1‐Arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines Histone Deacetylase Inhibitors Are Potent Cytokine Release Suppressors

A series of 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines ( 7 – 15 ) has been developed; the compounds exhibited potent histone deacetylase (HDAC) inhibitory activities. Notably, almost all of this series exhibited better HDAC‐inhibitory and antiproliferative activities than 3‐(1‐benzenesulfonyl‐1H‐indol‐5‐yl)‐N‐hydroxyacrylamide ( 6 ), as reported in a previous study. Among these compounds, 3‐[1‐(4‐methoxybenzenesulfonyl)‐2,3‐dihydro‐1H‐indol‐5‐yl]‐N‐hydroxyacrylamide ( 9 ) showed a two‐ to tenfold increase in activity compared to SAHA ( 1 ) in the suppression of lipopolysaccharide‐induced cytokine production. Compound 9 also caused a marked reduction in carrageenan‐induced acute inflammation in a rat model. Taken together, these data indicated that 1‐arylsulfonyl‐5‐(N‐hydroxyacrylamide)indolines HDAC inhibitors exhibit potent anti‐inflammatory activity.     

Synthesis and Biological Evaluation of 1‐Methyl‐1H‐indole–Pyrazoline Hybrids as Potential Tubulin Polymerization Inhibitors

A series of 1‐methyl‐1H‐indole–pyrazoline hybrids were designed, synthesized, and biologically evaluated as potential tubulin polymerization inhibitors. Among them, compound e19 [5‐(5‐bromo‐1‐methyl‐1H‐indol‐3‐yl)‐3‐(3,4,5‐trimethoxyphenyl)‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamide] showed the most potent inhibitory effect on tubulin assembly (IC₅₀=2.12 μm ) and in vitro growth inhibitory activity against a panel of four human cancer cell lines (IC₅₀ values of 0.21–0.31 μm ). Further studies confirmed that compound e19 can induce HeLa cell apoptosis, cause cell‐cycle arrest in G₂/M phase, and disrupt the cellular microtubule network. These studies, along with molecular docking and 3D‐QSAR modeling, provide an important basis for further optimization of compound e19 as a potential anticancer agent.     

Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers

Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1‐(5‐chloro‐1H‐indol‐3‐yl)‐2‐[(4‐cyanophenyl)thio]ethanone ( 13 ) and 1‐(5‐chloro‐1H‐indol‐3‐yl)‐2‐[(4‐nitrophenyl)thio]ethanone ( 14 ), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non‐haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long‐term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.     

Synthesis and characterization of 2‐hydroxyethylmethacrylate/2‐(3‐indol‐yl)ethylmethacrylamide‐based novel hydrogels as drug carrier with in vitro antibacterial properties

In this study, a new cationic monomer 2‐(3‐indol‐yl)ethylmethacrylamide (IEMA) derived from tryptamine was synthesized in a single step and characterized by Fourier transform infrared (FTIR), ¹H‐NMR, and ¹³C‐NMR. Then, one‐step preparation of novel poly[2‐hydroxyethylmethacrylate‐c‐2‐(3‐indol‐yl)ethylmethacrylamide], or p(HEMA‐c‐IEMA), copolymeric hydrogels has been performed successfully with IEMA and 2‐hydroxyethylmethacrylate (HEMA) as monomers using free radical aqueous polymerization. The hydrogels were characterized with scanning electron microscopy, FTIR, elemental analysis, thermogravimetric analysis, and texture profile analysis instruments. p(HEMA‐c‐IEMA) hydrogels were used for swelling, diffusion, drug release, and antibacterial activity studies. The drug‐release behavior of the hydrogels was determined as a function of time at 37 °C in pH 1.2 and 7.2. The swelling and drug‐release studies showed that an increased IEMA amount caused a higher increase in swelling and drug‐release values. Additionally, zero‐order, first‐order, and Higuchi equation kinetic models were applied to the drug‐release data, and the data fit well in the Higuchi model, and the Peppas power‐law model was applied to the release mechanism. Finally, the antibacterial activities of the hydrogels were screened against Gram‐positive bacteria (Bacillus cereus and Staphylococcus aureus) and Gram‐negative bacteria (Escherichia coli and Salmonella typhimurium). © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 45550.     

