RESUMO
New series of furan-thiazole hybrids (3a-f), thiazolo[2,3-c]-1,2,4-triazines (4a-f), their bioisosteres 1,3,4-thiadiazolo[2,3-c]-1,2,4-triazines (8a-d) and 1,2,4-triazino[4,3-b]-1,2,4-triazines (13a-e) were designed, synthesized and evaluated for their in vitro antitumor activities at the National Cancer Institute (NCI, USA). Among the synthesized compounds, 3d was found to exhibit promising broad spectrum antitumor activity (GI50 MG-MIDâ¯=â¯14.22⯵M) in a five-dose assay against the full panel NCI-cancer cell lines. 3d displayed higher antitumor activity against most tested cancer cell lines than 5-FU as reference. COMPARE analysis and molecular electrostatic potential computational study revealed that 3d probably exerts its antitumor properties through DNA binding similar to Clomesone. Further DNA binding studies using fluorescent terbium (Tb+3) probe revealed increased fluroresence of DNA-3d-Tb+3 mixture due to damage of the double-stranded DNA. Also, UV-vis absorption study was conducted which showed hyperchromic shift in DNA absorption confirming 3d-induced DNA damage. The assessed potency of 3d-induced DNA damage of calf thymus DNA showed a concentration as low as 2.04â¯ng/mL for a detectable DNA damage. Moreover, in silico calculation of physicochemical properties and druglikeness were in compliance to Lipinski's rule.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , DNA/metabolismo , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Tiazóis/química , Triazinas/química , Apoptose , Proliferação de Células , DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias/patologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
New pyrazolo[3,4-d]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed in vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity.
Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinonas/uso terapêutico , Triazóis/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Sítios de Ligação , Celecoxib/farmacologia , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Diclofenaco/farmacologia , Edema/tratamento farmacológico , Feminino , Granuloma/tratamento farmacológico , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirimidinonas/síntese química , Pirimidinonas/metabolismo , Pirimidinonas/farmacocinética , Ratos Wistar , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinéticaRESUMO
Two new series of pyrazolo[3,4-d]pyrimidine bearing thiazolidinone moiety were designed and synthesized. The newly synthesized compounds were evaluated for their in vitro (COX-1 and COX-2) inhibitory assay. Compounds that showed promising COX-2 selectivity were further subjected to in vivo anti-inflammatory screening applying formalin induced paw edema (acute model) and cotton-pellet induced granuloma (chronic model) assays using celecoxib and diclofenac sodium as reference drugs. The histopathological and ulcerogenic potential were also determined. In vivo anti-inflammatory data showed that compounds 2, 6, 7d displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, compounds 2, 3d, 3e, 7b and 7d displayed anti-inflammatory activity greater than or nearly equivalent to diclofenac sodium in the cotton pellet-induced granuloma assay. Moreover, most of the tested compounds revealed good gastrointestinal safety profile. Collectively, compounds 2 and 7d were considered as promising candidates in managing both acute and chronic inflammation with safe gastrointestinal margin.
