Compounds 1p Research Articles

The discovery of aryl-2-nitroethyl triamino pyrimidines as anti-Trypanosoma brucei agents

Pteridine reductase 1 (PTR1) is a catalytic protein belonging to the folate metabolic pathway in Trypanosmatidic parasites. PTR1 is a known target for the medicinal chemistry development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. In previous studies, new nitro derivatives were elaborated as PTR1 inhibitors. The compounds showing a diamino-pyrimidine core structure were previously developed but they showed limited efficacy. Therefore, a new class of phenyl-, heteroaryl- and benzyloxy-nitro derivatives based on the 2-nitroethyl-2,4,6-triaminopyrimidine scaffold were designed and tested. The compounds were assayed for their ability to inhibit T. brucei and L. major PTR1 enzymes and for their antiparasitic activity towards T. brucei and L. infantum parasites. To understand the structure-activity relationships of the compounds against TbPTR1, the X-ray crystallographic structure of the 2,4,6-triaminopyrimidine (TAP) was obtained and molecular modelling studies were performed. As a next step, only the most effective compounds against T. brucei were then tested against the amastigote cellular stage of T. cruzi, searching for a broad-spectrum antiprotozoal agent. An early ADME-Tox profile evaluation was performed. The early toxicity profile of this class of compounds was investigated by measuring their inhibition of hERG and five cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), cytotoxicity towards A549 cells and mitochondrial toxicity. Pharmacokinetic studies (SNAP-PK) were performed on selected compounds using hydroxypropyl-β-cyclodextrins (50 % w/v) to preliminarily study their plasma concentration when administered per os at a dose of 20 mg/kg. Compound 1p, showed the best pharmacodynamic and pharmacokinetic properties, can be considered a good candidate for further bioavailability and efficacy studies.

Anti-amoebic activity of a series of benzofuran/benzothiophene derivatives againstAcanthamoeba castellaniibelonging to the T4 genotype

To determine the anti-amoebic activity of benzofuran/benzothiophene-possessing compounds against Acanthamoeba castellanii of the T4 genotype. A series of benzofuran/benzothiophene-possessing compounds were tested for their anti-amoebic activities, in particular, to block encystation and excystation processes in amoebae. Cytotoxicity of the compounds were evaluated using lactate dehydrogenase (LDH) assays. The amoebicidal assay results revealed significant anti-amoebic effects against A. castellanii. Compounds 1p and 1e showed the highest amoebicidal activity, eliminating 68% and 64% of the amoebae, respectively. These compounds remarkably repressed both the encystation and excystation processes in A. castellanii. Furthermore, the selected compounds presented minimal cytotoxic properties against human cells, as well as considerably abridged amoeba-mediated cytopathogenicity when compared to the amoebae alone. Our findings show that benzofuran/benzothiophene derivatives depict potent anti-amoebic activities; thus these compounds should be used as promising and novel agents in the rationale development of therapeutic strategies against Acanthamoeba infections.

Positional scanning of natural product hispidol’s ring-B: discovery of highly selective human monoamine oxidase-B inhibitor analogues downregulating neuroinflammation for management of neurodegenerative diseases

Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative and neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic pathways and neuroinflammatory were addressed. A library of analogues of the natural product hispidol was prepared and evaluated for inhibition of monoamine oxidases (MAOs) isoforms. Several molecules emerged as selective potential MAO B inhibitors. The most promising compounds were further evaluated in vitro for their impact on microglia viability, induced production of proinflammatory mediators and MAO-B inhibition mechanism. Amongst tested compounds, 1p was a safe potent competitive reversible MAO-B inhibitor and inhibitor of microglial production of neuroinflammatory mediators; NO and PGE2. In-silico study provided insights into molecular basis of the observed selective MAO B inhibition. This study presents compound 1p as a promising lead compound for management of neurodegenerative disease.

External Photocatalyst-Free Visible Light-Promoted 1,3-Addition of Perfluoroalkyl Iodides to Vinyldiazoacetates

External Photocatalyst-Free Visible Light-Promoted 1,3-Addition of Perfluoroalkyl Iodides to Vinyldiazoacetates

Chiral Cobalt(II) Complex Catalyzed Asymmetric [2,3]-Sigmatropic Rearrangement of Allylic Selenides with α-Diazo Pyrazoleamides

Organoselenium compounds, due to their high structural diversity, special function, and biological activities, have drawn attention in synthetic chemistry. Herein, a novel example of chiral N,N′-di...

