Synthesis and evaluation of ent-Conduramine C-1 derivatives as α-glucosidase inhibitors via CSI-mediated amination reaction.

Concise synthesis of ent-conduramine C-1 and its derivatives has been achieved by using commercially available d-ribose. The key steps in the synthesis are regioselective and diastereoselective amination of polybenzyl ethers by chlorosulfonyl isocyanate (CSI), chelation-controlled carbonyl addition, and intramolecular olefin metathesis. All of the synthesized compounds were evaluated for inhibitory activity against α-glucosidase. The derivatives 18 (IC50 = 0.65 ± 0.03 mM) and 19 (IC50 = 0.26 ± 0.01 mM) were identified to be more potent than well-known α-glucosidase inhibitor acarbose (IC50 = 1.05 ± 0.17 mM) as a positive control.

Synthesis and biological evaluation of novel N-benzyltriazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors.

Histone deacetylases (HDAC) regulate post-translational acetylation and the inhibition of these enzymes has emerged as an intriguing disease therapeutic. Among them, class IIb HDAC6 has the unique characteristic of mainly deacetylating cytoplasmic proteins, suggesting clinical applications for neurodegenerative diseases, inflammation, and cancer. In this study, we designed a novel N-benzyltriazolyl-hydroxamate scaffold based on the known HDAC6 inhibitors nexturastat A and tubastatin A. Among the 27 derivatives, 3-fluoro-4-((3-(2-fluorophenyl)-1H-1,2,4-triazol-1-yl)methyl)-N-hydroxybenzamide 4u (HDAC6 IC50 = 7.08 nM) showed nanomolar HDAC6 inhibitory activity with 42-fold selectivity over HDAC1. Structure-activity relationship (SAR) and computational docking studies were conducted to optimize the triazole capping group. Docking analysis revealed that the capping group aligned with the conserved L1 pocket of HDAC6 and was associated with subtype selectivity. Overall, our study explored the triazole-based biaryl capping group and its substitution and orientation, suggesting a rationale for the design of HDAC6-selective inhibitors.