Identification of Indostat as a selective HDAC6 inhibitor for reducing inflammatory stimuli triggered by a synthetic analogue of viral double-stranded RNA in hippocampal neurons.

Abstract

Histone deacetylase 6 (HDAC6) has emerged as a key regulator of inflammatory and antiviral responses, making it an attractive target for the development of selective immunomodulatory agents. In this study, we designed, synthesized, and biologically evaluated a novel series of indolizine-based HDAC6 inhibitors (5a-m), exploiting the indolizine scaffold as a new cap group within the canonical HDAC pharmacophore. Most compounds displayed potent HDAC6 preferential inhibition in the low nanomolar range, with distinct selectivity profiles over other HDAC isoforms. Structure-activity relationship (SAR) studies highlighted the critical role of cap group decoration in balancing potency, leading to the identification of compound 5g(indostat) as the most promising candidate, showing excellent HDAC6 inhibition (IC50 = 14.7 nM). Physicochemical characterization demonstrated that 5g possesses a balanced solubility, stability, and lipophilicity. Its biological activity was further investigated in an in vitro hippocampal neuronal model of viral-like inflammation induced by poly(I:C). Under these conditions, 5g significantly reduced IL-6 secretion in a concentration-dependent manner, showing anti-inflammatory efficacy comparable to the pan-HDAC inhibitor SAHA, but with improved cellular tolerability. Mechanistic studies confirmed that 5g efficiently counteracted HDAC6 increased activity under poly(I:C) stress. Overall, this work identifies indolizine-based derivatives as a novel class of selective HDAC6 inhibitors and supports the therapeutic potential of HDAC6 targeting for the modulation of neuroinflammation associated with viral infections.

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