Design, synthesis and antitumor activity evaluation of novel IMPDH II and HDAC1 dual inhibitor

The development of multi-target inhibitors has garnered considerable attention in the field of cancer therapy. We have designed and synthesized a total of 80 derivatives, categorized into <b>A</b>, <b>B</b>, and <b>C</b> series. Among these compounds, C12 (<i>h</i>IMPDH II, IC₅₀ = 84.69 ± 0.83 nM; HDAC1, IC₅₀ = 81.75 ± 0.82 nM) and C18 (<i>h</i>IMPDH II, IC₅₀ = 820.50 ± 1.41 nM; HDAC1, IC₅₀ = 131.90 ± 1.02 nM) exhibited promising inhibitory activity against <i>h</i>IMPDH II and HDAC1. Compared to the IMPDH-positive compound MPA (IC₅₀ = 403.23 ± 2.92 nM) and the HDAC-positive compound SAHA (IC₅₀ = 1165.72 ± 1.22 nM), compound C12 (IC₅₀ value of 305.31 ± 0.67 nM) demonstrated superior anti-proliferative activity against K-562 cells <i>in vitro</i>. Compound C12 exhibited good liver microsomal stability with a moderate half-life (<i>T</i> _1/2). Furthermore, compound C12 exhibited acceptable <i>in vivo</i> pharmacokinetics of properties. In conclusion, compound C12 represents a potential new dual inhibitor targeting both <i>h</i>IMPDH II and HDAC1.