Targeting Asexual and Sexual Blood Stages of the Human Malaria Parasite P. falciparum with 7-Chloroquinoline-Based 1,2,3-Triazoles

Novel 4-amino-7-chloroquinoline-based 1,2,3-triazole hybrids were synthesised in good yields by Cu^I-catalysed Huisgen 1,3-dipolar cycloaddition reactions of 2-azido-N-(7-chloroquinolin-4-ylaminoalkyl)acetamides with various terminal alkynes. These new hybrids were screened in vitro against asexual blood stages of the chloroquine-sensitive 3D7 strain of P. falciparum. The most active compounds were further screened against asexual and sexual stages (gametocytes) of the chloroquine-resistant RKL-9 strain of P. falciparum. Although all compounds were less potent than chloroquine against the 3D7 strain, the three best compounds were appreciably more active than chloroquine against the RKL-9 strain, displaying IC₅₀ values of <100 nm , with one of them having an IC₅₀ of 2.94 nm . Further, the lead compounds were gametocytocidal with IC₅₀ values in the micromolar range, and were observed to induce morphological deformations in mature gametocytes. Most compounds demonstrated little or no cytotoxicity and exhibited good selectivity indices. The most active compounds represent promising candidates for further evaluation of their schizonticidal and gametocytocidal potential.     

N‐Cinnamoylation of Antimalarial Classics: Quinacrine Analogues with Decreased Toxicity and Dual‐Stage Activity

Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N‐cinnamoylated quinacrine surrogates, 9‐(N‐cinnamoylaminobutyl)‐amino‐6‐chloro‐2‐methoxyacridines, is reported. The compounds were found to be highly potent against both blood‐stage P. falciparum, chloroquine‐sensitive 3D7 (IC₅₀=17.0–39.0 nM ) and chloroquine‐resistant W2 and Dd2 strains (IC₅₀=3.2–41.2 and 27.1–131.0 nM , respectively), and liver‐stage P. berghei (IC₅₀=1.6–4.9 μM ) parasites. These findings bring new hope for the possible future “rise of a fallen angel” in antimalarial chemotherapy, with a potential resurgence of quinacrine‐related compounds as dual‐stage antimalarial leads.     

Design,Synthesis, Structure-Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl-1,2,4-Trioxanes as Potent Antiplasmodial as well as Anticancer Agents

A novel series of synthetic functionalized arylvinyl-1,2,4-trioxanes ( 8 a – p ) has been prepared and assessed for their in vitro antiplasmodial activity against the chloroquine-resistant Pf INDO strain of Plasmodium falciparum by using a SYBR green-I fluorescence assay. Compounds 8 g (IC₅₀=0.051 μM; SI=589.41) and 8 m (IC₅₀=0.059 μM; SI=55.93) showed 11-fold and >9-fold more potent antiplasmodial activity, respectively, as compared to chloroquine (IC₅₀=0.546 μM; SI=36.63). Different in silico docking studies performed on many target proteins revealed that the most active arylvinyl-1,2,4-trioxanes ( 8 g and 8 m ) showed dihydrofolate reductase (DHFR) binding affinities on a par with those of chloroquine and artesunate. The in vitro cytotoxic potentials of 8 a – p were also evaluated against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS-2B) and liver (LO2) cell lines. Following screening, five derivatives viz. 8 a , 8 h , 8 l , 8 m and 8 o (IC₅₀=1.65–31.7 μM; SI=1.08–10.96) were found to show potent cytotoxic activity against (A549) lung cancer cell lines, with selectivity superior to that of the reference compounds artemisinin (IC₅₀=100 μM), chloroquine (IC₅₀=100 μM) and artesunic acid (IC₅₀=9.85 μM; SI=0.76). In fact, the most active 4-naphthyl-substituted analogue 8 l (IC₅₀=1.65 μM; SI >10) exhibited >60 times more cytotoxicity than the standard reference, artemisinin, against A549 lung cancer cell lines. In silico docking studies of the most active anticancer compounds, 8 l and 8 m , against EGFR were found to validate the wet lab results. In summary, a new series of functionalized aryl-vinyl-1,2,4-trioxanes ( 8 a – p ) has been shown to display dual potency as promising antiplasmodial and anticancer agents.     

