RESUMO
The ambident electrophilic character of the 5-bromo-2-hydroxychalcones and the binucleophilic nature of 2-aminothiophenol were exploited to construct the 2-aryl-4-(4-bromo-2-hydroxyphenyl)benzo[1,5]thiazepines. The structures and conformation of these 2-aryl-4-(4-bromo-2-hydroxyphenyl)benzo[1,5]thiazepines were established with the use of spectroscopic techniques complemented with a single crystal X-ray diffraction method. Both 1H-NMR and IR spectroscopic techniques confirmed participation of the hydroxyl group in the intramolecular hydrogen-bonding interaction with a nitrogen atom. SC-XRD confirmed the presence of a six-membered intramolecularly hydrogen-bonded pseudo-aromatic ring, which was corroborated by the DFT method on 2b as a representative example in the gas phase. Compounds 2a (Ar = -C6H5), 2c (Ar = -C6H4(4-Cl)) and 2f (Ar = -C6H4(4-CH(CH3)2) exhibited increased inhibitory activity against α-glucosidase compared to acarbose (IC50 = 7.56 ± 0.42 µM), with IC50 values of 6.70 ± 0.15 µM, 2.69 ± 0.27 µM and 6.54 ± 0.11 µM, respectively. Compound 2f, which exhibited increased activity against α-glucosidase, also exhibited a significant inhibitory effect against α-amylase (IC50 = 9.71 ± 0.50 µM). The results of some computational approaches on aspects such as noncovalent interactions, calculated binding energies for α-glucosidase and α-amylase, ADME (absorption, distribution, metabolism and excretion) and bioavailability properties, gastrointestinal absorption and blood-brain barrier permeability are also presented.
Assuntos
Tiazepinas , alfa-Glucosidases , alfa-Glucosidases/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Acarbose/farmacologia , Simulação de Acoplamento Molecular , alfa-Amilases , Hidrogênio , Nitrogênio , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
The conformations of the title compounds were determined in solution (NMR and UV-Vis spectroscopy) and in the solid state (FT-IR and XRD), complemented with density functional theory (DFT) in the gas phase. The nonequivalence of the amide protons of these compounds due to the hindered rotation of the C(O)-NH2 single bond resulted in two distinct resonances of different chemical shift values in the aromatic region of their 1H-NMR spectra. Intramolecular hydrogen bonding interactions between the carbonyl oxygen and the sulfonamide hydrogen atom were observed in the solution phase and solid state. XRD confirmed the ability of the amide moiety of this class of compounds to function as a hydrogen bond acceptor to form a six-membered hydrogen bonded ring and a donor simultaneously to form intermolecular hydrogen bonded complexes of the type N-H···O=S. The distorted tetrahedral geometry of the sulfur atom resulted in a deviation of the sulfonamide moiety from co-planarity of the anthranilamide scaffold, and this geometry enabled oxygen atoms to form hydrogen bonds in higher dimensions.
Assuntos
Benzamidas/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Sulfonas/química , Compostos de Tosil/química , Difração de Raios X/métodos , Cristalografia por Raios X , Teoria da Densidade Funcional , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Estrutura MolecularRESUMO
The 5-acetyl-2-aryl-6-hydroxybenzo[b]furans 2a-h have been evaluated through in vitro enzymatic assay against targets which are linked to type 2 diabetes (T2D), namely, α-glucosidase, protein tyrosine phosphatase 1B (PTP1B) and ß-secretase. These compounds have also been evaluated for antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical scavenging method. The most active compounds against α-glucosidase and/or PTP1B, namely, 4-fluorophenyl 2c, 4-methoxyphenyl 2g and 3,5-dimethoxyphenyl substituted 2h derivatives were also evaluated for potential anti-inflammatory properties against cyclooxygenase-2 activity. The Lineweaver-Burk and Dixon plots were used to determine the type of inhibition on compounds 2c and 2h against α-glucosidase and PTP1B receptors. The interactions were investigated in modelled complexes against α-glucosidase and PTP1B via molecular docking.
Assuntos
Secretases da Proteína Precursora do Amiloide , Diabetes Mellitus Tipo 2/enzimologia , Furanos/química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/química , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , alfa-Glucosidases/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Ciclo-Oxigenase 2/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Furanos/síntese química , Humanos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/químicaRESUMO
A series of 2-arylbenzo[b]furan-appended 4-aminoquinazoline hybrids were prepared and evaluated for cytotoxicity in vitro against the human lung cancer (A549), colorectal adenocarcinoma (Caco-2), hepatocellular carcinoma (C3A) and cervical cancer (HeLa) cell lines. Compounds 10d and 10j exhibited significant cytotoxicity against the C3A and Caco-2 cell lines and induced apoptosis in these cell lines. Likewise, compounds 10d and 10e exhibited significant inhibitory activity towards epidermal growth factor receptor-tyrosine kinase phosphorylation (IC50 values of 29.3 nM and 31.1 nM, respectively) against Gefitinib (IC50 = 33.1 nM). Molecular docking of compounds 10 into EGFR-TK active site suggests that they bind to the region of EGFR like Gefitinib does. [Formula: see text].
Assuntos
Benzofuranos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Quinazolinas/química , Trifosfato de Adenosina/metabolismo , Apoptose/efeitos dos fármacos , Benzofuranos/química , Sítios de Ligação , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Receptores ErbB/metabolismo , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fosforilação , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
A series of 2-arylbenzo[c]furan-chalcone hybrids 3aâ»y have been synthesized and evaluated for antiproliferative effects against the human breast cancer (MCF-7) cell line and for its potential to induce apoptosis and also to inhibit tubulin polymerization and/or epidermal growth factor receptor-tyrosine kinase (EGFR-TK) phosphorylation. Most of these compounds exhibited moderate to significant antigrowth effects in vitro against the MCF-7 cell line when compared to the reference standard actinomycin D. The capabilities of the most cytotoxic benzofuran-chalcone hybrids 3b and 3i, to induce apoptosis, have been evaluated by Annexin V-Cy3 SYTOX staining and caspase-3 activation. The experimental and molecular docking results suggest that the title compounds have the potential to exhibit inhibitory effects against tubulin polymerization and epidermal growth factor receptor tyrosine kinase (EGFR-TK) phosphorylation. The modeled structures of representative compounds displayed hydrophobic interactions as well as hydrogen and/or halogen bonding with the protein residues. These interactions are probably responsible for the observed increased binding affinity for the two receptors and their significant antigrowth effect against the MCF-7 cell line.