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Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine–derived moiety and resulted in compounds that exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity when compared to the pan-HDAC inhibitor SAHA in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aβ-aggregation as well as significantly disrupted Aβ-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aβ-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a , which have the potential to treat AD. Image 1 • Novel acridine-containing histone deacetylase inhibitors have been developed. • Structure-activity relationship of the resulting compounds has been established. • Several compounds are identified as multiple HDAC-Aβ-aggregation-AChE inhibitors. • Compounds 11b and 6a enhance neurite outgrowth without significant neurotoxicity. • Compound 11b can permeate blood-brain barrier. [ABSTRACT FROM AUTHOR]

A series of C6-substituted N -hydroxy-2-quinolineacrylamides (3 – 15), with four types of bridging groups have been synthesized. Most of these compounds exhibit antiproliferative activity against A549 and HCT116 cells and Western blot analysis revealed that they are able to inhibit HDAC. Measurement of the HDAC isoform activity of ether-containing compounds showed that compound 9 has distinct HDAC6 selectivity, more than 300-fold over other isoforms. This paper describes the development of 6-aryloxy- N -hydroxy-2-quinolineacrylamides as potential HDAC6 inhibitors. [ABSTRACT FROM AUTHOR]

Abstract We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC 50 value of 1.1 μM, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of cancer cells, including MDR-positive cell lines with an IC 50 value of 49 nM (KB), 79 nM (A549), 63 nM (MKN45), 64 nM (KB-VIN10), 43 nM (KB-S15), and 46 nM (KB-7D). Dual inhibitory potential of compound 9 was found as it demonstrated significant inhibitory potential against HDAC1, 2 and 6 in comparison to MS-275 (6). Some key interactions of 9 with the amino acid residues of the active site of tubulin and with amino acid residues of HDAC 1 isoform have been figured out by molecular modeling. Compound 9 also demonstrated significant in vivo efficacy in the human non-small cell lung cancer A549 xenograft model as well as B-cell lymphoma BJAB xenograft tumor model. Graphical abstract Image 1 Highlights • A series of 1-Arylsulfonyl Indoline-Benzamides has been synthesized. • Compound 9 remarkably suppressed the growth of cancer cell lines. • The benzamide 9 displayed striking tubulin inhibition. • Compound 9 exhibited significant inhibitory potential against HDAC 1, 2 and 6. • Compound 9 also demonstrated significant in vivo efficacy. [ABSTRACT FROM AUTHOR]

This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC 50 = 4.3 nM) and HSP90a inhibition (IC 50 = 46.8 nM) along with substantial cell growth inhibitory effects with GI 50 = 0.76 μM (lung A549) and GI 50 = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI 50 = 0.37 μM) and lung H1975 cell lines (GI 50 = 0.13 μM) mediated through selective HDAC6 inhibition (IC 50 = 33.3 nM) and HSP90 inhibition (IC 50 = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area. Compound 17 downregulated PD-L1 expression in INF-γ treated H1975 lung cancer cells. Compound 17 in combination with afatinib enhanced antitumor efficacy. Image 1 • 1-Aroylisoindoline-hydroxamic acids as dual HDAC6/HSP90 inhibitors have been synthesized. • Compound 17 displays potent inhibition of HDAC6 isoform and HSP90a inhibition. • Compound 17 induced suppression of tumor growth in human H1975 xenografts. • Compound 17 downregulated PD-L1 expression in INF-γ treated H1975 lung cancer cells. • Compound 17 in combination with T cell immunotherapy might be worth investigating for treatment of cancer. [ABSTRACT FROM AUTHOR]