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Guided by computational analysis, herein we report the design, synthesis and evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis). The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative, docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat. Multistep syntheses afforded the visualized targets TOI1, TOI2, TOI3-rev and TOI4 whose biological evaluation confirmed the strength of HDAC8 inhibition with TOI4 displaying the greatest efficacy at varying concentrations. The results of this study lay the foundation for future design strategies toward more potent HDACis for HDAC8 isozymes and further therapeutic applications for neuroblastoma.

Histone deacetylases (HDAC) are being targeted for a number of diseases such as cancer, inflammatory disease, and neurological disorders. Within this family of 18 isozymes, HDAC4 is a prime target for glioma, one of the most aggressive brain tumors reported. Thus, the development of HDAC4 inhibitors could present a novel therapeutic route for glioma. In this work, molecular docking studies on cyclopropane hydroxamic acid derivatives identified five novel molecular interactions to the HDAC4 receptor that could be harnessed to enhance inhibitor binding. Thus, design guidelines for the optimization of potent HDAC4 inhibitors were developed which can be utilized to further the development of HDAC4 inhibitors. Using the developed guidelines, eleven novel cyclopropane hydroxamic acid derivatives were designed that outcompeted all original cyclopropane hydroxamic acids HDAC4 inhibitors studied in silico. The results of this work will be an asset to paving the way for further design and optimization of novel potent HDAC4 inhibitors for gliomas.