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1.
Bioorg Chem ; 148: 107429, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38728910

RESUMO

Cannabinoids bind to cannabinoid receptors CB1 and CB2 and their antitumoral activity has been reported against some various cancer cell lines. Some synthetic cannabinoids possessing indole rings such as JWH-015 and JWH-133 particularly bind to the cannabinoid CB2 receptor and it was reported that they inhibit the proliferation and growth of various cancer cells without their psychoactive effects. However, the pharmacological action mechanisms of the cannabinoids are completely unknown. In this study, we report the synthesis of some new cannabinoidic novel indoles and evaluate their anticancer activity on various cancerous and normal cell lines (U87, RPMI 8226, HL60 and L929) using several cellular and molecular assays including MTT assay, real-time q-PCR, scratch assay, DAPI assay, Annexin V-PE/7AAD staining, caspase3/7 activity tests. Our findings indicated that compounds 7, 10, 13, 16, and 17 could reduce cell viability effectively. Compound 17 markedly increased proapoptotic genes (BAX, BAD, and BIM), tumor suppressor gene (p53) expression levels as well as the BAX/BCL-2 ratio in U87 cells. In addition, 17 inhibited cell migration. Based on these results, 17 was chosen for determining the mechanism of cell death in U87 cells. DAPI and Annexin V-7AAD staining results showed that 17 induced apoptosis, moreover activated caspase 3/7 significantly. Hence, compound 17, was selected as a lead compound for further pharmacomodulation. To rationalize the observed biological activities of 17, our study also included a comprehensive analysis using molecular docking and MD simulations. This integrative approach revealed that 17 fits tightly into the active site of the CB2 receptor and is involved in key interactions that may be responsible for its anti-proliferative effects.


Assuntos
Antineoplásicos , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Indóis , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Indóis/farmacologia , Indóis/química , Indóis/síntese química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Relação Dose-Resposta a Droga , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Modelos Moleculares , Sobrevivência Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Acetamidas/farmacologia , Acetamidas/síntese química , Acetamidas/química
2.
Mol Divers ; 2023 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-37642887

RESUMO

The synthesis of 5H-imidazo[4,5-c]pyridines analogues (1a - 1h) and 4H-imidazo[4,5-b]pyridines (3a - 3c) was achieved by reacting 3,4-diaminopyridine or 2,3-diaminopyridine with Na2S2O5 adduct of corresponding benzaldehydes (a1 - a8). Alkylation of compounds (1a - 1h) and (3a - 3c) using 4-chlorobenzyl and /or butyl bromide under basic conditions (K2CO3, DMF) predominantly resulted in the formation of N5 regioisomers (2a - 2l) and N4,3 regioisomers (4a - 4c1,2), respectively. The N5,4,3-regioisomeric structures were confirmed using 2D-NOESY (Nuclear Overhauser Effect Spectroscopy) and HMBC (Heteronuclear Multiple Bond Correlation) spectra. The antibacterial and antifungal activities of the synthesized compounds (2a - 2g, 4a - 5d) were evaluated in vitro against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Methicillin resistant S. aureus, Enterococcus faecalis and Candida albicans, Candida parapsilosis. Among the synthesized compounds, promising activities were observed with compounds 2g, 2h, 4a and 4b with lowest MIC values (4-8 µg/mL). The compounds 2i, 2j, 2k, 2l showed moderate activity. Additionally, a computational approach (ADMETlab 2.0) was used to evaluate the drug likeness properties of the compounds.

3.
Eur J Med Chem ; 221: 113545, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34091216

RESUMO

A series of monocationic new guanidinobenzimidazole derivatives were prepared in a four step process starting from 2-nitro-1,4-phenylendiamine. Their antiparasitic activity against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani were evaluated in vitro. Two out of 20 tested monocationic compounds (7, 14) showed close activity with reference drug chloroquine against P. Falciparum. To understand the interactions between DNA minor groove and in vitro active compounds (7, 14) molecular docking studies were carried out. Stability and binding energies of DNA-ligand complexes formed by DNA with compounds 7 and 14 were measured by molecular dynamics simulations throughout 200 ns time. Root mean square deviation (RMSD) values of the ligands remained stable below 0.25 mm and root mean square fluctuation (RMSF) values of the active site residues with which it interacted decreased compared to the apo form. All compounds exhibited theoretical absorption, distribution, metabolism and excretion (ADME) profiles conforming to Lipinski's and Ghose's restrictive rules.


Assuntos
Antiprotozoários/farmacologia , Benzimidazóis/farmacologia , Guanidina/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Benzimidazóis/síntese química , Benzimidazóis/química , Cátions/síntese química , Cátions/química , Cátions/farmacologia , Relação Dose-Resposta a Droga , Guanidina/síntese química , Guanidina/química , Leishmania donovani/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos
4.
Z Naturforsch C J Biosci ; 71(11-12): 409-413, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27505087

RESUMO

A series of 2,5-disubstituted-benzoxazole derivatives (1-13) were evaluated as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results demonstrated that the compounds exhibited a broad spectrum of AChE and BChE inhibitory activity ranging between 6.80% and 90.21% except one compound which showed no activity against AChE at the specified molar concentration. Another derivative displayed a similar activity to that of reference drug (galanthamine) for inhibition of AChE and BChE. In addition, molecular docking of the compounds into active site of AChE was performed using recombinant human AChE (PDB ID: 4ey6) in order to understand ligand-protein interactions.


Assuntos
Benzoxazóis/química , Benzoxazóis/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Butirilcolinesterase/efeitos dos fármacos , Domínio Catalítico , Humanos , Simulação de Acoplamento Molecular
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