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This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.

Benzo[b]thienyl hydroxamic acids, a novel class of histone deacetylase (HDAC) inhibitors, were identified via a targeted screen of small molecule hydroxamic acids. Various substitutions were explored in the C5- and C6-positions of the benzo[b]thiophene core to characterize SAR and develop optimal inhibitors. It was determined that substitution at the C6-position of the benzo[b]thiophene core with a three-atom spacer yielded optimal HDAC1 inhibition and anti-proliferative activity in murine erythroleukemia (SC-9) cells.

Apicidins are a class of cyclic tetrapeptides that do not contain the classical electrophilic alpha-keto epoxide yet are potent (nM) inhibitors of histone deacetylase and antiprotozoal agents. These compounds showed broad-spectrum activities against the apicomplexan family of protozoa including Plasmodium sp (malarial parasite), Toxoplasma gondii, Cryptosporidium sp., and Eimeria sp. These cyclic peptides contain a beta-turn amino acid (R)-Pip or (R)-Pro, (S)-N-methoxy Trp, (S)-Ile, or (S)-Val, and either (S)-2-amino-8-oxodecanoic acid or a modified (S)-2-amino-8-oxodecanoic acid. The isolation and structure elucidation of new apicidins from two Fusarium species, temperature-dependent NMR studies of apicidin, NMR and molecular modeling based conformation of the 12-membered macrocyclic ring, and selected chemical modifications of apicidin have been detailed in this paper. The cyclic nature of the peptide, the C-8 keto group, and the tryptophan are all critical for the biological activity.