity against Non-Small Cell Lung Cancer (NSCLC) cell line A549, using MTT bioassay. Compounds 5d, 5i, 5j showed the highest cytotoxic activity with IC50 values of 0.27⯱â¯0.01, 0.30⯱â¯0.02, and 0.32⯱â¯0.012⯵M respectively with sorafenib as reference (IC50 3.85⯱â¯0.27⯵M). These compounds were chosen for further investigations against various biological targets known to play roles in NSCLC specifically: vascular endothelial growth factor receptor 2 (VEGFR2), B-RAF and matrix metalloproteinase 9 (MMP9). Encouraging results were exhibited by the three compounds against the selected targets. Compound 5j was specially promising as it exhibited inhibitory activity of VEGFR2 close to sorafenib (IC50 0.11⯱â¯0.01⯵M), most potent B-RAF activity inhibition (IC50 0.178⯱â¯0.004⯵M) and MMP9 inhibition (IC50 0.08⯱â¯0.004⯵M). Moreover, cell cycle analysis of A549 cells treated with 5j exhibited cell cycle arrest at G2-M phase and pro-apoptotic activity as indicated by Annexin V-FITC staining. Also, it reflected antinvasive and antimigration properties to A549 cells. Additionally, docking study of 5j on VEGFR2, B-RAF and MMP9 revealed that it binds to the target enzymes in a similar way as the co-crystallized ligand. The three compounds exhibited significantly high selectivity to A549 cancer cells against the normal human fetal lung fibroblast cell line WI-38 with higher selectivity index compared to sorafenib (5d IC50 136.76⯱â¯2.38⯵M, SIâ¯=â¯506.52; 5i IC50 89.20⯱â¯2.11⯵M, SIâ¯=â¯297.33; 5j IC50 79.60⯱â¯3.8⯵M, SIâ¯=â¯248.75; sorafenib IC50 30.32⯱â¯2.41⯵M, SIâ¯=â¯7.88). In conclusion, compounds 5d, 5i and 5j, specially 5j are promising anticancer agents targeting important pathways in NSCLC and warrant further preclinical and clinical trials.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Tiadiazinas/química , Tiadiazinas/farmacologia , Células A549 , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/patologia , Metaloproteinase 1 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Simulação de Acoplamento Molecular , Metástase Neoplásica/prevenção & controle , Proteínas Proto-Oncogênicas B-raf/efeitos dos fármacos , Tiadiazinas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacosRESUMO
A series of dihydropyrimidine (DHPM) derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues. The new compounds were screened for their cytotoxic activity toward 60 cancer cell lines according to NCI (USA) protocol. Seven compounds were further examined against the most sensitive cell lines, leukemia HL-60(TB) and MOLT-4. The most active compounds were 9m against HL-60(TB) (IC50 = 56 nM) and 9n against MOLT-4 (IC50 = 80 nM), more potent than monastrol (IC50 = 147 and 215 nM, respectively). Cell cycle analysis of HL-60(TB) cells treated with 9m and MOLT-4 cells treated with 9n showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Oxidiazóis/farmacologia , Pirimidinas/farmacologia , Tionas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , 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 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/químicaRESUMO
Inhibition of angiogenesis through inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) has been applied in cancer therapy because of its important role in promoting cancer growth and metastasis. In the presented study, a series of benzimidazol-furan hybrids was designed and synthesized through facile synthetic pathways. Evaluation of the synthesized compounds for their in vitro cytotoxic activity against breast (MCF-7) and hepatocellular (HepG2) carcinoma cell lines was performed. Two of the synthesized conjugates, 10b and 15, showed potent antiproliferative properties against MCF-7 cell line (IC50 = 21.25, 21.35 µM, respectively) in comparison to tamoxifen (IC50 = 21.57 µM). Additionally, compounds 10a, 10b, 15 and 17 showed promising potency (IC50 = 25.95, 22.58, 26.94 and 31.06 µM, respectively) against liver carcinoma cell line HepG2 in contrast to cisplatin (IC50 = 31.16 µM). Moreover, in vitro evaluation of the synthesized compounds for their effect on the level of VEGFR-2 in MCF-7 cell line showed their potent inhibitory activity relative to control untreated cells. Four compounds 10a, 10b, 14 and 15 showed 92-96% reduction in VEGFR-2 level, compared with tamoxifen and sorafenib which showed inhibition percentage of 98% and 95.75%, respectively. Compound 10a was found to have promising VEGFR-2 inhibitory activity (IC50 = 0.64 µM) in comparison to sorafenib (IC50 = 0.1 µM). Molecular docking was performed to study the binding pattern of the newly synthesized compounds with VEGFR-2 active site. Molecular docking attributed their good VEGFR-2 inhibitory activity to their hydrogen bonding interaction with the key amino acids in VEGFR-2 active site, Glu885 and Asp1046, and their hydrophobic interaction by their 2-furylbenzimidazole moiety with the allosteric hydrophobic back pocket in a type III inhibitors-like binding mode. The binding interaction is augmented by a ring substituent with long chain extension at position 1 of the benzimidazole due to its hydrophobic interaction with the hydrophobic side chains of the amino acids at the interface between the ATP binding site and the allosteric back pocket. Structure-activity relationship (SAR) was inferred for future optimization based on the performed biological and docking studies.
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Desenho de Fármacos , Furanos/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Células Hep G2 , Humanos , Células MCF-7 , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
A series of (benzimidazol-2-yl)-aniline (1) derivatives has been synthesized and evaluated as glycogen phosphorylase (GP) inhibitors. Kinetics studies revealed that compounds displaying a lateral heterocyclic residue with several heteroatoms (series 3 and 5) exhibited modest inhibitory properties with IC50 values in the 400-600µM range. Arylsulfonyl derivatives 7 (Ar: phenyl) and 9 (Ar: o-nitrophenyl) of 1 exhibited the highest activity (series 2) among the studied compounds (IC50 324µM and 357µM, respectively) with stronger effect than the p-tolyl analogue 8.
Assuntos
Compostos de Anilina/farmacologia , Benzimidazóis/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicogênio Fosforilase/antagonistas & inibidores , Compostos de Anilina/síntese química , Compostos de Anilina/química , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Glicogênio Fosforilase/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Coelhos , Relação Estrutura-AtividadeRESUMO
A newly synthesized series of anticancer compounds comprising thiazolo[3,2-a]pyrimidine derivatives 6a-q bearing a benzimidazole moiety was produced via a one-pot reaction of N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-2-cyanoacetamide 5 with 2-aminothiazole and an appropriate aromatic aldehyde. Compound 7 was obtained via the reaction of 4-(1H-benzo[d]imidazol-2yl)benzenamide 1 with carbon disulphide and methyl iodide in the presence of concentrated aqueous solution of NaOH, then treated with o-phenylenediamine to give N-(4-1H-benzo[d]imidazol-2-yl)phenyl)-1H-benzo[d]imidazol-2-amine 8. The structures of the newly synthesized compounds were confirmed by analytical and spectroscopic measurements (IR, MS, and (1) H NMR). The synthesized products were screened and studied for their in vitro antitumor activity against three human cancer cell lines (namely colorectal cancer cell line HCT116, human liver cancer cell line HepG2, and human ovarian cancer cell line A2780) and their Aurora A kinase and KSP inhibitory activities. All newly synthesized compounds revealed marked results comparable with the standard drug CK0106023. The compounds 6e and 6k of the thiazolopyrimidine derivatives were the most active compounds when tested against the three cell lines in comparison with the standard drug CK0106023, and showed potent dual KSP and Aurora A kinase inhibition.