6,7‐Dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinolines as Superior Reversal Agents for P‐Glycoprotein‐Mediated Multidrug Resistance

P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7‐dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2‐[(1‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]phenyl}‐1H‐1,2,3‐triazol‐4‐yl)methoxy]‐N‐(p‐tolyl)benzamide (compound 7 h ) was identified as a potent modulator of P‐gp‐mediated MDR, with high potency (EC₅₀=127.5±9.1 nM ), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR‐related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P‐gp‐mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P‐gp‐mediated MDR that has good potential for further development.     

Silica Supported Sodium Hydrogen Sulfate and Amberlyst‐15: Two Efficient Heterogeneous Catalysts for Facile Synthesis of Bis‐ and Tris(1H‐indol‐3‐yl)methanes from Indoles and Carbonyl Compounds[1]

Bis‐ and tris(1H‐indol‐3‐yl)methanes are synthesized in high yields by an electrophilic substitution reaction of indoles with carbonyl compounds under mild reaction conditions using two efficient heterogeneous catalysts, silica supported sodium hydrogen sulfate (NaHSO₄⋅SiO₂) and amberlyst‐15. The second catalyst can be reused.     

Design and Synthesis of DNA‐Interactive β‐Carboline–Oxindole Hybrids as Cytotoxic and Apoptosis‐Inducing Agents

A new series of (E)‐3‐[(1‐aryl‐9H‐pyrido[3,4‐b]indol‐3‐yl)methylene]indolin‐2‐one hybrids were synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines, namely, HCT‐15, HCT‐116, A549, NCI‐H460, and MCF‐7, including HFL. Among the tested compounds, (E)‐1‐benzyl‐5‐bromo‐3‐{[1‐(2,5‐dimethoxyphenyl)‐9H‐pyrido[3,4‐b]indol‐3‐yl]methylene}indolin‐2‐one ( 10 s ) showed potent cytotoxicity against HCT‐15 cancer cells with an IC₅₀ value of 1.43±0.26 μm and a GI₅₀ value of 0.89±0.06 μm . Notably, induction of apoptosis by 10 s on the HCT‐15 cell line was characterized by using different staining techniques, such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects, various assays such as annexin V‐FITC/PI, DCFDA, and JC‐1were performed. The flow cytometric analysis revealed that compound 10 s arrests the HCT‐15 cancer cells at the G0/G1 phase of the cell cycle. Additionally, western blot analysis indicated that treatment of 10 s on HCT‐15 cancer cells led to decreased expression of anti‐apoptotic Bcl‐2 and increased protein expression of both pro‐apoptotic Bax and caspase‐3, ‐8, and ‐9, and cleaved PARP with reference to actin. Next, a clonogenic assay revealed the inhibition of colony formation in HCT‐15 cancer cells by 10 s in a dose‐dependent manner. Moreover, upon testing on normal human lung cells (HFL), the compounds were observed to be safer with a low toxicity profile. In addition, viscosity and molecular‐docking studies showed that compound 10 s has typical intercalation with DNA.     

[Carboxyl‐11C]Labelling of Four High‐Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography

Cytosolic phospholipase A2α (cPLA2α) may play a critical role in neuropsychiatric and neurodegenerative disorders associated with oxidative stress and neuroinflammation. An effective PET radioligand for imaging cPLA2α in living brain might prove useful for biomedical research, especially on neuroinflammation. We selected four high‐affinity (IC₅₀ 2.1–12 nm ) indole‐5‐carboxylic acid‐based inhibitors of cPLA2α, namely 3‐isobutyryl‐1‐(2‐oxo‐3‐(4‐phenoxyphenoxy)propyl)‐1H‐indole‐5‐carboxylic acid ( 1 ); 3‐acetyl‐1‐(2‐oxo‐3‐(4‐(4‐(trifluoromethyl)phenoxy)phenoxy)propyl)‐1H‐indole‐5‐carboxylic acid ( 2 ); 3‐(3‐methyl‐1,2,4‐oxadiazol‐5‐yl)‐1‐(2‐oxo‐3‐(4‐phenoxyphenoxy)propyl)‐1H‐indole‐5‐carboxylic acid ( 3 ); and 3‐(3‐methyl‐1,2,4‐oxadiazol‐5‐yl)‐1‐(3‐(4‐octylphenoxy)‐2‐oxopropyl)‐1H‐indole‐5‐carboxylic acid ( 4 ), for labelling in carboxyl position with carbon‐11 (t_1/2=20.4 min) to provide candidate PET radioligands for imaging brain cPLA2α. Compounds [¹¹C] 1 – 4 were obtained for intravenous injection in adequate overall yields (1.1–5.5 %) from cyclotron‐produced [¹¹C]carbon dioxide and with moderate molar activities (70–141 GBq μmol^?1) through the use of Pd⁰‐mediated [¹¹C]carbon monoxide insertion on iodo precursors. Measured logD_7.4 values were within a narrow moderate range (1.9–2.4). After intravenous injection of [¹¹C] 1 – 4 in mice, radioactivity uptakes in brain peaked at low values (≤0.8 SUV) and decreased by about 90 % over 15 min. Pretreatments of the mice with high doses of the corresponding non‐radioactive ligands did not alter brain time–activity curves. Brain uptakes of radioactivity after administration of [¹¹C] 1 to wild‐type and P‐gp/BCRP dual knock‐out mice were similar (peak 0.4 vs. 0.5 SUV), indicating that [¹¹C] 1 and others in this structural class, are not substrates for efflux transporters.     

