Novel N‐Hydroxyheptanamides Incorporating 7‐Hydroxy‐2‐Oxo‐2 <i>H</i> ‐Chromene‐3‐Carboxamides as Histone Deacetylase Inhibitors and Cytotoxic Agents: Design, Synthesis, and Biological Evaluation

Abstract In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized a series of novel N ‐hydroxyheptanamides incorporating 7‐hydroxy‐2‐oxo‐2 H ‐chromene‐3‐carboxamides ( 6a‐o ). Biological evaluation showed that these hydroxamic acids were generally cytotoxic against five human cancer cell lines including A549 (human lung carcinoma), DD1 (human colon adenocarcinoma), Huh‐7 (human hepatocellular carcinoma), NCCIT (human embryonic carcinoma), H23 (adenocarcinoma; non‐small cell lung cancer) and a normal cell line Vero. It was found that the N‐hydroxyheptanamides ( 6a , 6m‐o ) were the most potent towards human embryonic carcinoma cancer cells (NCCIT) with IC 50 values of 1.95–0.79 µM compared to the reference drug, Vorinostat (SAHA) ( IC 50 , 1.73 µM). Additionally, some selected compounds were tested for toxicity against the normal cell line Vero. The result indicated that the selected compounds exhibited lower to similar toxicity towards Vero cells compared to Ellipticine. Moreover, these compounds also showed excellent HDAC inhibitory effect with IC 50 values of 0.094–0.054 µM, six to ten‐fold more potent than Vorinostat (SAHA) ( IC 50 , 0.630 µM). Docking studies performed with some potent compounds 6a , 6m‐o using Autodock Vina showed that these compounds bound to HDAC2 with relatively high binding affinities from ‐18.218 to ‐15.656 kcal/mol compared to SAHA (‐18.176 kcal/mol) and Trichostatin A (‐18.780 kcal/mol).