Design,Synthesis and Biological Evaluation of Novel 1,3,5-Triazines: Effect of Aromatic Ring Decoration on Affinity to 5-HT7 Receptor

Considering the key functions of the 5-HT₇ receptor, especially in psychiatry, and the fact that effective and selective 5-HT₇ receptor ligands are yet to be available, in this work, we designed and synthesized novel 1,3,5-triazine derivatives particularly based on the evaluation of the effect of substituents at aromatic rings on biological activity. The tested compounds showed high affinity to the 5-HT₇ receptor, particularly ligands N²-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N⁴-phenethyl-1,3,5-triazine-2,4,6-triamine 2 (K_i = 8 nM) and N²-(2-(1H-indol-3-yl)ethyl)-N⁴-(2-((4-fluorophenyl)amino)ethyl)-1,3,5-triazine-2,4,6-triamine 12 (K_i = 18 nM) which showed moderate metabolic stability, and affinity to the CYP3A4 isoenzyme. As for the hepatotoxicity evaluation, the tested compounds showed moderate cytotoxicity only at concentrations above 50 µM. Compound 12 exhibited less cardiotoxic effect than 2 on Danio rerio in vivo model.     

Synthesis, absorption and fluorescence properties of N-triazinyl derivatives of 2-aminoanthracene

N-(4,6-dichloro-1,3,5-triazin-2-yl)-2-aminoanthracene was synthesized by substitution of one chlorine atom of 2,4,6-trichloro-1,3,5-triazine with 2-aminoanthracene. A new series of N-triazinyl-2-aminoanthracenes was prepared by nucleophilic substitution of one or both chlorine atoms on N-(4,6-dichloro-1,3,5-triazin-2-yl)-2-aminoanthracene with electron-donating methoxy or phenylamino groups. The UV/Vis absorption, fluorescence and excitation spectra as well as the fluorescence quantum yields of the prepared compounds were measured in 1,4-dioxane, ethyl acetate, dibutyl ether and acetonitrile; nanosecond kinetics of the fluorescence decay was measured in different solvents. The influence of the character of the substituent on triazinyl ring and of the solvent polarity upon the absorption and fluorescence spectra and fluorescence quantum yields are discussed.     

Electrochemical behavior of a new <Emphasis Type="Italic">s</Emphasis>-triazine-based dendrimer

The electrochemical behavior of a new G-2-s-triazine-based dendrimer, 2,4,6-tris-{4-{4,6-bis-{4-{4,6-bis-[(1S,2S)-1,3-dihydroxy-1-(4-nitrophenyl)-prop-2-ylamino]-s-triazin-2-yl}-piperazin-1-yl}-s-triazin-2-yl}-piperazin-1-yl}-s-triazine, (I), was studied in dimethylsulfoxide solution by cyclic voltammetry, on platinum and graphite electrodes. The electrochemical properties of I were compared with that of one of its precursor, N-{4,6-bis{4-{4,6-bis[(1S,2S)-1,3-dihydroxy-1-(4-nitrophenyl)-prop-2-ylamino]-s-triazin-2-yl}-piperazin-1-yl}-triazin-2-yl}-piperazine), (II), together with that of the starting material, (1S,2S)-2-amino-1-(4-nitrophenyl)-propane-1,3-diol (“p-nitrophenylserinol”), (III).     

Trifluoromethylcinnamanilide Michael Acceptors for Treatment of Resistant Bacterial Infections

A series of thirty-two anilides of 3-(trifluoromethyl)cinnamic acid (series 1) and 4-(trifluoromethyl)cinnamic acid (series 2) was prepared by microwave-assisted synthesis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). All the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. (2E)-3-[3-(Trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]prop-2-enamide (1j), (2E)-N-(3,5-dichlorophenyl)-3-[3-(trifluoromethyl)phenyl]prop-2-enamide (1o) and (2E)-N-[3-(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)-phenyl]prop-2-enamide (2i), (2E)-N-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(trifluoromethyl)phenyl]-prop-2-enamide (2p) showed antistaphylococcal (MICs/MBCs 0.15–5.57 µM) as well as anti-enterococcal (MICs/MBCs 2.34–44.5 µM) activity. The growth of M. marinum was strongly inhibited by compounds 1j and 2p in a MIC range from 0.29 to 2.34 µM, while all the agents of series 1 showed activity against M. smegnatis (MICs ranged from 9.36 to 51.7 µM). The performed docking study demonstrated the ability of the compounds to bind to the active site of the mycobacterial enzyme InhA. The compounds had a significant effect on the inhibition of bacterial respiration, as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity but also bactericidal activity. Preliminary in vitro cytotoxicity screening was assessed using the human monocytic leukemia cell line THP-1 and, except for compound 2p, all effective agents did show insignificant cytotoxic effect. Compound 2p is an interesting anti-invasive agent with dual (cytotoxic and antibacterial) activity, while compounds 1j and 1o are the most interesting purely antibacterial compounds within the prepared molecules.     

