Synthesis and biological evaluation of acridine-based histone deacetylase inhibitors as multitarget agents against Alzheimer's disease.

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 Aß-aggregation as well as significantly disrupted Aß-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aß-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.

Intercalating Electron Dyes for TEM Visualization of DNA at the Single-Molecule Level.

Staining compounds containing heavy elements (electron dyes) can facilitate the visualization of DNA and related biomolecules by using TEM. However, research into the synthesis and utilization of alternative electron dyes has been limited. Here, we report the synthesis of a novel DNA intercalator molecule, bis-acridine uranyl (BAU). NMR spectroscopy and MS confirmed the validity of the synthetic strategy and gel electrophoresis verified the binding of BAU to DNA. For TEM imaging of DNA, two-dimensional DNA origami nanostructures were used as a robust microscopy test object. By using scanning transmission electron microscopy (STEM) imaging, which is favored over conventional wide-field TEM for improved contrast, and therefore, quantitative image analysis, it is found that the synthesized BAU intercalator can render DNA visible, even at the single-molecule scale. For comparison, other staining compounds with a purported affinity towards DNA, such as dichloroplatinum, cisplatin, osmium tetroxide, and uranyl acetate, have been evaluated. The STEM contrast is discussed in terms of the DNA-dye association constants, number of dye molecules bound per base pair, and the electron-scattering capacity of the metal-containing ligands. These findings pave the way for the future development of electron dyes with specific DNA-binding motifs for high-resolution TEM imaging.

Design, synthesis and evaluation of acridine and fused-quinoline derivatives as potential anti-tuberculosis agents.

The synthesis of twelve acridine and polycyclic acridine derivatives prepared via the Friedländer reaction is described. The one-pot reactions of 2-amino-5-chloro or 5-nitro-benzophenones and a variety of cyclanones and indanones were carried out in a MW oven under TFA catalysis in good yields. The products were designed according natural antituberculosis products and were evaluated for growth inhibitory activity towards Mycobacterium tuberculosis H37Rv (Mtb) through the National Institute of Allergy and Infectious Diseases (NIAID, USA). Three of them underwent additional testings. The cyclopenta[b]quinoline derivative 9 and the acridine derivative 13 showed remarkable MIC values against the rifampin resistant strain. The former exhibited bactericidal activity at 50 µg/mL, its intracellular activity is similar to rifampin and it was not cytotoxic at low concentrations so it can be considered a new lead compound.

Synthesis and in vitro evaluation of 7-methoxy-N-(pent-4-enyl)-1,2,3,4-tetrahydroacridin-9-amine-new tacrine derivate with cholinergic properties.

Cholinesterase inhibitors are, so far, the only successful strategy for the symptomatic treatment of Alzheimer's disease. Tacrine (THA) is a potent acetylcholinesterase inhibitor that was used in the treatment of Alzheimer's disease for a long time. However, the clinical use of THA was hampered by its low therapeutic index, short half-life and liver toxicity. 7-Methoxytacrine (7-MEOTA) is equally pharmacological active compound with lower toxicity compared to THA. In this Letter, the synthesis, biological activity and molecular modelling of elimination by-product isolated during synthesis of 7-MEOTA based bis-alkylene linked compound is described.

Synthesis and in vitro evaluation of N-(Bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine as a cholinesterase inhibitor with regard to Alzheimer's disease treatment.

A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.

Synthesis of monomeric and dimeric acridine compounds as potential therapeutics in Alzheimer and prion diseases.

Starting from substituted 9-chloroacridines, a series of quinacrine and spacered dimeric acridine compounds was prepared. Their ability to interrupt the protein association of prion- and Alzheimer-specific proteins and Ab peptides was explored using a fast screening system based on FACS analysis. The bis-acridines displayed a higher activity than the corresponding monomers. Among these derivatives, best results were obtained with the 2,4-dimethoxy-6-nitro compound 7h for Abeta-peptides and the 2-methoxy-6-nitro compound 7f for PrP.

Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents.

Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP(Sc), which is a misfolded isoform of the normal cellular prion protein PrP(C). Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP(C) and the suppression of PrP(Sc) accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC50s in the nanomolar range.

Synthesis and biological activity of novel acridinylidene and benzylidene thiazolidinediones.

A novel set of acridinylidene thiazolidinediones and benzylidene thiazolidinediones was synthesized by nucleophilic addition of cyanoacrylates. Some of these compounds were evaluated for their glucose lowering capability and their effects on the triglyceride level in alloxan diabetic mice.

Synthesis and anti-inflammatory evaluation of 9-phenoxyacridine and 4-phenoxyfuro[2,3-b]quinoline derivatives. Part 2.

Mast cells, neutrophils and macrophages are important inflammatory cells that have been implicated in the pathogenesis of acute and chronic inflammatory diseases. To explore a novel anti-inflammatory agent, we have synthesized certain 9-phenoxyacridine and 4-phenoxyfuro[2,3-b]quinoline derivatives and evaluated their anti-inflammatory activities. The title compounds were synthesized by reaction of either 9-chloroacridine or 3,4-dichlorofuro[2,3-b]quinoline with appropriate Ar-OH and their anti-inflammatory activities were studied on inhibitory effects on the activation of mast cells, neutrophils and macrophages. Four 9-(4-formylphenoxy)acridine derivatives 2b-2e were proved to be more potent than the reference inhibitor, mepacrine for the inhibition of rat peritoneal mast cell degranulation with IC(50) values of 6.1, 5.9, 13.5, and 4.7 microM, respectively. Compounds 2c, 3b, 3c, and 5a also showed potent inhibitory activity (IC(50)=4.3-18.3 microM) for the secretion of lysosomal enzyme and beta-glucuronidase from neutrophils. In addition, 2d, 3a, and 4 inhibited TNF-alpha formation from the N9 cells (the brain resident macrophages) with IC(50) vales less then 10 microM. These results indicated that acridine derivatives exhibited more potent anti-inflammatory activities than their respective furo[2,3-b]quinoline counterparts (4 vs 9; 5a vs 10a; 5b vs 10b).

