Novel benzimidazole-linked (thio)barbiturates as non-hydroxamate HDAC6 inhibitors targeting leukemia: Design, synthesis, and structure-activity relationship.

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, novel easy-to-prepare benzimidazole-linked (thio)barbiturate derivatives were designed and synthesized as HDAC6 inhibitors. The proposed structures of the title compounds were confirmed based on their spectral data and elemental analyses. The newly synthesized compounds were screened in vitro against HDAC6. All tested compounds showed potent HDAC6 inhibition at the nanomolar level. Several compounds displayed a remarkable HDAC6 inhibitory activity (IC  = 48.85-75.62 nM), superior to that of the reference drug suberoylanilide hydroxamic acid (SAHA; IC  = 91.73 nM). The most potent derivatives were further assessed for their in vitro anticancer activity against two human leukemia cell lines. Thiobarbiturate 3e was two times more potent than SAHA against the tested cells. The detailed structure-activity relationship was also described. Furthermore, molecular docking simulation revealed the ability of the title compounds to chelate the catalytic Zn ion located within the binding pocket of HDAC6. In silico evaluation of physicochemical properties indicated that the target compounds are promising candidates in terms of pharmacokinetic aspects.