Design,Synthesis, Molecular Docking Analysis and Biological Evaluations of 4-[(Quinolin-4-yl)amino]benzamide Derivatives as Novel Anti-Influenza Virus Agents

In this study, a series of 4-[(quinolin-4-yl)amino]benzamide derivatives as the novel anti-influenza agents were designed and synthesized. Cytotoxicity assay, cytopathic effect assay and plaque inhibition assay were performed to evaluate the anti-influenza virus A/WSN/33 (H1N1) activity of the target compounds. The target compound G07 demonstrated significant anti-influenza virus A/WSN/33 (H1N1) activity both in cytopathic effect assay (EC₅₀ = 11.38 ± 1.89 µM) and plaque inhibition assay (IC₅₀ = 0.23 ± 0.15 µM). G07 also exhibited significant anti-influenza virus activities against other three different influenza virus strains A/PR/8 (H1N1), A/HK/68 (H3N2) and influenza B virus. According to the result of ribonucleoprotein reconstitution assay, G07 could interact well with ribonucleoprotein with an inhibition rate of 80.65% at 100 µM. Furthermore, G07 exhibited significant activity target PA−PB1 subunit of RNA polymerase according to the PA−PB1 inhibitory activity prediction by the best pharmacophore Hypo1. In addition, G07 was well drug-likeness based on the results of Lipinski’s rule and ADMET prediction. All the results proved that 4-[(quinolin-4-yl)amino]benzamide derivatives could generate potential candidates in discovery of anti-influenza virus agents.     

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC₅₀ = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.     

Preparation and characterization of novel grafted polyethylene based azo-polymers bearing oligo(ethylene glycol) spacers

Novel grafted azo-polymers were prepared from commercial low density polyethylene plates (PE). First, precursor polymers were synthesized by reacting PE in the presence of acryloyl chloride using gamma radiation. Further esterification of the resulting grafted polymers with four new amino-nitro substituted azobenzene derivatives bearing oligo(ethylene glycol) segments: N-methyl-N-{4-[(E)-(4-nitrophenyl)diazenyl]phenyl}-N-(5-hydroxy-3-oxapentas-1-yl)amine (RED-PEG-2), N-methyl-N-{4-[(E)-(4-nitrophenyl)diazenyl]phenyl}-N-(8-hydroxy-3,6-dioxaoctas-1-yl)amine (RED-PEG-3), N-methyl-N-{4-[(E)-(4-nitrophenyl)diazenyl]phenyl}-N-(11-hydroxy-3,6,9-trioxaundecas-1-yl)amine (RED-PEG-4) and N-methyl-N-{4-[(E)-(4-nitrophenyl)diazenyl]phenyl}-N-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecas-1-yl)amine (RED-PEG-6) led to the formation of branched azo-polymers. These polymers were characterized and their thermal and optical properties were studied. Besides, the influence of the irradiation dose, irradiation time and the structure of the dyes on the properties of the obtained polymers are discussed.     

一种磺胺类碳酸酐酶Ⅸ抑制剂的合成

为发展一种适合18F标记用于CAⅨ检测的特异性PET探针,该文以对氨基苯磺酰胺和三嗪为主要原料,用乙二醇、2-氟乙醇、对甲基苯磺酰氯对三嗪环进行适当修饰,合成了可能具有高亲和力和选择性的CAⅨ抑制剂4-[4-(2-氟乙氧基)-6-(2-羟基乙氧基)-1,3,5-三嗪-2-亚胺基]苯磺酰胺,用于前期生物学评价和探针放射化学合成的参比化合物,同时合成了用作18F标记的前体化合物4-(4,6-双[2-(4-甲基苯磺酰氧基)乙氧基]-1,3,5-三嗪-2-亚胺基)苯磺酰胺,这两个化合物的收率分别为27.6%和13.1%,可满足下一步放射化学标记的需要。上述工作为进一步发展CAⅨ特异性PET探针建立了基础。     

