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 A, B, and C series. Among these compounds, C12 (hIMPDH II, IC₅₀ = 84.69 ± 0.83 nM; HDAC1, IC₅₀ = 81.75 ± 0.82 nM) and C18 (hIMPDH II, IC₅₀ = 820.50 ± 1.41 nM; HDAC1, IC₅₀ = 131.90 ± 1.02 nM) exhibited promising inhibitory activity against hIMPDH 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 in vitro. Compound C12 exhibited good liver microsomal stability with a moderate half-life (T _1/2). Furthermore, compound C12 exhibited acceptable in vivo pharmacokinetics of properties. In conclusion, compound C12 represents a potential new dual inhibitor targeting both hIMPDH II and HDAC1.