Exploration of novel hydroxamic acid-based candidates integrating chalcone scaffold cap as multitarget HDAC inhibitors: design, anti-prostatic cancer assessment, in silico docking and molecular dynamic simulation

Two novel series of hydroxamic acid hybrids were designed and synthesised as anticancer agents via histone deacetylase isozymes (HDACs) inhibitors. Antiproliferative effects of novel compounds were evaluated against DU-145 and PC-3 (prostate cancer) and MG-63 (osteosarcoma) cell lines. Compound 5d emerged as the most potent against DU-145 and PC-3 (prostate cancer) with IC$_{50}$ values of 0.93 and 1.05 µM, exhibiting inhibiting HDAC 2, 4, 6, and 8 with IC50 values of 0.86, 0.17, 1.17, and 0.15 µM respectively. As a result, it was selected for mechanistic investigations. Apoptotic cell death modality was predominantly detected in the three cell lines, accompanied by cell cycle arrest in the S phase in prostate cancer cell lines, whereas it caused cell cycle arrest in MG-63 osteosarcoma cells in the G0/G1 phase. Docking studies confirmed its high affinity for HDACs, and an atomistic standard 100 ns dynamic simulation supported the stability of these interactions. In conclusion, all these findings suggested the potential use of this compound for treating prostate cancer with bone metastasis.