Synthesis of some new 3-mercapto-5-substituted-1,2,4-triazine-s-triazoles for evaluation as antimicrobial agents

The synthesis of several S- and N-substituted derivatives of 5-[(5,6-diphenyl-1,2,4-triazin-3-yl)oxymethyl]-s-triazole-3-thiol, 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)-oxymethyl]-5,6-dihydrothiazolo-[3,2-b]-s-briazole, 2-[(5,6-diphenyl-1, 2,4-triazin-3-yl)oxymethyl]-5H,6,7-dihydro-s-triazolo-[3,2-b]-1,3-thiazine, 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)oxymethyl]-5,6-dihydrothiazolo-[3,2-b]-s-triazol-5-one and 2-[(5,6-diphenyl-1,2,4-triazin-3-yl)oxymethyl]-6-phenylthiazolo-[3,2-b]-s-triazole is reported. All the novel compounds have been screened for antimicrobial activity and one of them showed noteworthy activity.     

The Phenoxyalkyltriazine Antagonists for 5-HT6 Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases

Among the serotonin receptors, one of the most recently discovered 5-HT₆ subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT₆ receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT₆ receptor. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT₆ receptor target.     

Inhibition Studies on Carbonic Anhydrase Isoforms I,II, IX,and XII with a Series of Sulfaguanidines

Two novel sulfaguanidine series, six N-(N,N′-dialkyl/dibenzyl-carbamimidoyl) benzenesulfonamide derivatives and nine N-(N-alkyl/benzyl-carbamimidoyl) benzenesulfonamide derivatives, were obtained by desulfidative amination of easily accessible dimethyl arylsulfonylcarbonimidodithioates under catalyst- and base-free conditions. The newly synthesized compounds were tested for the inhibition of four different isozymes of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). Both series reported here were inactive against the off-target isozymes hCA I and II (K_i>100 μM). Interestingly, all investigated compounds inhibited both target isozymes hCA IX and XII in the submicromolar to micromolar ranges in which K_i values spanned from 0.168 to 0.921 μM against hCA IX and from 0.335 to 1.451 μM against hCA XII. The results indicated that N-(N-alkyl/benzyl-carbamimidoyl) benzenesulfonamides were slightly more potent inhibitors than N-(N,N′-dialkyl/dibenzyl-carbamimidoyl) benzenesulfonamides. Among the evaluated compounds, N-n-octyl-substituted N-carbamimidoylbenzenesulfonamide showed the most significant activity with a K_i value of 0.168 μM against hCA IX, which was four-fold more selective toward this isozyme versus hCA XII. Again, another derivative from N-(N-alkyl/benzyl-carbamimidoyl) benzenesulfonamide series, N-p-methylbenzyl-substituted N-carbamimidoylbenzenesulfonamide, demonstrated superior inhibitory activity against hCA XII with a K_i value of 0.335 μM.     

Dibenzofuran, 4-Chromanone,Acetophenone, and Dithiecine Derivatives: Cytotoxic Constituents from Eupatorium fortunei

Five new compounds, eupatodibenzofuran A (1), eupatodibenzofuran B (2), 6-acetyl-8-methoxy-2,2-dimethylchroman-4-one (3), eupatofortunone (4), and eupatodithiecine (5), have been isolated from the aerial part of Eupatorium fortunei, together with 11 known compounds (6‒16). Compounds 1 and 2 featured a new carbon skeleton with an unprecedented 1-(9-(4-methylphenyl)-6-methyldibe nzo[b,d]furan-2-yl)ethenone. Among the isolates, compound 1 exhibited potent inhibitory activity with IC₅₀ values of 5.95 ± 0.89 and 5.55 ± 0.23 μM, respectively, against A549 and MCF-7 cells. The colony-formation assay demonstrated that compound 1 (5 μM) obviously decreased A549 and MCF-7 cell proliferation, and Western blot test confirmed that compound 1 markedly induced apoptosis of A549 and MCF-7 cells through mitochondrial- and caspase-3-dependent pathways.     

