Synthesis, Biological, and Molecular Docking Studies on 4,5,6,7-Tetrahydrobenzo[b]thiophene Derivatives and Their...

Initiation of colorectal carcinogenesis may be induced by chromosomal instability caused by oxidative stress or indirectly by bacterial infections. Moreover, proliferating tumor cells are characterized by reprogrammed glucose metabolism, which is associated with upregulation of PDK1 and LDHA enzymes. In the present study, some 4,5,6,7-tetrahydrobenzo[b]thiophene derivatives in addition to Fe₃O₄ and Fe₃O₄/SiO₂ nanoparticles (NPs) supported with a new Schiff base were synthesized for biological evaluation as PDK1 and LDHA inhibitors as well as antibacterial, antioxidant, and cytotoxic agents on LoVo and HCT-116 cells of colorectal cancer (CRC). The results showed that compound 1b is the most active as PDK1 and LDHA inhibitor with IC₅₀ values (μg/mL) of 57.10 and 64.10 compared to 25.75 and 15.60, which were produced by the standard inhibitors sodium dichloroacetate and sodium oxamate, respectively. NPs12a,b and compound 1b exhibited the strongest antioxidant properties with IC₅₀ values (μg/mL) of 80.0, 95.0, and 110.0 μg/mL, respectively, compared to 54.0 μg/mL, which was produced by butylated hydroxy toluene. Moreover, NPs12a and carbamate derivative 3b exhibited significant cytotoxic activities with IC₅₀ values (μg/mL) of 57.15 and 81.50 (LoVo cells) and 60.35 and 71.00 (HCT-116 cells). Thus, NPs12a and compound 3b would be considered as promising candidates suitable for further optimization to develop new chemopreventive and chemotherapeutic agents against these types of CRC cell lines. Besides, molecular docking in the colchicine binding site of the tubulin (TUB) domain revealed a good binding affinity of 3b to the protein; in addition, the absorption, distribution, metabolism, and excretion (ADME) analyses showed its desirable drug-likeness and oral bioavailability characteristics.