Nucleobase Modified Adefovir (PMEA) Analogues as Potent and Selective Inhibitors of Adenylate Cyclases from Bordetella pertussis and Bacillus anthracis

A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non‐cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell‐based assays. The 8‐aza‐7‐deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC₅₀=16 nm ) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell‐free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC₅₀ values ranging from 0.5 to 21 nm ). Moreover, 7‐halo‐7‐deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC₅₀ values ranging from 4.1 to 5.6 μm in HEK293 cell‐based assays.     

3, 4‐Dihydroxymandelic acid amides of alkylamines as antioxidants for lipids

The antioxidative and radical scavenging activity of the 3, 4‐dihydroxymandelic acid (DHMA) amides of hexylamine, 2‐ethylhexylamine, octylamine, and cyclohexylamine was determined by several physicochemical test systems. The amides were synthesized by protecting group‐free coupling of in situ prepared N‐hydroxysuccinimidylester of DHMA and the amines. The radical scavenging activity was determined using the DPPH (2, 2‐diphenyl‐1‐picrylhydrazyl) method and by quenching superoxide anions generated using a horse radish peroxidase/H₂O₂ system. In the DPPH assay, all amides show higher radical scavenging activity (EC₅₀ 0.09‐0.12 mol/mol_DPPH) compared to the standard antioxidants ascorbic acid (EC₅₀ 0.27 mol/mol_DPPH) and tocopherol (EC₅₀ 0.25 mol/mol_DPPH). The amides are also more potent superoxide radical scavengers (IC₅₀ < 600 nm) than standard ascorbic acid (IC₅₀ 700 nm). Activity against lipid peroxidation was determined by accelerated autoxidation of highly unsaturated oils and squalene using the Rancimat. Again, the antioxidative potentials of the DHMA amides against lipid oxidation as determined by the Rancimat, are at least equal or higher compared to the standard lipid antioxidants tocopherol, BHT, BHA, and ascorbylpalmitate (concentration in soybean oil 0.05%, all other oils 0.025%, squalene 0.005%). In squalene, an equi‐amount mixture of DHMA octylamide and α‐tocopherol shows a synergistic effect. Last but not least, the amides are able to protect an emulsion of linoleic acid/β‐carotene against oxidation initiated by N, N‐azodiisobutyramidine dihydrochloride (IC₅₀ 0.19‐0.77 mmol/l, ascorbic acid > 0.9, tocopherol 0.08). The DHMA octylamide in combination with ascorbic acid shows a synergistic antioxidative effect in the emulsion model. In conclusion, the new alkylamides of DHMA are easy to synthesize, potent radical scavengers and protect lipids, in particular the highly unsaturated, both in bulk and in emulsions against autoxidation.     

Aryl Bis‐Sulfonamide Inhibitors of IspF from Arabidopsis thaliana and Plasmodium falciparum

2‐Methylerythritol 2,4‐cyclodiphosphate synthase (IspF) is an essential enzyme for the biosynthesis of isoprenoid precursors in plants and many human pathogens. The protein is an attractive target for the development of anti‐infectives and herbicides. Using a photometric assay, a screen of 40 000 compounds on IspF from Arabidopsis thaliana afforded symmetrical aryl bis‐sulfonamides that inhibit IspF from A. thaliana (AtIspF) and Plasmodium falciparum (PfIspF) with IC₅₀ values in the micromolar range. The ortho‐bis‐sulfonamide structural motif is essential for inhibitory activity. The best derivatives obtained by parallel synthesis showed IC₅₀ values of 1.4 μm against PfIspF and 240 nm against AtIspF. Substantial herbicidal activity was observed at a dose of 2 kg ha^?1. Molecular modeling studies served as the basis for an in silico search targeted at the discovery of novel, non‐symmetrical sulfonamide IspF inhibitors. The designed compounds were found to exhibit inhibitory activities in the double‐digit micromolar IC₅₀ range.     