Synthesis and Characterization of Some New Bis-Pyrazolyl-Thiazoles Incorporating the Thiophene Moiety as Potent Anti-Tumor Agents

A new series of 1,4-bis(1-(5-(aryldiazenyl)thiazol-2-yl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)benzenes 3a–i were synthesized via reaction of 5,5′-(1,4-phenylene)bis(3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide) (1) with hydrazonoyl halides 2a–i. In addition, reaction of 1 with ethyl chloroacetate afforded bis-thiazolone derivative 8 as the end product. Reaction of compound 8 with methyl glyoxalate gave bis-thiazolone derivative 10. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their alternative syntheses. All the synthesized compounds were evaluated for their anti-tumor activities against hepatocellular carcinoma (HepG2) cell lines, and the results revealed promising activities of compounds 3g, 5e, 3e, 10, 5f, 3i, and 3f with IC₅₀ equal 1.37 ± 0.15, 1.41 ± 0.17, 1.62 ± 0.20, 1.86 ± 0.20, 1.93 ± 0.08, 2.03 ± 0.25, and 2.09 ± 0.19 μM, respectively.     

一种含氟原子和三嗪环的磺胺类化合物的合成

为开发一种新型碳酸酐酶抑制剂,并进一步合成一种检测肿瘤乏氧的PET分子影像探针,以4-氨基甲基苯磺酰胺盐酸盐、三嗪为主要起始原料,通过用2-氟乙醇、乙二醇对三嗪环加以修饰,合成了可能具有高亲和力和选择性的碳酸酐酶抑制剂4-{[4-(2-氟基乙氧基)-6-(2-羟基乙氧基)-1,3,5-三嗪-2-氨基]甲基}苯磺酰胺。该化合物含有碳酸酐酶抑制剂所含有的活性基团磺胺,同时含有氟原子和三嗪环,是个很有潜力的碳酸酐酶抑制剂,该化合物的总收率为18.5%,可用于下一步实验中的前期生物学评价和PET分子影像探针放射化学合成的参比化合物。     

The synthesis of N-derivatives of 3-aminoperylene and their absorption and fluorescence properties

N-Acetyl and N-triazinyl 3-aminoperylenes were prepared. N-(4,6-Dichloro-1,3,5-triazin-2-yl)-3-aminoperylene was synthesized by the condensation of 3-aminoperylene with cyanuric chloride; other N-triazinyl derivatives were prepared by the successive substitution of chlorine atoms with methoxy or aniline groups. The structure and purity of the compounds were confirmed by elemental analysis, NMR spectroscopy and mass spectrometry. The UV/vis absorption, fluorescence and excitation spectra as well as the fluorescence quantum yields for the compounds were measured in dibutyl ether, 1,4-dioxane, ethyl acetate and acetonitrile; fluorescence lifetimes were measured in ethyl acetate and dimethyl sulfoxide. The influences of both the character of the N-substituent and the solvent polarity upon the spectra and quantum yields are discussed.     

Investigation of NPB Analogs That Target Phosphorylation of BAD-Ser99 in Human Mammary Carcinoma Cells

The design and development of a small molecule named NPB [3-{(4(2,3-dichlorophenyl)piperazin-1-yl}{2-hydroxyphenyl)methyl}-N-cyclopentylbenzamide], which specifically inhibited the phosphorylation of BAD at Ser99 in human carcinoma cells has been previously reported. Herein, the synthesis, characterization, and effect on cancer cell viability of NPB analogs, and the single-crystal X-ray crystallographic studies of an example compound (4r), which was grown via slow-solvent evaporation technique is reported. Screening for loss of viability in mammary carcinoma cells revealed that compounds such as 2[(4(2,3-dichlorophenyl)piperazin-1-yl][naphthalen-1-yl]methyl)phenol (4e), 5[(4(2,3-dichlorophenyl)piperazin-1-yl][2-hydroxyphenyl)methyl)uran-2-carbaldehyde (4f), 3[(2-hydroxyphenyl][4(p-tolyl)piperazin-1-yl)methyl)benzaldehyde (4i), and NPB inhibited the viability of MCF-7 cells with IC₅₀ values of 5.90, 3.11, 7.68, and 6.5 µM, respectively. The loss of cell viability was enhanced by the NPB analogs synthesized by adding newer rings such as naphthalene and furan-2-carbaldehyde in place of N-cyclopentyl-benzamide of NPB. Furthermore, these compounds decreased Ser99 phosphorylation of hBAD. Additional in silico density functional theory calculations suggested possibilities for other analogs of NPB that may be more suitable for further development.     

