Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors

Abstract

Inhibitors of sirtuin-2 deacetylase (SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in α-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate.

The Discovery of a Highly Selective 5,6,7,8‐Tetrahydrobenzo[4,5]thieno[2,3‐d]pyrimidin‐4(3H)‐one SIRT2 Inhibitor that is Neuroprotective in an in vitro Parkinson’s Disease Model

“…[29] These include the physiological inhibitor nicotinamide (1), [30] the 2-hydroxy-naphthaldehyde derivatives sirtinol (2), [31] cambinol [32] and salermide (3), [33] AGK2 (4), [28,34] AK-7 (5) [35] and its analogous 3-(N-arylsulfamoyl)benzamide derivatives, [36] the natural dilactone tanikolide dimer (6), [37] splitomicin derivatives, [38,39] suramin, [40] NAD + derivatives, [41] 3'-phenethyloxy-2-anilinobenzamide analogues (7), [42] our previously identified 10,11-dihydro-5H-dibenz[b,f]azepine derivative 8, [43] thieno[3,2-d]pyrimidine-6-carboxamides (9), [44] thioacetylated pseudopeptides, [45] and a variety of recently discovered inhibitors. [46][47][48][49] There are still a number of significant challenges in the development of SIRT inhibitors however. These include the pressing need for more potent inhibitors, with the majority of inhibitors exhibiting IC 50 values in the high micromolar range, the need for more selective inhibitors against a given isoform, and the need for further mechanism of action studies to aid compound development.…”

Discovery and preliminary evaluation of 2-aminobenzamide and hydroxamate derivatives containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors

“…Thus they may be promising lead compounds for the development of novel anti-tumor drug potentially via inhibiting HDACs.To further investigate the interactions between these compounds and HDACs, we performed docking simulations to model the possible binding modes using Glide contains the catalytic Zn 2+ ion, which is pentacoordinated with Asp181, His183, and Asp269 as well as 2-amino group of N-2-aminophenyl and the carbonyl oxygen of the benzamide moiety of 10f. In addition to coordinating Zn 2+ in a bidentate fashion, simultaneously, compound 10f forms hydrogen bonding interactions with His145, HDAC 8 can best be rationalized by the presence of the voluminous Trp141 of HDAC 8 at the bottom of the tunnel, which would impair effective Zn 2+ ion binding by bulky aniline ring of derivatives(10), as compared to a corresponding Leu144 in HDAC 2.The docking simulation result indicated that hydroxamate derivatives(11) were nicely bound to the active binding site of HDAC 8. The situation was similar to that observed for SAHA in complex with HDAC 8.…”

Design and Evaluation of 3-(Benzylthio)benzamide Derivatives as Potent and Selective SIRT2 Inhibitors

“…9 Many of the synthesized compounds increased α-tubulin acetylation and inhibited polyQ aggregation in several neuronal cell lines. 9 However, the reported compounds suffered from rapid metabolic oxidative demethylation at the sulfonamide nitrogen to the corresponding inactive metabolites (Figure 1). 9 The inactivity of the demethylated analogues can be attributed to the hydrophilic properties of the sulfonamide group and, more decisively, to the formation of an acidic moiety, which can be partially ionized at physiological pH.…”

“…9 However, the reported compounds suffered from rapid metabolic oxidative demethylation at the sulfonamide nitrogen to the corresponding inactive metabolites (Figure 1). 9 The inactivity of the demethylated analogues can be attributed to the hydrophilic properties of the sulfonamide group and, more decisively, to the formation of an acidic moiety, which can be partially ionized at physiological pH. For example, the calculated pK a of demethylated analogue 2 using MarvinSketch is 6.7, which means that 83.4% (as calculated by the Henderson−Hasselbalch equation) of this compound is negatively charged and involved in electrostatically enforced hydrogen bonding interactions with water molecules, resulting in a high desolvation energy.…”