Design, and synthesis of N‐benzyl spiro‐piperidine hydroxamic acid‐based derivatives: Histone deacetylase inhibitory activity and drug‐likeness prediction

Nonselective histone deacetylase (HDAC) inhibitors show dose‐limiting side effects due to the inhibition of multiple, essential HDAC subtypes that can be limited by selective inhibitors. We herein synthesized a new series of N‐benzyl spiro‐piperidinehydroxamic acid‐based derivatives, which have been identified as a zinc‐binding group by combining privileged structures with hydroxamic acid and N‐benzyl spiro‐piperidine. All the synthesized compounds had good antiproliferative activity against various tumor cell lines and were non‐toxic to the normal cells, AD293. Compound with halogen substitution (8i: 2,4‐dichloro and 8k: 2,4‐difluoro) shown 101.5‐ and 108‐fold selectivity towars HDAC6 inhibition over HDAC8 in‐vitro fluorometric‐based assay and compared with Tubastatin A. The obtained in‐vitro results were in agreement with molecular docking studies. The identified novel compounds occupy the catalytic domain of HDAC6 selectively and shed light on the role of both chlorine and fluorine instead of fluorination on benzohydroxamate‐based (ACS Med. Chem. Lett. 2021, 12(11), 1810–1817) structure over class I isoforms. These obtained results can be used in the design of novel, highly selective HDAC6 inhibitors.