Effects of the Surface Densities of Glycoclusters on the Determination of Their IC50 and Kd Value Determination by Using a Microarray

Pseudomonas aeruginosa (PA) is an opportunistic bacterium involved in 10–30 % of nosocomial diseases. It causes severe lung injury to cystic fibrosis patients, often leading to patient death. PA strains are multidrug resistant, thus making the design of new therapeutics a challenge for public health. One promising therapeutic option is to design glycoclusters that target the virulence factor of PA. LecA is a galactose‐specific lectin that might be involved in adhesion and biofilm formation by PA. The DNA‐directed immobilization (DDI) microarray is a powerful tool for screening and understanding of structure–activity relationships between glycoclusters and lectins. High‐throughput and multiplexed analysis of lectin–glycocluster interactions on a DDI microarray allows measurement of IC₅₀ and dissociation constant (K_d) values with minute amounts of material. In order to study the robustness of the DDI microarray in determination of IC₅₀ and K_d values, the impact of glycocluster surface density was investigated. The data obtained show that measured IC₅₀ values were influenced by glycocluster surface density: as the density of glycoclusters increases, the measured IC₅₀ values increase too. In contrast, the measured K_d values were not affected by glycocluster surface density, provided that the experimental conditions allow interaction between glycocluster and lectin at single‐molecule level (no surface cluster effect).     

Synthesis and Evaluation of New Antagonists of Bacterial Quorum Sensing in Vibrio harveyi

Bacterial quorum sensing has received much attention in recent years because of its relevance to pathological events such as biofilm formation. Based on the structures of two lead inhibitors (IC₅₀: 35–55 μM ) against autoinducer‐2‐mediated quorum sensing identified through virtual screening, we synthesized 39 analogues and examined their inhibitory activities. Twelve of these new analogues showed equal or better inhibitory activities than the lead inhibitors. The best compound showed an IC₅₀ value of ～6 μM in a whole‐cell assay using Vibrio harveyi as the model organism. The structure–activity relationship is discussed herein.     

Aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole and vorozole templates

Concurrent inhibition of aromatase and steroid sulfatase (STS) may provide a more effective treatment for hormone‐dependent breast cancer than monotherapy against individual enzymes, and several dual aromatase–sulfatase inhibitors (DASIs) have been reported. Three aromatase inhibitors with sub‐nanomolar potency, better than the benchmark agent letrozole, were designed. To further explore the DASI concept, a new series of letrozole‐derived sulfamates and a vorozole‐based sulfamate were designed and biologically evaluated in JEG‐3 cells to reveal structure–activity relationships. Amongst achiral and racemic compounds, 2‐bromo‐4‐(2‐(4‐cyanophenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)ethyl)phenyl sulfamate is the most potent DASI (aromatase: IC₅₀=0.87 nM ; STS: IC₅₀=593 nM ). The enantiomers of the phenolic precursor to this compound were separated by chiral HPLC and their absolute configuration determined by X‐ray crystallography. Following conversion to their corresponding sulfamates, the S‐(+)‐enantiomer was found to inhibit aromatase and sulfatase most potently (aromatase: IC₅₀=0.52 nM ; STS: IC₅₀=280 nM ). The docking of each enantiomer and other ligands into the aromatase and sulfatase active sites was also investigated.     

Synthesis of α‐Branched Acyclic Nucleoside Phosphonates as Potential Inhibitors of Bacterial Adenylate Cyclases

Inhibition of Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF), key virulence factors with adenylate cyclase activity, represents a potential method for treating or preventing toxemia related to whooping cough and anthrax, respectively. Novel α‐branched acyclic nucleoside phosphonates (ANPs) having a hemiaminal ether moiety were synthesized as potential inhibitors of bacterial adenylate cyclases. ANPs prepared as bisamidates were not cytotoxic, but did not exhibit any profound activity (IC₅₀>10 μm ) toward ACT in J774A.1 macrophages. The apparent lack of activity of the bisamidates is speculated to be due to the inefficient formation of the biologically active species (ANPpp) in the cells. Conversely, two 5‐haloanthraniloyl‐substituted ANPs in the form of diphosphates were shown to be potent ACT and EF inhibitors with IC₅₀ values ranging from 55 to 362 nm .     

Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists

To determine the eutomers of potent GluN2B‐selective N‐methyl‐d ‐aspartate (NMDA) receptor antagonists with a 3‐benzazepine scaffold, 7‐benzyloxy‐3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols (S)‐ 2 and (R)‐ 2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers of (S)‐ 2 and (R)‐ 2 provided the enantiomeric phenols (S)‐ 3 and (R)‐ 3 [3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine‐1,7‐diol] and methyl ethers (S)‐ 4 and (R)‐ 4 . All enantiomers were obtained with high enantiomeric purity (≥99.7 % ee). The absolute configurations were determined by CD spectroscopy. R‐configured enantiomers turned out to be the eutomers in receptor binding studies and two‐electrode voltage clamp experiments. The most promising ligand of this compound series is the R‐configured phenol (R)‐ 3 , displaying high GluN2B affinity (K_i=30 nm ), high inhibition of ion flux (IC₅₀=61 nm ), and high cytoprotective activity (IC₅₀=93 nm ). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.     

Design,Synthesis, and in vitro Biological Evaluation of 3,5‐Dimethylisoxazole Derivatives as BRD4 Inhibitors

BRD4 has been identified as a potential target for blocking proliferation in a variety of cancer cell lines. In this study, 3,5‐dimethylisoxazole derivatives were designed and synthesized with excellent stability in liver microsomes as potent BRD4 inhibitors, and were evaluated for their BRD4 inhibitory activities in vitro. Gratifyingly, compound 11 h [3‐((1‐(2,4‐difluorophenyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl)‐6‐(3,5‐dimethylisoxazol‐4‐yl)‐4‐phenyl‐3,4‐dihydroquinazolin‐2(1H)‐one] exhibited robust potency for BRD4(1) and BRD4(2) inhibition with IC₅₀ values of 27.0 and 180 nm , respectively. Docking studies were performed to illustrate the strategy of modification and analyze the conformation in detail. Furthermore, compound 11 h was found to potently inhibit cell proliferation in the BRD4‐sensitive cell lines HL‐60 and MV4‐11, with IC₅₀ values of 0.120 and 0.09 μm , respectively. Compound 11 h was further demonstrated to downregulate c‐Myc levels in HL‐60 cells. In summary, these results suggest that compound 11 h is most likely a potential BRD4 inhibitor and is a lead compound for further investigations.     

8‐Benzyltetrahydropyrazino[2,1‐f]purinediones: Water‐Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases

8‐Benzyl‐substituted tetrahydropyrazino[2,1‐f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual‐target‐directed A₁/A_2A adenosine receptor antagonists were identified. Several compounds showed triple‐target inhibition; one of the best compounds was 8‐(2,4‐dichloro‐5‐fluorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐f]purine‐2,4(1H,3H)‐dione ( 72 ) (human AR: K_i A₁ 217 nM , A_2A 233 nM ; IC₅₀ MAO‐B: 508 nM ). Dichlorinated compound 36 [8‐(3,4‐dichlorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐f]purine‐2,4(1H,3H)‐dione] was found to be the best triple‐target drug in rat (K_i A₁ 351 nM , A_2A 322 nm; IC₅₀ MAO‐B: 260 nM ), and may serve as a useful tool for preclinical proof‐of‐principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease‐modifying treatment of neurodegenerative diseases are expected to show advantages over single‐target therapeutics.     

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.     