Gold‐Catalysis: Highly Efficient and Regio‐Selective Carbonyl Migration in Alkynyl‐Substituted Indole‐3‐Carboxamides Leading to Azepino[3,4‐b]indol‐1‐ones

An unprecedented rearrangement/anellation sequence allows the clean synthesis of azepino[3,4‐b]indol‐1‐ones from readily available starting materials. Alkyne‐substituted indole‐3‐carboxamides were prepared and converted to azepino[3,4‐b]indol‐1‐ones by the SPhosAuNTf₂ catalyst (SPhos=2‐dicyclohexylphosphino‐2′,6′‐dimethoxybiphenyl). The new connectivity, which involves an unprecedented 3,2‐shift of an acylamino group for the product formation, was proven by a crystal structure analysis.     

Catalytic performance of methacrylate‐based poly‐4‐(dialkylamino)‐pyridines: activity prediction via NMR shifts

The synthesis of the 4‐(dialkylamino)pyridine derivative 3‐(4‐(pyridin‐4‐yl)piperazin‐1‐yl)propyl methacrylate and its copolymerization with n‐butyl methacrylate are presented. The catalytic activity was evaluated in the acylation of tert‐butanol with acetic anhydride yielding tert‐butyl acetate. It is observed that the activity of polymer‐attached 4‐(dimethylamino)pyridine analogues correlates remarkably well with the chemical shift of the β‐pyridyl protons. Differences in catalytic efficiency result from distinct electronic densities of the pyridine ring, while embedding the catalytically active moiety into a polymeric structure has nearly no deleterious effect on the performance. © 2015 Society of Chemical Industry     

Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands

Inhibition of adenosine A_2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A_2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A_2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A_2AR (K_i=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).     

Copper‐Assisted Click Reactions for Activity‐Based Proteomics: Fine‐Tuned Ligands and Refined Conditions Extend the Scope of Application

Copper‐catalysed alkyne–azide 1,3‐dipolar cycloaddition (CuAAC) is the predominantly used bioconjugation method in the field of activity‐based protein profiling (ABPP). Several limitations, however, including conversion efficiency, protein denaturation and buffer compatibility, restrict the scope of established procedures. We introduce an ABPP customised click methodology based on refined CuAAC conditions together with new accelerating copper ligands. A screen of several triazole compounds revealed the cationic quaternary {3‐[4‐({bis[(1‐tert‐butyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]amino}methyl)‐1H‐1,2,3‐triazol‐1‐yl]propyl}trimethylammonium trifluoroacetate (TABTA) to be a superior ligand. TABTA exhibited excellent in vitro conjugation kinetics and optimal ABPP labelling activity while almost exclusively preserving the native protein fold. The application of this CuAAC‐promoting system is amenable to existing protocols with minimal perturbations and is even compatible with previously unusable buffer systems such as Tris ? HCl.     

