RESUMO
BACKGROUND: Aripiprazole is a quinolinone derivative. It shows a high affinity for neurotransmitters dopamine and serotonin receptors, which can overcome the blood-brain barrier (BBB) to reach the central nervous system (CNS) to exert therapeutic effects. Its radioiodination may lead to high radiochemical yield and improved its affinity. Aripiprazole radioiodination is an aromatic electrophilic substitution. OBJECTIVE: Herein, we investigate the favorable atom site of the aromatic electrophilic substitution of aripiprazole by calculating the Fukui indices of heavy atoms and ESP charges of the parent molecule. METHODS: The calculations have been carried out at the B3LYP/LanL2DZ level of theory. The iodinated aripiprazole structure is confirmed by comparing the experimental and the predicted 1H NMR chemical shifts of the parent molecule and its iodinated forms. RESULTS: Finally, the electronic properties of aripiprazole and its iodinated form were calculated at the same level of theory. Nucleophilic Fukui indices and ESP charges calculations confirm that C8 is the most favorable site of the electrophilic substitution. The calculated electronic properties (e.g, gap energy, electron affinity, and electronegativity) of aripiprazole and its iodinated form reveal the higher reactivity of iodinated aripiprazole compared with aripiprazole. CONCLUSION: This may explain the higher affinity of iodinated aripiprazole and the increase of its radiochemical yield.
Assuntos
Aripiprazol/síntese química , Teoria da Densidade Funcional , Radioisótopos do Iodo/química , Marcação por Isótopo , Modelos QuímicosRESUMO
ß-glucuronidase is a lysosomal glycosidase enzyme which catalyzes the extracellular matrix of cancer and normal cells and the glycosaminoglycans of the cell membrane, which is important for cancer cell proliferation, invasion, and metastasis. Liver cancer, colon carcinoma, and neoplasm bladder are triggered by the increase of the level of ß-glucuronidase activity. The most valuable structures are indole and oxadiazole which has gain immense attention because of its pharmacological behavior and display many biological properties. Twenty-two (1â»22) analogs of indole based oxadiazole were synthesized and screened for their inhibitory potential against ß-glucuronidase. Majority of the compounds showed potent inhibitory potential with IC50 values ranging between 0.9 ± 0.01 to 46.4 ± 0.9 µM, under positive control of standard drug d-saccharic acid 1,4 lactone (IC50 = 48.1 ± 1.2 µM). Structural activity relationship (SAR) has been established for all synthesized compounds. To shed light on molecular interactions between the synthesized compounds and ß-glucuronidase, 1, 4, and 6 compounds were docked into the active binding site of ß-glucuronidase. The obtained results showed that this binding is thermodynamically favorable and ß-glucuronidase inhibition of the selected compounds increases with the number of hydrogen bonding established in selected compound-ß-glucuronidase complexes.