Design,Synthesis, and Evaluation of 2‐Amino‐6‐nitrobenzothiazole‐Derived Hydrazones as MAO Inhibitors: Role of the Methylene Spacer Group

A series of 2‐amino‐6‐nitrobenzothiazole‐derived extended hydrazones were designed, synthesized, and investigated for their ability to inhibit monoamine oxidase A and B (MAO‐A/MAO‐B). The compounds were found to exhibit inhibitory activities in the nanomolar to micromolar range. Some of the compounds showed excellent potency and selectivity against the MAO‐B isoform. N′‐(5‐Chloro‐2‐oxoindolin‐3‐ylidene)‐2‐(6‐nitrobenzothiazol‐2‐ylamino)acetohydrazide (compound 31 ) showed the highest MAO‐B inhibitory activity (IC₅₀=1.8±0.3 nm , selectivity index [SI]=766.67), whereas compound 6 [N′‐(1‐(4‐bromophenyl)ethylidene)‐2‐(6‐nitrobenzothiazol‐2‐ylamino)acetohydrazide] was found to be the most active MAO‐A inhibitor (IC₅₀=0.42±0.003 μm ). Kinetic studies revealed that compounds 6 and 31 exhibit competitive‐type reversible inhibition against both MAO‐A and MAO‐B, respectively. Structure–activity relationship (SAR) studies disclosed several structural aspects significant for potency and the contribution of the methylene spacer toward MAO‐B inhibitory potency, with minimal or no neurotoxicity. Molecular modeling studies yielded a good correlation between experimental and theoretical inhibitory data. Binding pose analysis revealed the significance of cumulative effects of π–π stacking and hydrogen bond interactions for effective stabilization of virtual ligand–protein complexes. Further optimization studies of compound 31 , including co‐crystallization of inhibitor–MAO‐B complexes, are essential to develop these compounds as potential therapeutic agents for MAO‐B‐associated neurodegenerative diseases.     

Asymmetric Synthesis and Biological Evaluation of Glycosidic Prodrugs for a Selective Cancer Therapy

A severe limitation in cancer therapy is the often insufficient differentiation between malign and benign tissue using known chemotherapeutics. One approach to decrease side effects is antibody‐directed enzyme prodrug therapy (ADEPT). We have developed new glycosidic prodrugs such as (?)‐(1S)‐ 26 b based on the antibiotic (+)‐duocarmycin SA ((+)‐ 1 ) with a QIC₅₀ value of 3500 (QIC₅₀=IC₅₀ of prodrug/IC₅₀ of prodrug+enzyme) and an IC₅₀ value for the corresponding drug (prodrug+enzyme) of 16 pM . The asymmetric synthesis of the precursor (?)‐(1S)‐ 19 was performed by arylation of the enantiomerically pure epoxide (+)‐(S)‐ 29 (≥98 % ee).     

BODIPY‐Appended 2‐(2‐Pyridyl)benzimidazole Platinum(II) Catecholates for Mitochondria‐Targeted Photocytotoxicity

Platinum(II) complexes of the type [Pt(L)(cat)] ( 1 and 2 ), in which H₂cat is catechol and L represents two 2‐(2‐pyridyl)benzimidazole ligands with 4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene (BODIPY) pendants, were synthesized to achieve mitochondria‐targeted photocytotoxicity. The complexes showed strong absorptions in the range λ=510–540 nm. Complex 1 exhibited intense emission at λ=525 nm in 1 % DMSO/water solution (fluorescence quantum yield of 0.06). Nanosecond transient absorption spectral features indicated an enhanced population of the triplet excited state in di‐iodinated complex 2 . The generation of singlet oxygen by complex 2 upon exposure to visible light, as evidenced from experiments with 1,3‐diphenylisobenzofuran, is suitable for photodynamic therapy because of the remarkable photosensitizing ability. The complexes resulted in excellent photocytotoxicity in HaCaT cells (half maximal inhibitory concentration IC₅₀≈3 μm , λ=400–700 nm, light dose=10 J cm^?2), but they remained non‐toxic in the dark (IC₅₀>100 μm ). Confocal microscopy images of 1 and Pt estimation from isolated mitochondria showed colocalization of the complexes in the mitochondria. Complex 2 displayed generation of reactive oxygen species induced by visible light, disruption of the mitochondrial membrane potential, and apoptosis.     