Heme Oxygenase Inhibition by 1‐Aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and Their Derivatives

Previous studies by our research group have been concerned with the design of selective inhibitors of heme oxygenases (HO‐1 and HO‐2). The majority of these were based on a four‐carbon linkage of an azole, usually an imidazole, and an aromatic moiety. In the present study, we designed and synthesized a series of inhibition candidates containing a shorter linkage between these groups, specifically, a series of 1‐aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and their derivatives. As regards HO‐1 inhibition, the aromatic moieties yielding best results were found to be halogen‐substituted residues such as 3‐bromophenyl, 4‐bromophenyl, and 3,4‐dichlorophenyl, or hydrocarbon residues such as 2‐naphthyl, 4‐biphenyl, 4‐benzylphenyl, and 4‐(2‐phenethyl)phenyl. Among the imidazole‐ketones, five ( 36 – 39 , and 44 ) were found to be very potent (IC₅₀<5 μM ) toward both isozymes. Relative to the imidazole‐ketones, the series of corresponding triazole‐ketones showed four compounds ( 54 , 55 , 61 , and 62 ) having a selectivity index >50 in favor of HO‐1. In the case of the azole‐dioxolanes, two of them ( 80 and 85 ), each possessing a 2‐naphthyl moiety, were found to be particularly potent and selective HO‐1 inhibitors. Three non‐carbonyl analogues ( 87 , 89 , and 91 ) of 1‐(4‐chlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone were found to be good inhibitors of HO‐1. For the first time in our studies, two azole‐based inhibitors ( 37 and 39 ) were found to exhibit a modest selectivity index in favor of HO‐2. The present study has revealed additional candidates based on inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications.     

Sigma‐2 Receptor Agonists as Possible Antitumor Agents in Resistant Tumors: Hints for Collateral Sensitivity

With the aim of contributing to the development of novel antitumor agents, high‐affinity σ₂ receptor agonists were developed, with 6,7‐dimethoxy‐2‐[4‐[1‐(4‐fluorophenyl)‐1H‐indol‐3‐yl]butyl]‐1,2,3,4‐tetrahydroisoquinoline ( 15 ) and 9‐[4‐(6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinolin‐2‐yl)butyl]‐9H‐carbazole ( 25 ) showing exceptional selectivity for the σ₂ subtype. Most of the compounds displayed notable antiproliferative activity in human MCF7 breast adenocarcinoma cells, with similar activity in the corresponding doxorubicin‐resistant MCF7adr cell line. Surprisingly, a few compounds, including 25 , displayed enhanced activity in MCF7adr cells over parent cells, recalling the phenomenon of collateral sensitivity, which is under study for the treatment of drug‐resistant tumors. All of the compounds showed interaction with P‐glycoprotein (P‐gp), and 15 and 25 , with the greatest activity, were able to revert P‐gp‐mediated resistance and reestablish the antitumor effect of doxorubicin in MCF7adr cells. We therefore identified a series of σ₂ receptor agonists endowed with intriguing antitumor properties; these compounds deserve further investigation for the development of alternate strategies against multidrug‐ resistant cancers.     

Isoxazole‐Based‐Scaffold Inhibitors Targeting Cyclooxygenases (COXs)

A new set of cyclooxygenase (COX) inhibitors endowed with an additional functionality was explored. These new compounds also contained either rhodamine 6G or 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline, two moieties typical of efflux pump substrates and inhibitors, respectively. Among all the synthesized compounds, two new COX inhibitors with opposite selectivity were discovered: compound 8 [N‐(9‐{2‐[(4‐{2‐[3‐(5‐chlorofuran‐2‐yl)‐4‐phenylisoxazol‐5‐yl]acetamido}butyl)carbamoyl]phenyl‐6‐(ethylamino)‐2,7‐dimethyl‐3H‐xanthen‐3‐ylidene}ethanaminium chloride] was found to be a selective COX‐1 inhibitor, whereas 17 (2‐[3,4‐bis(4‐methoxyphenyl)isoxazol‐5‐yl]‐1‐[6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2‐(1H)‐yl]ethanone) was found to be a sub‐micromolar selective COX‐2 inhibitor. However, both were shown to interact with P‐glycoprotein. Docking experiments helped to clarify the molecular aspects of the observed COX selectivity.     

