Synthesis, Molecular Docking, and In Silico ADMET Studies of New Thiadiazoles, Chalcones, and Pyrazolines Incorporating Alkaloid Like Structure as Antibacterial Agent

2-(6,7-Dimethoxy-3,4-dihydroisoquinolin-1-yl)-3-(3,4,5-trimethoxyphenyl)acrylonitrile 3 was obtained from Knoevenagel condensation of 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetonitrile 1 with 3,4,5-trimethoxybenzaldehyde 2. The latter arylidene 3 was used as a useful precursor in the synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines 8–10 upon heating with hydrazonoyl halides under reflux in chloroform in the presence of triethylamine. Utility of 3-acetyl-8,9-dimethoxy-2-(3,4,5-trimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carbonitrile 8 with the appropriate reagents in the synthesis of thiadiazoles, chalcones, and pyrazolines using convenient conditions like acetonitrile/TEA, ethanolic sodium hydroxide, and ethanol, respectively. The structures of newly synthesized compounds were established using elemental analyses and spectral data. All synthesized derivatives were tested for antibacterial efficiency against Gram-negative and Gram-positive bacteria. The MIC using resazurin was studied for the most reactive compounds 19d, 19e, 25, and 28. Compound 19e showed the strongest activity against S. aureus (MIC: 0.195%), while compound 28 was most effective against Listeria (MIC: 0.39%) and E. coli (MIC: 3.1%). Moreover, compound 19d showed strong broad activity, with MICs ranging from 0.39%–6.25% across all tested strains. On the other hand, compound 25 displayed the weakest activity against S. aureus (MIC: 50%). According to docking study, the most effective compound 19d, which demonstrated the highest binding affinity toward the three tested proteins: A0A0E1R719]. Compound 19d binds to the active site ofE. coli DNA Gyrase B (∆G = −8.7 kcal/mol), Salmonella DNA gyrase A (∆G = −7.6 kcal/mol) and Listeria transglycosylase enzyme (∆G = −8.5 kcal/mol) through 10, 12, and 6 interactions, respectively. ADMET profiling of all synthesized compounds showed moderate-to-low aqueous solubility (LogS: −7.083 to −7.587), high lipophilicity (LogP/LogD: 3.832 to 6.895), and poor intestinal absorption (HIA < 1.2%). Overall, significant structural optimization is needed to enhance their pharmacokinetic and safety profiles.