A new family of trinuclear Ru(II) polypyridyl complexes acting as pH-induced fluorescence switch

Tripodal ligands 1,3,5-tris{4-((1,10-phenanthroline-[5,6-d]imidazol-2-yl)phenoxy)methyl}-2,4,6-trimethylbenzene (L¹), 1,1,1-tris{4-((1,10-phenanthroline-[5,6-d]imidazol-2-yl)phenoxy)methyl}propane (L²), 2,2′,2′′-tris{4-((1,10-phenanthroline-[5,6-d]imidazol-2-yl)phenoxy)ethyl}amine (L³), and corresponding Ru(II) complexes [(bpy)₆L^1–3(Ru^II)₃](PF₆)₆, shortly called (Ru–L^1–3), have been synthesized. UV–vis absorption and fluorescence spectra of these complexes are both strongly dependent on the pH of the buffer solution. These complexes act as pH-induced off–on–off fluorescence switch through protonation and deprotonation of the imidazole-containing ligands.     

活性酯法合成来氟米特

2-氯-4,6-二甲氧基-1,3,5-三嗪和N-甲基吗啉反应得到氯化4-(4,6-二 甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉,其与5-甲基异(噁)唑-4-甲酸反应制备2-(5-甲基异(噁)唑-4-甲酰氧基)-4,6-二甲氧基-1,3,5-三嗪,所得化合物与4-三氟甲基苯胺反应合成标题化合物,总收率约72％(以...     

Optical properties and aggregation of novel azo-dyes bearing an end-capped oligo(ethylene glycol) side chain in solution,solid state and Langmuir–Blodgett films

Optical properties and aggregation of two novel azo-dyes N-methyl-N-{4-[(E)-(4-nitrophenyl)diazenyl]phenyl}-N-(3,6,9-trioxadecas-1-yl)amine (RED-PEGM-3) and N-methyl-N-{4-[(E)-(4-nitrophenyl)diazenyl] phenyl}-N-(3,6,9,12,15,18,21,24-octaoxapentaeicos-1-yl)amine (RED-PEGM-8) were studied by UV–vis spectroscopy in solution, solid state and Langmuir–Blodgett films. The results were compared to those obtained for their precursor 1-amino-4′-nitroazobenzene (Disperse Orange 3, DO3) and 1-N-methylamino-4′-nitroazobenzene (RED-H). Increasing the polarity of methanol:water mixtures gave rise to the formation of H-aggregates for all dyes. Similar aggregates were also detected in cast films. NOESY, 2D ¹H NMR experiments carried out in aqueous solutions of RED-PEGM-8 revealed the formation of atypical antiparallel H-aggregates. Only RED-PEGM-3 gave traces of J-aggregates in the solid state. RED-PEGM-3 and RED-PEGM-8 readily form J-aggregates in Y-type Langmuir–Blodgett films.     

Discovery of a Potent and Selective JNK3 Inhibitor with Neuroprotective Effect Against Amyloid β-Induced Neurotoxicity in Primary Rat Neurons

As members of the MAPK family, c-Jun-N-terminal kinases (JNKs) regulate the biological processes of apoptosis. In particular, the isoform JNK3 is expressed explicitly in the brain at high levels and is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we prepared a series of five 6-dihydroxy-1H-benzo[d]imidazoles as JNK3 inhibitors and found them have potential as neuroprotective agents. Following a previous lead scaffold, benzimidazole moiety was modified with various aryl groups and hydroxylation, and the resulting compounds exhibited JNK3 inhibitory activity with improved potency and selectivity. Out of 37 analogues synthesized, (S)-cyclopropyl(3-((4-(2-(2,3-dihydrobenzo[b][1,4]dioxin -6-yl)-5,6-dihydroxy-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino) piperidin-1-yl)methanone (35b) demonstrated the highest JNK3 inhibition (IC₅₀ = 9.7 nM), as well as neuroprotective effects against Aβ-induced neuronal cell death. As a protein kinase inhibitor, it also showed excellent selectivity over other protein kinases including isoforms JNK1 (>1000 fold) and JNK2 (−10 fold).