Bicyclic Derivatives of the Potent Dual Aromatase–Steroid Sulfatase Inhibitor 2‐Bromo‐4‐{[(4‐cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenylsulfamate: Synthesis,SAR, Crystal Structure,and in vitro and in vivo Activities

The design and synthesis of a series of bicyclic ring containing dual aromatase–sulfatase inhibitors (DASIs) based on the aromatase inhibitor (AI) 4‐[(4‐bromobenzyl)(4H‐1,2,4‐triazol‐4‐yl)amino]benzonitrile are reported. Biological evaluation with JEG‐3 cells revealed structure–activity relationships. The X‐ray crystal structure of sulfamate 23 was determined, and selected compounds were docked into the aromatase and steroid sulfatase (STS) crystal structures. In the sulfamate‐containing series, compounds containing a naphthalene ring are both the most potent AI ( 39 , IC_{50 AROM}=0.25 nM ) and the best STS inhibitor ( 31 , IC_{50 STS}=26 nM ). The most promising DASI is 39 (IC_{50 AROM}=0.25 nM , IC_{50 STS}=205 nM ), and this was evaluated orally in vivo at 10 mg kg^?1, showing potent inhibition of aromatase (93 %) and STS (93 %) after 3 h. Potent aromatase and STS inhibition can thus be achieved with a DASI containing a bicyclic ring system; development of such a DASI could provide an attractive new option for the treatment of hormone‐dependent breast cancer.     

MAO Inhibitory Activity of 2‐Arylbenzofurans versus 3‐Arylcoumarins: Synthesis,in vitro Study,and Docking Calculations

Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3‐arylcoumarin derivatives were previously described as interesting selective MAO‐B inhibitors. Preserving the trans‐stilbene structure, a series of 2‐arylbenzofuran and corresponding 3‐arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO‐A and MAO‐B. In general, both types of derivatives were found to be selective MAO‐B inhibitors, with IC₅₀ values in the nano‐ to micromolar range. 5‐Nitro‐2‐(4‐methoxyphenyl)benzofuran ( 8 ) is the most active compound of the benzofuran series, presenting MAO‐B selectivity and reversible inhibition (IC₅₀=140 nM ). 3‐(4′‐Methoxyphenyl)‐6‐nitrocoumarin ( 15 ), with the same substitution pattern as that of compound 8 , was found to be the most active MAO‐B inhibitor of the coumarin series (IC₅₀=3 nM ). However, 3‐phenylcoumarin 14 showed activity in the same range (IC₅₀=6 nM ), is reversible, and also severalfold more selective than compound 15 . Docking experiments for the most active compounds into the MAO‐B and MAO‐A binding pockets highlighted different interactions between the derivative classes (2‐arylbenzofurans and 3‐arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds.     

Design,Synthesis, and Biological Evaluation of Pyrazoline‐Based Hydroxamic Acid Derivatives as Aminopeptidase N (APN) Inhibitors

Aminopeptidase N (APN) has been recognized as a target for anticancer treatment due to its overexpression on diverse malignant tumor cells and association with cancer invasion, metastasis and angiogenesis. Herein we describe the synthesis, biological evaluation, and structure–activity relationship study of two new series of pyrazoline analogues as APN inhibitors. Among these compounds, 5‐(2‐(2‐(hydroxyamino)‐2‐oxoethoxy)phenyl)‐3‐phenyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamide (compound 13 e ) showed the best APN inhibition with an IC₅₀ value of 0.16±0.02 μm , which is more than one order of magnitude lower than that of bestatin (IC₅₀=9.4±0.5 μm ). Moreover, compound 13 e was found to inhibit the proliferation of diverse carcinoma cells and to show potent anti‐angiogenesis activity. At the same concentration, compound 13 e presents significantly higher anti‐angiogenesis activity than bestatin in human umbilical vein endothelial cells (HUVECs) capillary tube formation assays. The putative binding mode of 13 e in the active site of APN is also discussed.