Vanillin-tethered quinazolin-2,4-dione analogues through five- and/or six-membered nitrogen-containing heterocycles as antibacterial agents: synthesis, biological evaluation and molecular docking study

Abstract

The escalating threat of drug-resistant bacteria confirms the urgent need to develop and identify new and potent antibacterial inhibitors. In the present research study, the molecular hybridization strategy involved the synthesis of vanillin linked to a quinazolin-2,4-dione skeleton through five- and/or six-membered nitrogen-containing heterocycles such as pyrazole, isoxazole and/or pyrimidine 1–15 and testing them for their in vitro antibacterial studies. The vanillin-derived chalcone 1 was synthesized by treatment of 3-(4-acetyl-phenyl)-1H-quinazolin-2,4-dione with 4-hydroxy-3-methoxybenzaldehyde (vanillin) through a base-catalyzed Claisen–Schmidt condensation reaction, then used as a key precursor for synthesis of a series of 14 bioactive compounds 2–15 by treatment with nitrogen nucleophiles via Michael addition reaction. Subsequently, the newly prepared compounds were structurally confirmed by well-known spectroscopic techniques such as FT-IR, ¹H-NMR, ¹³C-NMR, mass spectroscopy, and elemental analysis. All the molecules were evaluated in vitro for their antibacterial activities, showing moderate to good potency, with compounds 2, 5 and 11 having significant activity comparable to the standard drug ciprofloxacin. Moreover, molecular docking simulations were also conducted to investigate the possible interactions of the bioactive moieties of compounds, ciprofloxacin, co-crystalized ligand and two references with the target enzyme. The binding scores correlated with the biological activity of the compounds, with energy scores ranging from −9.9 to −7.4 kcal mol⁻¹, comparable to ciprofloxacin. Interestingly, the molecules 2, 5 and 11 formed highly stable H-bond, pi-cation and pi–sigma interactions with the amino acid residues LYS487, SER401, THR352, GLN348, SER347, and SER303, which are playing an important role in ensuring efficient binding of the ligand with glucoseamine-6-phosphate (GlcN-6-P) synthase (PDBID׃1moq). The enhanced antibacterial activity was ascribed to the presence of electron donating-groups –OH, and –OCH₃ attached to pyrazole and/or isoxazole moieties, respectively. To evaluate the structural confirmation and chemical reactivity behavior of the quinazolin-2,4-dione skeleton, semiempirical studies were achieved. Overall, the findings underscore the potential of vanillin linked to quinazolin-2,4-dione skeletons through five- and/or six-membered nitrogen-containing heterocycles, particularly 2, 5 and 11, as promising candidates for development of potent antibacterial inhibitors.