Multitarget bioactive benzo[f]quinoline heterocycles from a thiocarbohydrazone scaffold: synthesis, biological...

A series of benzo[f]quinoline-thiocarbohydrazone derivatives (3-12) was synthesized from 3-chlorobenzo[f]quinoline-2-carbaldehyde and thiocarbohydrazide through controlled cyclization/acylation pathways, affording the target heterocycles in 73-91% yields. Compound 7 was a potent antioxidant measured by DPPH (88.14 ± 1.19% scavenging) and ABTS (79.18 ± 1.60% scavenging) assays compared to ascorbic acid (96.64 ± 0.65% and 95.76 ± 0.83%, respectively). Additionally, compound 7 had the highest inhibition of microbial growth against S. aureus, B. subtilis and E. coli (83.75 ± 3.75%, 83.65 ± 2.34%, and 84.48 +/- 0.91% respectively) at 50 μg/mL in antibacterial assays, whereas compound 10 exhibited the highest inhibition of P. aeruginosa (78.70 ± 1.79%). Compound 10 also inhibited biofilm formation better than the other compounds against all tested organisms, with S. aureus 83.99 ± 3.07%, B. subtilis 81.11 ± 3.56%, E. coli 78.82 ± 2.23%, and P. aeruginosa 79.92 ± 2.42%. DFT (B3LYP/6-31G(d)) was used to design and support compound 3's proposed formation mechanism and to predict its electronic reactivities (Eg = 3.08 eV; μ = 3.56 D). Molecular Docking validated the activity data with compound 7 displaying very strong binding energies at antioxidant targets (1DGF: -12.93 kcal/mol, Ki = 4.98 μM, RMSD = 0.90 Å; 3QFA: -12.91 kcal/mol, Ki = 3.01 μM, RMSD = 0.87 Å), while 100 ns MD simulations corroborated the stability of the binding mode.