Search

New molecular hybrids were synthesized by combining tetrahydroquinoline (THQ) and isoxazole (ISX) scaffolds, in search for chemical structures with improved pharmacological properties. Our tetrahydroquinoline (THQ) and isoxazole (ISX) hybrids differ in the X and Y substituents: FM53 (X = H; Y= H), FM49 (X = CH 3 ; Y= OCH 3 ), FM50 (X = Cl; Y= H) and FM48 (X = Cl; Y= OCH 3 ). Aiming at exploring their bioactivity in liver cancer cells, in this paper we report the effect of four THQ-ISX hybrids on viability, respiration and oxidative stress in Hep-G2 human hepatoma cells. In addition, we measured the alterations induced by these compounds on oxygen uptake and respiratory chain enzymes in isolated mitochondria. Cell viability assay indicated that these THQ-ISX hybrids displayed antiproliferative activity on Hep-G2 cells. Among these, FM50 (IC 50  = 5.2 ± 1.9 μM) and FM53 (IC 50  = 6.8 ± 0.7 μM) had the highest cytotoxicity. These four hybrids also inhibited the Hep-G2 cells respiration in the uncoupled state, with FM50 decreasing all respiratory states (basal, leak, uncoupled). While only FM49 and FM53 altered the Hep-G2 cells redox function. In terms of mitochondrial bioenergetics, THQ-ISX hybrids decreased the oxygen consumption in state 3 (via complex I and II), and also inhibited NADH oxidase and NADH cytochrome c reductase enzyme activities. In these experiments, the structural homologues FM50 and FM53 had a remarkable inhibitory effect (~50%) with respect to FM49 and FM48. These results show that THQ-ISX hybrids are promising compounds for hepatoma cancer treatment and that the phenyl substituent (Y= H) in the ISX scaffold intensifies both, the cytotoxicity in Hep-G2 cells and, inhibition of electron transport through complex I of the mitochondrial respiratory chain., (Copyright © 2019 Elsevier B.V. All rights reserved.)