Synthesis, Characterization, In Vitro Anticancer Evaluation, ADMET Properties, and Molecular Docking of Novel 5-Sulfanyl Substituted (Thiazol-4-yl)-Phosphonium Salts

Seven TPP+ new 5-sulfanyl substituted (thiazol-4-yl) phosphonium salts functionalized with different substituents were designed, synthesized, and studied against the NCI-60 human cancer cell lines. Compounds 1-4 show the total average parameters GI₅₀=0.7-2.7 μM, TGI=7.0-14.6 μM, and LC₅₀=25.2-41.8 μM, and compounds 5-7 show GI₅₀=0.3-0.5 μM, TGI=1.3-3.1 μM, and LC₅₀=3.6-4.0 μM. The most active compound 7 demonstrated the best anticancer results against leukemia (K-562, GI₅₀=0.141 μM; RPMI-8226, GI₅₀=0.143 μM), ovarian cancer (NCI/ADR-RES, GI₅₀=0.142 μM), breast cancer (HS578T, GI₅₀=0.175 μM; MDA-MB-468, GI₅₀=0.101 μM), melanoma (SK-MEL-5, GI₅₀=0.155 μM), and colon cancer (COLO 205, GI₅₀=0.163 μM). All compounds showed low cytotoxicity against the leukemia subpanel (LC₅₀>100 μM). The SAR analysis reveals the critical role of the substitutes at the thiazole C2 and C5 positions. Adding the phenyl, p-tolyl, or 4-chlorophenyl group to the C2 position in compounds 5-7 increases anticancer effectiveness. According to the NCI COMPARE analysis, compounds 2-3 showed a very high (r=0.92, 0.81) correlation with morpholino-doxorubicin. Molecular docking-analyzing the antitumor mechanism of compounds 1-4 action demonstrated that the DNA chain is a probable biotarget. The ADMET analysis acknowledges the favorable prognosis using compounds as potential anticancer agents.