Synthesis and In Silico Evaluation of Thiazole, Thiazolidinone, and Pyrimidinethione Candidates Bearing A Benzo[h]Quinoline Scaffold as Potential Antiproliferative Agents

Heterocyclic systems including benzoquinolines are targeted molecules in synthetic and medicinal chemistry because they represent an essential framework in many biologically active agents. Thus, some benzo[h]quinoline-based thiazolidinone, thiazole, and pyrimidinethione candidates were designed and synthesized through reactions of benzo[h]quinoline-thiosemicarbazone with diverse carbon-centered electrophiles. The purity of compounds obtained was also confirmed with HPLC analysis. The in vitro antiproliferative activity against HepG2 and MCF-7 cancer cell lines showed the most potency of thiazolidinone 4 (IC50 = 10.18 ± 1.5 & 8.22 ± 1.3 µM) and pyrimidinethione 9 (IC50 = 8.16 ± 1.4 & 9.23 ± 1.2 µM) compared to doxorubicin (IC50 = 4.52 ± 0.3 & 4.15 ± 0.1 µM), being capable of possible chelation with key nucleobases. In silico target prediction recognized kinase as a more probable target, and molecular docking simulation toward EGFR enzyme (breast cancer kinase, PDB ID: 3W32) offered the best docking score of thiazolidinone 4 (S-score = −7.6064 kcal/mol), exhibiting main binding to EGFR enzyme active pockets with a binding energy nearer to doxorubicin (reference, S-score = −7.7989 kcal/mol) and W32 (co-crystallized ligand, S-score = −7.9107 kcal/mol). This indicated strong bonding to key nucleobases and amino acids through H-bonding (between carbonyl oxygen and LYS 745, common with doxorubicin) and hydrophobic interactions (between benzene ring and VAL 726), which may reveal its potential action as an antiproliferative agent and EGFR inhibitor. Also, modeling pharmacokinetics offered their desirable drug-likeness and oral bioavailability. This work may aid in developing new potent antitumor agents.