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1.
ACS Med Chem Lett ; 13(8): 1337-1344, 2022 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-35978694

RESUMEN

Using cycloalkyl and electron-donating groups to decrease the carbonyl electrophilicity, a novel series of 2-(quinoline-4-yloxy)acetamides was synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Structure-activity relationship studies led to selective and potent antitubercular agents with minimum inhibitory concentrations in the submicromolar range against drug-sensitive and drug-resistant Mtb strains. An evaluation of the activity of the lead compounds against a spontaneous qcrB mutant strain indicated that the structures targeted the cytochrome bc 1 complex. In addition, selected molecules inhibited Mtb growth in a macrophage model of tuberculosis infection. Furthermore, the leading compound was chemically stable depending on the context and showed good kinetic solubility, high permeability, and a low rate of in vitro metabolism. Finally, the pharmacokinetic profile of the compound was assessed after oral administration to mice. To the best of our knowledge, for the first time, a 2-(quinoline-4-yloxy)acetamide was obtained with a sufficient exposure, which may enable in vivo effectiveness and its further development as an antituberculosis drug candidate.

2.
Toxicol In Vitro ; 48: 11-25, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29288082

RESUMEN

Octyl gallate (OG) is an antioxidant that has shown anti-tumor, anti-diabetic and anti-amyloidogenic activities. Mitochondria play an important role in hepatocellular carcinoma, mainly by maintaining accelerated cellular proliferation through the production of ATP. Thus, the mitochondria may be a target for antitumor therapies. Here, we investigated the effects of OG in the hepatocarcinoma cell line (HepG2) and the mechanisms involved. We report, for the first time, that treatment with OG for 24h inhibited HepG2 cell growth by decreasing mitochondrial activity and mass, which led to the reduction of ATP levels. This reduction in the energy supply triggered a decrease in Ki67 protein expression, leading cells to cycle arrest. In addition, treatment with two doses of OG for 48h induced loss of mitochondrial functionality, mitochondrial swelling and apoptosis. Finally, we report that HepG2 cells had no resistance to treatment after multiple doses. Collectively, our findings indicate that metabolic dysregulation and Ki67 protein reduction are key events in the initial anti-proliferative action of OG, whereas mitochondrial swelling and apoptosis induction are involved in the action mechanism of OG after prolonged exposure. This suggests that OG targets mitochondria, thus representing a candidate for further research on therapies for hepatocarcinoma.


Asunto(s)
Adenosina Trifosfato/metabolismo , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Ácido Gálico/análogos & derivados , Antígeno Ki-67/biosíntesis , Mitocondrias/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/ultraestructura , Proliferación Celular/efectos de los fármacos , Resistencia a Medicamentos , Metabolismo Energético/efectos de los fármacos , Ácido Gálico/farmacología , Células Hep G2 , Humanos , Antígeno Ki-67/efectos de los fármacos , Dilatación Mitocondrial/efectos de los fármacos , Orgánulos/efectos de los fármacos , Orgánulos/ultraestructura , Fagosomas/efectos de los fármacos
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