Pharmacological and toxicological aspects of new imidazoacridinone antitumor agents.

Imidazoacridinones represent a new group of antitumor compounds developed by J. Konopa and coworkers in Gdansk, Poland (W.M. Cholody, J. Med. Chem., 33: 49-52, 1990). The compounds exert activity against a broad spectrum of human tumors in the National Cancer Institute in vitro screening scheme. In this work, the in vitro cytotoxicity, cellular pharmacology, and genotoxic/transforming potential of five selected imidazoacridinones were studied. The compounds were highly cytotoxic (0.01-0.40 microM) to dividing cells, such as Friend erythroleukemia cells (line F4-6), V79 Chinese hamster cells, and exponentially growing C3H/M2 mouse fibroblasts. In contrast, nondividing primary rat hepatocytes and C3H/M2 cells in confluency were less sensitive to the toxicity of the imidazoacridinones. Multidrug-resistant-overexpressing F4-6 cells, 200-fold resistant to doxorubicin, showed only partial resistance (4-10 fold) to the imidazoacridinones. The cellular transport of the fluorescent imidazoacridinones occurred rapidly, and most of the drug fluorescence was localized in the nucleus. Cellular accumulation and retention of two selected imidazoacridinones (C-1310 and C-1311) in sensitive as well as in resistant F4-6 cells were determined with laser-excited flow cytometry. After an incubation with C-1311 and C-1310 for 60 min at 37 degrees C, the cellular accumulation of the less cytotoxic compound C-1310 was greater than that of C-1311, and for both compounds, the fluorescence in the resistant F4-6 cells was one-half of that in the sensitive F4-6 cells. Lowered temperature (4 degrees C) reduced the cellular accumulation for both compounds in the sensitive and in the resistant F4-6 cells and was comparable to the uptake in resistant F4-6 cells. The treatment of the resistant F4-6 cells with the multidrug-resistant modulator verapamil led to an enhanced accumulation of C-1310 and C-1311 by the cells. All five compounds produced a dose-dependent inhibition of [3H]uridine and [14C]thymidine incorporation and, except for C-1336, preferentially inhibited DNA synthesis. The affinity of the imidazoacridinones to DNA is also indicated by an increase of the DNA melting point by 9-11 degrees C. The mutagenic potential of the imidazoacridinones was investigated in the hypoxanthine guanine phosphoribosyl transferase test; the compounds C-1310 and C-1311 were additionally tested in the Salmonella typhimurium-microsome assay. Limited mutagenicity was detected in the hypoxanthine guanine phosphoribosyl transferase test, and in Salmonella typhimurium, mutagenicity was observed only in the strain TA1537. Furthermore, no induction of DNA repair synthesis was observed after treatment of primary hepatocytes with the five imidazoacridinones. The compounds did not transform C3H/M2 fibroblasts. One derivative, C-1336, led to a significant induction of cell differentiation in Friend erythroleukemia cells. The results of this study show that the imidazoacridinones display a strong cytotoxic effect in rapidly dividing cells and only a partial resistance toward multidrug resistant cells; in addition, they showed a limited mutagenic potential in V79 fibroblasts and Salmonella typhimurium and no transforming potential in C3H/M2 cells. The imidazoacridinones are, therefore, an interesting group of new antitumor agents, and further in vivo studies are warranted to explore the usefulness of these compounds for the treatment of human cancer.

Syntheses of 9-acridine- and 2-phenanthridinemethanols as potential antimalarials.

alpha-(1-Piperidinylmethyl)-9-acridinemethanol (3), alpha-[(dibutylamino)ethyl]-9-acridanmethanol (4a), and alpha-[(dibutylamino)methyl]-2-phenanthridinemethanol (5) have been made and all are ineffective as antimalarials against Plasmodium berghei in mice. 9-Acridinyloxirane showed no significant mutagenicity for strains TA 98 or TA 100 of Salmonella typhimurium.

10-Hydroxy-3,4-dihydroacridine-1,9(2H,10H)-diones, a new group of malaricidal and coccidiostatic compounds.

2-Nitrobenzaldehydes and 1,3-cyclohexanediones condense in a mixture of hydrochloric acid and glacial acetic acid to 10-hydroxy-3,4-dihydroacridine-1,9(2H,10H)-diones. Many compounds of this group reveal a pronounced coccidiostatic and malaricidal effect in vivo even against drug-resistant malaria parasites. Synthesis and chemotherapeutic results as well as structure-activity relationships are described.

Synthesis and biological evaluation of 2-(9-acridinyl)ethyl-N-substituted carbamates and their hydrochlorides and 10-N-oxides.

The syntheses of 2-(9-acridinyl)ethyl-N-substituted carbamates and their hydrochlorides and 10-N-oxides are reported along with biological results in the areas of antineoplastic, antimalarial, and CNS activity screening. The compounds showed negative biological activity in the areas tested.