Novel heteroaromatic compounds bearing thiosemicarbazone as anti-cancer and anti-bacterial agents: Synthesis, cytotoxic and biological screening, molecular docking and DFT analysis

Novel heteroaromatic compounds (Hc1, Hc2, Hc3, Hc4) were obtained, and their structure were confirmed using various spectroscopic methods, including elemental analysis, fourier transform infrared (FT-IR) spectroscopy, proton and carbon nuclear magnetic resonance (1H/13C-NMR) spectroscopy, and molar conductance measurement. The biological activities of the heteroaromatic compounds against several Gram-positive (Micrococcus luteus ATCC9341, Staphylococcus epidermidis ATCC12228, Bacillus cereus RSKK863, Listeria monocytogenes ATCC 19111), and Gram-negative bacterial strains (Pseudomonas aeruginosa ATCC27853, Klebsiella pneumonia ATCC27853, Enterobacter aerogenes ATCC51342, Salmonella typhi H NCTC9018394, Shigella dysenteriae NCTC2966, Proteus vulgaris RSKK96026) were evaluated using the well-diffusion method. In general, the heteroaromatic compounds demonstrated a stronger inhibitory effect against Gram-positive bacteria. Hc1, Hc2 and Hc3 showed the highest inhibitory effect against B. cereus and L. monocytogenes. The compound (Hc4) showed the highest antibacterial activity and antifungal activity against Bacillus cereus and C. albicans, respectively. The cytotoxic activity of the heteroaromatic compounds was assessed against the non-small cell lung cancer cell line (NCI-H460) using the NutriCulture Cell Viability Detection Kit-8 (CVDK-8). Among the synthesized heteroaromatic compounds, Hc3 exhibited significant cytotoxic activity with an IC50 value of 141.3 & micro;g/mL, whereas compounds Hc1, Hc2, and Hc4 did not display significant toxicity at the tested concentrations. The molecular geometry of the heteroaromatic compound (Hc3) was optimized using Gaussian 09 W at the B3LYP/6-311++G (d,p) level of theory. Key structural parameters such as bond lengths, bond angles, and dihedral angles were determined through the same computational framework. Electronic features, including frontier molecular orbitals, global reactivity descriptors, and molecular electrostatic potential surfaces, were analyzed to explore intramolecular charge distribution and predict reactive sites. To evaluate the biological potential of the heteroaromatic compound (Hc3), molecular docking studies were performed. Additionally, drug-likeness assessment based on Lipinski's Rule of Five and ADME profiling revealed favorable pharmacokinetic characteristics. Molecular docking studies revealed that compound Hc3 showed a binding energy of -4.09 kcal/mol against the EGFR target (PDB ID: 1UWH), exhibiting key interactions such as hydrogen bonding and It-interactions with the active site residues. Based on all the results, it can be said that new heteroaromatic compounds have significant potential in the pharmaceutical field.