Rational design of phenyl thiophene (pyridine) derivatives that overcome P-glycoprotein mediated MDR in MCF-7/ADR cell

Novel Benzo Five-Membered Heterocycle Derivatives as P-Glycoprotein Inhibitors: Design, Synthesis, Molecular Docking, and Anti-Multidrug Resistance Activity

“…In addition, the RF (reversal fold) values of all three P-gp inhibitors (verapamil 24.3, cyclosporin A 72.6, tariquidar 283.2) were consistent with previous reports. − Furthermore, compounds c1–c31 showed acceptable MDR reversal activity with RF ranging from 10.0 to 204.4, wherein the RF values of compounds c3, c10, c12, c13, c14, c16, c17, c23 , and c30 were 204.4, 99.1, 88.3, 112.7, 108.7, 86.4, 137.6, 76.3, and 100.4, respectively. The results indicated that the RF values of these compounds exceeded those of the first-generation P-gp inhibitors verapamil, cyclosporin, and reported phenylfuran, phenylthiophene, phenylpyridine, and phenylpyrimidine derivatives, − which were consistent with the results predicted by the abovementioned molecular simulations.…”

“…Given the importance of the alkoxy-substituent group, the effects of alkoxy group substations of phenylindole derivatives (different chain lengths and numbers on the phenyl ring) on the reversal activity were investigated. As shown in Table , compounds c4–c9 showed weaker reversal activity (IC 50 = 1.4680–2.9780 μM, RF = 16.5–33.6) than compound c4 (IC 50 = 1.0630 μM, RF = 46.4), indicating that the reversal activity of target compounds decreased as the alkoxy chain length increased.…”

“…Given the importance of the alkoxy-substituent group, 34 the effects of alkoxy group substations of phenylindole derivatives (different chain lengths and numbers on the phenyl ring) on the reversal activity were investigated. As shown in benzyloxy group exhibited poor reversal activity, which indicated that the introduction of the ring on the phenyl ring-bridged carbon had no significant effect on the reversal activity.…”

“…In order to develop more selective and effective P-gp inhibitors, we previously designed multiple series of tetrahydroisoquinoline derivatives with substitution of phenylfuran, phenylthiophene, phenylpyridine, and phenylpyrimidine. − In consequence, tetrahydroisoquinoline and phenyl heterocyclic were found to be important active fragments for the MDR reversal activity. Based on the abovementioned principle of “higher molecular weight, larger Log P value, longer skeletal structure”, a new skeleton system was designed by using ring-merging and fragment-growing strategies (Figure ).…”