One-Pot Synthesis of 1-Thia-4-azaspiro[4.4/5]alkan-3-ones via Schiff Base: Design, Synthesis, and Apoptotic Antiproliferative Properties of Dual EGFR/BRAF V600E Inhibitors.

In this investigation, novel 4-((quinolin-4-yl)amino)-thia-azaspiro[4.4/5]alkan-3-ones were synthesized via interactions between 4-(2-cyclodenehydrazinyl)quinolin-2(1 H )-one and thioglycolic acid catalyzed by thioglycolic acid. We prepared a new family of spiro-thiazolidinone derivatives in a one-step reaction with excellent yields (67-79%). The various NMR, mass spectra, and elemental analyses verified the structures of all the newly obtained compounds. The antiproliferative effects of 6a - e , 7a , and 7b against four cancer cells were investigated. The most effective antiproliferative compounds were 6b , 6e , and 7b . Compounds 6b and 7b inhibited EGFR with IC 50 values of 84 and 78 nM, respectively. Additionally, 6b and 7b were the most effective inhibitors of BRAF V600E (IC 50 = 108 and 96 nM, respectively) and cancer cell proliferation (GI 50 = 35 and 32 nM against four cancer cell lines, respectively). Finally, the apoptosis assay results revealed that compounds 6b and 7b had dual EGFR/BRAF V600E inhibitory properties and showed promising antiproliferative and apoptotic activity.