Crafting Carbazole-Based Vorinostat and Tubastatin-A-like Histone Deacetylase (HDAC) Inhibitors with Potent in Vitro and in Vivo Neuroactive Functions

[Image: see text] Small-molecule inhibitors of HDACs (HDACi) induce hyperacetylation of histone and nonhistone proteins and have emerged as potential therapeutic agents in most animal models tested. The established HDACi vorinostat and tubastatin-A alleviate neurodegenerative and behavioral conditions in animal models of neuropsychiatric disorders restoring the neurotrophic milieu. In spite of the neuroactive pharmacological role of HDACi (vorinostat and tubastatin-A), they are limited by efficacy and toxicity. Considering these limitations and concern, we have designed novel compounds 3–11 as potential HDACi based on the strategic crafting of the key pharmacophoric elements of vorinostat and tubastatin-A into architecting a single molecule. The molecules 3–11 were synthesized through a multistep reaction sequence starting from carbazole and were fully characterized by NMR and mass spectral analysis. The novel molecules 3–11 showed remarkable pan HDAC inhibition and the potential to increase the levels of acetyl H3 and acetyl tubulin. In addition, few novel HDAC inhibitors 4–8, 10, and 11 exhibited significant neurite outgrowth-promoting activity with no observable cytotoxic effects, and interestingly, compound 5 has shown comparably more neurite growth than the parent compounds vorinostat and tubastatin-A. Also, compound 5 was evaluated for possible mood-elevating effects in a chronic unpredictable stress model of Zebrafish. It showed potent anxiolytic and antidepressant-like effects in the novel tank test and social interaction test, respectively. Furthermore, the potent in vitro and in vivo neuroactive compound 5 has shown selectivity for class II over class I HDACs. Our results suggest that the novel carbazole-based HDAC inhibitors, crafted with vorinostat and tubastatin-A pharmacophoric moieties, have potent neurite outgrowth activity and potential to be developed as therapeutics to treat depression and related psychiatric disorders.