Assuntos
Antineoplásicos/síntese química , Aurora Quinase A/antagonistas & inibidores , Benzimidazóis/síntese química , Cinesinas/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células HCT116 , Células Hep G2 , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
On continuation to our work, new quinoxalin-2(1H)-ones were synthesized to study their cytotoxic effect against HepG-2 and MCF-7 with their effect on the human tyrosine kinase (TRK). Compounds 12, 18, 15, 13, 11a, 20 and 16, respectively, were found to be more potent than cisplatin against HepG2 and selective to TRK. Also, compounds 12, 18, 20, 13, 14, and 22, respectively, exhibited decidedly activity against MCF-7 and selectivity against human TRK compared to cisplatin. A molecular docking study was also performed to gain comprehensive understanding into plausible binding modes and to conclude the structure activity relationships of the synthesized compounds. Moreover, anti-inflammatory activity was studied. Compounds 12, 15, 18 and 22 were found to be potent and selective against COX-2.
Assuntos
Antineoplásicos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Quinoxalinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Hep G2 , Humanos , Células MCF-7 , Estrutura Molecular , Quinoxalinas/síntese química , Quinoxalinas/química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
2-(2-Furyl)-1H-benzimidazoles 3-11 were synthesized and tested for their in vitro VEGF inhibition in MCF-7 cancer cell line. Compound 5a was more potent than Tamoxifen, and compounds 3b, 5a, 5c, 6b, 7a and 10 showed promising potency. Furthermore, compounds (6b, 7a and 10) showed remarkable selective inhibition of COX-2 enzyme close to that of Celecoxcib. Additionally, docking studies were performed using AutoDock 4.2 into the VEGFR2 kinase. Significant correlation exists between the biological activity (IC50 and %VEGF inhibition) against MCF-7 cell line and the molecular docking results (Ki and ΔGb) with correlation coefficients (R(2)) of 0.5513 and 0.4623 respectively. Accordingly, most of the synthesized 2-(2-furyl)-1H-benzimidazoles showed strong antiangiogenic activity against VEGFR2 kinase.
Assuntos
Inibidores da Angiogênese , Benzimidazóis , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Células MCF-7 , Espectrometria de Massas , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
The 2-(5-methyl-2-furyl)-1H-benzimidazole moiety has shown promising activity against vascular endothelial growth factor (VEGF)-induced angiogenesis. In part I of this study, we have synthesized new analogs and tested their anti-angiogenic potentials. Here, we continue our previous study with different new analogs. Some compounds show promising cytotoxic activity against the human breast cancer cell line MCF-7, with IC50 in the range of 7.80-13.90 µg/mL, and exhibited remarkable in vitro inhibition against VEGF in the MCF-7 cancer cell line, with 95-98% of inhibition in comparison to tamoxifen as reference (IC50: 8.00 µg/mL, % of inhibition = 98%). Additionally, a molecular docking study was carried out to gain insight into plausible binding modes and to understand the structure-activity relationships of the synthesized compounds.
Assuntos
Inibidores da Angiogênese/farmacologia , Benzimidazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Benzimidazóis/síntese química , Benzimidazóis/química , Neoplasias da Mama/irrigação sanguínea , Feminino , Humanos , Concentração Inibidora 50 , Células MCF-7 , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Relação Estrutura-Atividade , Tamoxifeno/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
As a continuation to our previous work in synthesizing antitumor benzimidazoles, a series of 2-((1H-benzo[d]imidazol-2-yl)methylthio)-4-(substituted)-6-phenylpyrimidine-5-carbonitriles was synthesized. Evaluation of the synthesized compounds for their in vitro cytotoxic activity against twelve cell lines namely, Cervical carcinoma (KB), Ovarial carcinoma (SK OV-3), CNS cancer (SF-268), Non small lung cancer (NCI H460), Colonadenocarcinoma (RKOP27), Leukaemia (HL60, U937, K562), Melanoma (G361, SK-MEL-28) and Neuroblastoma (GOTO, NB-1) revealed their marked potency when compared with known anticancer drugs.