Bifunctional 1-[4-Methoxy-3-(chloromethyl)]benzaldehyde in the Synthesis of Hybrid Derivatives of 4-Methylquinoline-2-thiol

Objective: The aim of this work was to synthesize quinoline derivatives and hybrid compounds in which the quinoline nucleus is linked to either a 2,4,6-triarylpyrimidine or a 4,5,6,7-tetrahydrobenzo[b]thiophene moiety. The synthesized compounds were then screened for their antibacterial and fungicidal activities. These biological evaluations were complemented by a theoretical molecular docking study. Methods: The antimicrobial and antifungal activity of quinoline derivatives was studied by the agar diffusion method against hospital strains of Escherichia coli and Staphylococcus aureus bacteria and Candida albicans fungi. The docking study was conducted against the RNA-dependent RNA polymerase (RdRp) complex with the SARS-CoV-2 virus NSP7 and NSP8 proteins, the kinase domain of the human epidermal growth factor receptor (EGFR), and doubly phosphorylated human mitogen-activated protein kinase 14 (MAPK14) in complex with the activating transcription factor (ATF2). Results and Discussion: 4-Methoxybenzaldehyde functionalized at position 2 of the benzene ring with a 4-methyl-2-sulfanylquinoline fragment was used as the starting material to obtain substituted 1-arylprop-2-en-1-ones, which were further converted into 4-substituted-2-cyano-4-oxobut-2-enoate and hybrid compounds—4-methyl-2-sulfanylquinoline–2-phenyl-6-arylpyrimidines and 4-methyl-2-sulfanylquinoline–tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one. Some of the synthesized derivatives showed pronounced antibacterial activities against S. aureus and E. coli and antifungal activities against C. albicans. The molecular docking data predict antiviral and antitumor activities in the synthesized compounds, highlighting their promise for further research. Conclusions: A series of novel 4-methyl-2-sulfanylquinoline derivatives and their hybrid structures with pyrimidine and tetrahydrobenzothienopyrimidinone scaffolds were successfully synthesized. Several compounds demonstrated pronounced antibacterial and antifungal activity in experimental assays. Furthermore, molecular docking studies predicted promising antiviral and antitumor potential. These combined experimental and in silico results provide a strong rationale for further investigation of these quinoline derivatives as lead compounds for the development of novel antimicrobial and antiviral agents.