Target-oriented synthesis of benzoquinoline-embedded candidates: antimicrobial potential and in silico insights

A new series of benzo[h]quinoline-based derivatives was synthesized using a thiocarbohydrazone scaffold as a versatile intermediate for the construction of diverse nitrogen- and sulfur-containing heterocycles, including tetrazine, thiadiazole, triazole, pyrazole, and thiadiazine motifs. These structural variations were designed to investigate the influence of heterocyclic frameworks on antimicrobial activity and to identify promising lead compounds. The synthesized derivatives were evaluated for in vitro antimicrobial activity against a panel of Gram-positive and Gram-negative bacteria, as well as C. albicans. Antimicrobial assessment was performed using agar well diffusion to measure inhibition zones (IZ) and broth microdilution to determine minimum inhibitory concentrations (MIC). Most compounds exhibited moderate to significant activity, with IZ values typically ranging from 9.0 to 16.0 mm. Compound 14 emerged as the most potent derivative, displaying broad-spectrum activity with inhibition zones up to 15.0 mm and MIC values ranging from 13.0 to 23.0 mg mL^-1 across tested strains, with remarkable MBC values ranging from 20.0 to 35.0 mg mL^-1 with reduction of CFU per mL culture of the most tested strains, especially S. aureus that reduced to 16.0 CFU per mL^-1. Compounds 10 and 13 also demonstrated notable activity, particularly against E. coli and B. cereus. To rationalize the observed biological activity, molecular docking studies were conducted for compounds 10, 13, and 14 using DNA gyrase B (PDB ID: 4KFG) as the target, with novobiocin as a reference inhibitor. The docking results suggested favorable binding affinities and key interactions within the active site, consistent with the experimental activity trend. Molecular dynamics simulations further supported the time-dependent stability of the selected ligand-protein complexes. In addition, ADME and BOILED-Egg analyses highlighted compound 10 as the most pharmacokinetically favorable candidate, exhibiting an optimal balance between lipophilicity and polarity and high predicted gastrointestinal absorption. In contrast, compounds 13 and 14 showed reduced permeability, while gentamicin displayed poor passive diffusion due to its high polarity. Overall, these findings identify benzo[h]quinoline-based candidates, particularly compound 10, as promising scaffolds for further antimicrobial drug development.