Synthesis and Evaluation of N‐Phenylpyrrolamides as DNA Gyrase B Inhibitors

ATP‐competitive inhibitors of DNA gyrase and topoisomerase IV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N‐phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from E. coli and Staphylococcus aureus. Antibacterial activities were studied against Gram‐positive and Gram‐negative bacterial strains. The most potent compound displayed an IC₅₀ of 47 nm against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 μm against the Gram‐positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux‐pump‐deficient E. coli strain (MIC=6.25 μm ) and against wild‐type E. coli in the presence of efflux pump inhibitor PAβN (MIC=3.13 μm ). Here we describe new findings regarding the structure–activity relationships of N‐phenylpyrrolamide DNA gyrase B inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds.     

Glucocerebrosidase Enhancers for Selected Gaucher Disease Genotypes by Modification of α‐1‐C‐Substituted Imino‐D‐xylitols (DIXs) by Click Chemistry

A series of hybrid analogues was designed by combination of the iminoxylitol scaffold of parent 1C9‐DIX with triazolylalkyl side chains. The resulting compounds were considered potential pharmacological chaperones in Gaucher disease. The DIX analogues reported here were synthesized by CuAAC click chemistry from scaffold 1 (α‐1‐C‐propargyl‐1,5‐dideoxy‐1,5‐imino‐D ‐xylitol) and screened as imiglucerase inhibitors. A set of selected compounds were tested as β‐glucocerebrosidase (GBA1) enhancers in fibroblasts from Gaucher patients bearing different genotypes. A number of these DIX compounds were revealed as potent GBA1 enhancers in genotypes containing the G202R mutation, particularly compound DIX‐28 (α‐1‐C‐[(1‐(3‐trimethylsilyl)propyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl]‐1,5‐dideoxy‐1,5‐imino‐D ‐xylitol), bearing the 3‐trimethylsilylpropyl group as a new surrogate of a long alkyl chain, with approximately threefold activity enhancement at 10 nM . Despite their structural similarities with isofagomine and with our previously reported aminocyclitols, the present DIX compounds behaved as non‐competitive inhibitors, with the exception of the mixed‐type inhibitor DIX‐28.     

Rational Design,Synthesis, and Potency of N‐Substituted Indoles,Pyrroles, and Triarylpyrazoles as Potential Fructose 1,6‐Bisphosphatase Inhibitors

By using computer modeling and lead structures from our earlier SAR results, a broad variety of pyrrole‐, indole‐, and pyrazole‐based compounds were evaluated as potential fructose 1,6‐bisphosphatase (FBPase) inhibitors. The docking studies yielded promising structures, and several were selected for synthesis and FBPase inhibition assays: 1‐[4‐(trifluoromethyl)benzoyl]‐1H‐indole‐5‐carboxamide, 1‐(α‐naphthalen‐1‐ylsulfonyl)‐7‐nitro‐1H‐indole, 5‐(4‐carboxyphenyl)‐3‐phenyl‐1‐[3‐(trifluoromethyl)phenyl]‐1H‐pyrazole, 1‐(4‐carboxyphenylsulfonyl)‐1H‐pyrrole, and 1‐(4‐carbomethoxyphenylsulfonyl)‐1H‐pyrrole were synthesized and tested for inhibition of FBPase. The IC₅₀ values were determined to be 0.991 and 1.34 μM , and 575, 135, and 32 nM , respectively. The tested compounds were significantly more potent than the natural inhibitor AMP (4.0 μM ) by an order of magnitude; indeed, the best inhibitor showed an IC₅₀ value toward FBPase more than two orders of magnitude better than that of AMP. This level of activity is virtually the same as that of the best currently known FBPase inhibitors. This work shows that such indole derivatives are promising candidates for drug development in the treatment of type II diabetes.     

Discovery of 7‐Aryl‐Substituted (1,5‐Naphthyridin‐4‐yl)ureas as Aurora Kinase Inhibitors

As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7‐aryl‐1,5‐naphthyridin‐4‐yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5‐Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1‐cyclopropyl‐3‐[7‐(1‐methyl‐1H‐pyrazol‐4‐yl)‐1,5‐naphthyridin‐4‐yl]urea ( 49 ), displayed IC₅₀ values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer‐related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.     

Efficient and Practical Syntheses of (R)‐(5‐Amino‐2,3‐dihydro‐1H‐inden‐2‐yl)‐carbamic Acid Methyl Ester

Efficient and practical syntheses of enantiomerically pure (R)‐(5‐amino‐2,3‐dihydro‐1H‐inden‐2‐yl)‐carbamic acid methyl ester ( 1 ) by three different routes via the resolution of different aminoindan intermediates are described.