RESUMO
BACKGROUND: Pyrimidines have widespread activity and have shown potent antibacterial and anticancer activity. OBJECTIVE: To synthesise a range of pyrimidine diones and test them for their antibacterial and anticancer activity. METHOD: The pyranopyrimidin-2,4-dione derivatives (1-7) were synthesized in a one-pot reaction by reacting malononitrile and barbituric acid with several aromatic aldehydes in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in aqueous medium. The compounds were tested for their antibacterial activity using the broth microdilution method and for their cytotoxicity against three cell lines, HeLa (cervical cancer), Caco-2 (human colon adenocarcinoma) and HEK 293 (human embryonic kidney cells) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. RESULTS: Compounds 1-7 were successfully synthesized in yields of >90%. The 3,4-dihydroxyaryl (3) and the 2,5- dimethoxyaryl (7) derivatives were novel. Compounds 3, 5 (4'-methoxy derivative) and 6 (2',3'-dimethoxy derivative) showed antibacterial activity comparable to or better than the standard ampicillin. All the test compounds 1-7 showed good anticancer activity. The IC50 values ranged from 3.46 to 37.13 µM (HeLa); 136.78 to 297.05 µM (Caco-2) and 137.84 to 333.81 µM (HEK293). The best activity was seen in the HeLa cell line when compared to the standard 5FU (5-Fluorouracil IC50 of 41.85 µM), with 1, 2, 5 and 7 having IC50 values of 10.64, 3.46, 4.36 and 4.44 µM respectively. Additionally, two representative compounds (1 and 7) found to be potent against the two cell lines (HeLa and HEK 293) were docked into the binding site of human kinesin Eg5 with the aim of predicting their binding propensities and to establish their mechanism of action. The Lipinski parameters of these compounds were also computed and analysed for their drug-likeness. CONCLUSION: Compound 6 is an excellent candidate for a broad spectrum antibiotic with MBCs of 45.6-365.2 µM, while both 3 and 6 have the potential to be developed into an antibiotic against MRSA, with MBCs of 183-199 µM. Since all synthesized compounds showed IC50 values of 10 µM or less especially against the HeLa cells, they can be considered good lead compounds for anticancer agents. Additionally, the docking simulations suggested a good binding affinity of the compounds with Eg5 and indicated their anti-cancer action, at least partially, through its inhibition. The predicted Lipinski descriptors also indicated the potential of these compounds as an orally active drug.
Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Pirimidinonas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Células HeLa , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Relação Estrutura-AtividadeRESUMO
Mnk1 and Mnk2 are protein kinases responsible for phosphorylating eIF4E, a eukaryotic initiation factor responsible for initiating translation. Inhibiting Mnk1 and Mnk2 could therefore play a role in treating metabolic diseases such as cancer, diabetes, and hyperlipidemia. A wide range of sulfoximine substituted quinazolines were synthesised and evaluated for their Mnk1 and Mnk2 inhibitory activity. Amongst these compounds, 26 quinazolines showed activity against Mnk1 at <100 nM and 54 showed activity against Mnk2 at 1 nM. The results indicate that this scaffold is much more active against Mnk2 than Mnk1. The synthesised compounds may be future drugs in the treatment of metabolic diseases.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Quinazolinas/farmacologia , Desenho de Fármacos , Fator de Iniciação 4E em Eucariotos/metabolismo , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/fisiopatologia , Patentes como Assunto , Quinazolinas/química , Compostos de Enxofre/químicaRESUMO
Quinolines substituted at C-2 on the quinoline scaffold have shown interesting anticancer activity in a number of anticancer assays such as breast (MCF-7, MDA-MB 231), human cervical epithelioid (HeLa), oral squamous cell carcinoma (SAS), human stomach adenocarcinoma (AGS, MKN45), hepatocellular (SKHep, HepG-2, Hep-3B), prostate (PC-3, DU145), lung (A549, H-460), gastric (HGC, MNK-74), leukemia (K562, U937, REH, NALM6, CEM/ADR 5000), colon (Colo-205, HCT 116, SW620, Caco-2, HT29), neuroblastoma (IMR32), CNS (SF-268), oesophageal (EAC) and melanoma (A-375). They have been synthesised by a number of strategies starting with isatin, anilines, nitrobenzenes and benzamides and some even with cyclohexanone and cyclohexa-1,3-diones with ammonium acetate. Many of the synthetic strategies employ the derivatisation of quinoline precursors itself. We review here the synthesis of 145 bioactive anticancer quinolines substituted at the 2-position and their anticancer activity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Quinolinas/química , Quinolinas/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Humanos , Estrutura Molecular , Neoplasias/patologia , Quinolinas/síntese químicaRESUMO
In the biologically active title compound, C26H26O5, the pyran ring of the chromene unit adopts a half-chair conformation. The C=C double bond of the propenone unit exhibits a trans conformation and the carbonyl group is syn conformation to the double bond. The dihedral angle between the benzene ring and the benzopyran-one moiety is 31.54â (4)°. The mol-ecular structure is stabilized by an intra-molecular C=Oâ¯H-O hydrogen bond.
RESUMO
In the title compound, C16H11NO4, the dihedral angle between the ten-membered chromen-4-one ring system (r.m.s. deviation = 0.0095â Å) and the benzene ring is 86.16â (5)°. In the crystal, mol-ecules are linked into a three-dimensional network by weak C-Hâ¯O hydrogen bonds. The crystal studied was a non-merohedral twin, with the minor twin component refining to 0.093â (1).
RESUMO
In the title compound, C16H11NO4, the dihedral angle between the 10-membered coplanar chromone ring system and the benzene ring is 77.83â (3)°. In the crystal, weak C-Hâ¯O hydrogen bonds link the mol-ecules into a three-dimensional network.
RESUMO
The title compound, C(22)H(21)FO(2), exhibits substitutional disorder of the F atom and a H atom in the asymmetric unit with different occupancies, the refined F:H ratio being 0.80â (2):0.20â (2). The dihedral angle between the fluorinated benzene ring and the benzene ring of the chromanone system is 37.30°. There are two relatively high residual electron-density peaks associated with the disorder.
RESUMO
In the title compound, C(17)H(14)O(3), the dihedral angle between the meth-oxy-benzene unit and the benzene ring of the chromanone system is 64.12â (3)°. The crystal structure is stabilized by weak C-Hâ¯O inter-actions.
RESUMO
The distinctive feature of the structure of the title compound, C(16)H(10)Cl(2)O(2), is the formation of a zigzag chain along [100] via Clâ¯Cl inter-actions [3.591â (1) and 3.631â (1)â Å]. The chroman-one moiety is fused with the benzene ring and adopts a half-chair conformation. The dihedral angle between the benzene ring of the chromanone moiety and the dichlorobenzene plane is 56.14â (8)°.