Assuntos
Anti-Inflamatórios/síntese química , Desenho de Fármacos , Edema/tratamento farmacológico , Pirazóis/química , Pirimidinas/química , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/uso terapêutico , Celecoxib/uso terapêutico , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/metabolismo , Inibidores de Ciclo-Oxigenase/uso terapêutico , Diclofenaco/uso terapêutico , Edema/induzido quimicamente , Edema/veterinária , Feminino , Granuloma/induzido quimicamente , Granuloma/tratamento farmacológico , Granuloma/veterinária , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiazolidinas/químicaRESUMO
New pyrazolo[3,4-d]pyrimidines substituted with various functionalities or attached to a substituted pyrazole ring through different linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity using in vitro COX-1/COX-2 inhibition assay and in vivo formalin induced paw edema and cotton pellet-induced granuloma assays. Results revealed that compounds 17b and 18 possessed COX-1/COX-2 selectivity indices higher than diclofenac sodium and celecoxib. However, compounds 16a,b exhibited selectivity indices higher than diclofenac sodium and nearly equivalent to celecoxib, whereas, 9b displayed selectivity index comparable to diclofenac sodium. In vivo anti-inflammatory data showed that compounds 9b, 16a, 18 displayed anti-inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, the pyrazolyl derivatives 9b, 16b and 17b displayed anti-inflammatory activity about 2-2.5-fold that of diclofenac sodium and nearly 8-10.5-fold that of celecoxib in the cotton pellet-induced granuloma assay. The ulcerogenic effect of the active compounds was also investigated and results revealed that compounds 16a, 17a,b and 18 showed good gastrointestinal safety profile. Based on this, compounds 16a and 18 were considered as safe and effective leads in managing acute inflammation, while, 17b was prominent in controlling chronic inflammation.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antiulcerosos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/tratamento farmacológico , Pirazóis/farmacologia , Pirimidinas/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antiulcerosos/síntese química , Antiulcerosos/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Edema/induzido quimicamente , Edema/metabolismo , Feminino , Formaldeído , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Relação Estrutura-AtividadeRESUMO
The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. Herein we describe the design and synthesis of a novel series of 1,2,4-triazine derivatives based on our lead NCI 748494/1, possessing different N-linkers to aromatic and heterocyclic rings. In addition, a molecular hybrid series combining the 1,2,4-triazine scaffold to the well-known anticancer drug 6-mercaptopurine (6-MP) was synthesized in order to explore its "double-drug" antitumor effect. The synthesized compounds were evaluated for their in vitro antitumor activity against three c-Met addicted cancer cell lines (A549, HT-29 and MKN-45). Most compounds showed moderate to excellent antitumor activity. Compound 3d showed potent inhibitory activity more than reference Foretinib, BMS-777607 and NCI 748494/1 with IC50 values in the range 0.01-0.31⯵M against the cancer cell lines. The calculated IC50 of 3d against c-Met kinase was found to be 2.71⯵M, which is more potent than NCI 748494/1 (IC50â¯=â¯31.70⯵M). Docking studies were performed to identify the binding mode of 3d with c-Met kinase domain in comparison to moderate and weak derivatives. The present study clearly demonstrates that 1,2,4-triazine ring exhibits promising antitumor activity and the double-drug optimization strategy led to identifying 3d as a potent c-Met kinase inhibitor suitable for further development.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Triazinas/farmacologia , Aminopiridinas/farmacologia , Anilidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridonas/farmacologia , Quinolinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química , Triazinas/metabolismoRESUMO
In silico target fishing approach using PharmMapper server identified c-Met kinase as the selective target for our previously synthesized compound NCI 748494/1. This approach was validated by in vitro kinase assay which showed that NCI 748494/1 possessed promising inhibitory activity against c-Met kinase (IC50=31.70µM). Assessment of ADMET profiling, drug-likeness, drug score as well as docking simulation for the binding pose of that compound in the active site of c-Met kinase domain revealed that NCI 748494/1 could be considered as a promising drug lead. Based on target identification and validation, it was observed that there is structure similarity between NCI 748494/1 and the reported type II c-Met kinase inhibitor BMS-777607. Optimization of our lead NCI 748494/1 furnished newly synthesized 1,2,4-triazine derivatives based on well-established structure-activity relationships, whereas three compounds namely; 4d, 7a and 8c displayed excellent in vitro cytotoxicity against three c-Met addicted cancer cell lines; A549 (lung adenocarcinoma), HT-29 (colon cancer) and MKN-45 (gastric carcinoma); with IC50 values in the range 0.01-1.86µM. In vitro c-Met kinase assay showed 8c to possess the highest c-Met kinase inhibition profile (IC50=4.31µM). Docking of the active compounds in c-Met kinase active site revealed strong binding interactions comparable to the lead NCI 748494/1 and BMS-777607, suggesting that c-Met inhibition is very likely to be the mechanism of the antitumor effect of these derivatives.