Synthesis, Anticancer Assessments, Molecular Docking, and Pharmacokinetic Properties of New Phenothiazine-Thiazolidin-4-one Conjugates
摘要
In this study, newly targeted phenothiazine-thiazolidin-4-one conjugates were synthesized and their structures were obtained using IR, NMR, and MS techniques. The cytotoxic effects of these newly synthesized compounds were evaluated in three different tumor cell lines: PC3, HepG2, and MCF-7. They exhibited significant cytotoxic selectivity toward the PC3 and MCF-7 cell lines, with some showing varying levels of activity against HepG2 cells. Conjugates 4a and 8b were particularly effective, demonstrating the highest cytotoxicity against the PC3 and MCF-7 lines, with IC50 values of 7.12 ± 0.29 μM and 8.29 ± 0.30 μM, respectively. Additionally, the inhibition of carbonic anhydrases (CAIX and CAXII) was assessed by comparing the synthesized conjugates to the reference compound acetazolamide (AZA). Conjugates 4a, 4b, 4c, and 8b strongly inhibited CAIX, with IC50 values of 0.063 ± 0.012, 0.060 ± 0.033, 0.066 ± 0.009 μM, and 0.071 ± 0.043 μM, respectively, while showing limited inhibition of CAXII. Among the eight synthesized conjugates, their interactions with specific 3IAI amino acids were evaluated. The results showed that conjugates 8a and 8c had the highest binding affinities, suggesting that they may be further developed. The pharmacokinetic properties (absorption, distribution, metabolism, and elimination) of the phenothiazine-thiazolidin-4-one conjugates were predicted using SwissADME. Conjugates 8a, 8b, and 8c exhibited low gastrointestinal absorption and poor solubility, with conjugate 8a raising concerns regarding its drug-likeness criteria.