Bioassay of ferulic acid derivatives as influenza neuraminidase inhibitors.

Four series of ferulic acid derivatives were designed, synthesized, and evaluated for their neuraminidase (NA) inhibitory activities against influenza virus H1N1 in vitro. The pharmacological results showed that the majority of the target compounds exhibited moderate influenza NA inhibitory activity, which was also better than that of ferulic acid. The two most potent compounds were 1m and 4a with IC50 values of 12.77 ± 0.47 and 12.96 ± 1.34 μg/ml, respectively. On the basis of the biological results, a preliminary structure-activity relationship (SAR) was derived and discussed. Besides, molecular docking was performed to study the possible interactions of compounds 1p, 2d, 3b, and 4a with the active site of NA. It was found that the 4-OH-3-OMe group and the amide group (CON) of ferulic acid amide derivatives were two key pharmacophores for NA inhibitory activity. It is meaningful to further modify the natural product ferulic acid to improve its influenza NA inhibitory activity.

Synthesis and Evaluation of in vitro Antiplatelet Aggregation Activities of 2-Methoxy-5-Aminobenzamides

Objective: According to the principles of drug design, the structures of picotamide and betrixaban were combined to design novel series of 2-methoxy-5-aminobenzamides. A total of twenty new compounds 1a-1t have been synthesized and evaluated for their antiplatelet aggregation activities in vitro. Methods: In the structural design of target compounds 1a-1t, the betrixaban was retained group characteristics and the picotamide was retained its 1, 3, 4-substitution position. With 2-methoxybenzoic acid as starting material, compounds 1a-1t were synthesized after 5 steps of nitration, acylation, ammoniation, reduction and secondary ammoniation. And their antiplatelet aggregation activities in vitro were assessed by the Born test with ADP, arachidonic acid and collagen as inducing agents, respectively, and with aspirin and picotamide as two reference drugs. Results: The compound 1f (46.14%±0.07) had the highest activity for ADP and its IC50 value was 0.17 µM, far better than the two control drugs aspirin (0.44 µM) and picotamide (0.47 µM). The IC50 value of four compounds 1i (0.24 µM), 1j (0.22 µM), 1r (0.25 µM) and 1t (0.24 µM), displayed higher antiplatelet activities in vitro for AA than aspirin (0.43 µM) and picotamide (0.34 µM). Evaluation of cytotoxicity activity of the compounds against L929 cells line revealed that at lower concentration of 10 µmol·L-1, compound 1p had lower effect on L929 cells, and its cell survival rate (88.24%±4.16) was higher than that (82.35%±4.16) of picotamide. Conclusion: Novel series of 2-methoxy-5-aminobenzamides has shown higher in vitro antiplatelet activities and lower effect on L929 cells at lower concentration.

Synthesis and in vitro activities on anti-platelet aggregation of 4-methoxyisophthalamides

A series of 4-methoxyisophthalamides (1d–1w) were designed and synthesized and their chemical structures were confirmed by IR, MS, 1H-NMR, and 13C-NMR. The in vitro on anti-platelet aggregation activities of these compounds were assessed by using Born method. Compounds with higher activities were selected to continue research via Cell Counting Kit-8 (CCK-8) assays of their cytotoxicities. Biological screening results revealed four compounds 1h, 1i, 1q, and 1v exhibited higher activities than the control drugs on against the platelet aggregation induced by adenosine triphosphate (ADP). Moreover, compounds 1p and 1q exhibited higher in vitro activities than picotamide induced by collagen at the concentration of 1.3 μM. Compound 1p also possessed anti-platelet aggregation activity superior to the control drug picotamide induced by arachidonic acid (AA) at the concentration of 1.3 μM. At the same time, the result of cytotoxicities exhibited that none of the compounds have significant cytotoxicities. Therefore, 4-methoxyisophthalamides are potential to become novel anti-platelet drugs with high activities and minimum toxicities.

Design and one-pot synthesis of 2-thiazolylhydrazone derivatives as influenza neuraminidase inhibitors.

Two series of novel 2-thiazolylhydrazone derivatives were designed and synthesized via one-pot reaction of benzaldehyde derivatives, [Formula: see text]-haloketones and thiosemicarbazide. The structures of compounds 1 and 2 were characterized by [Formula: see text] NMR and [Formula: see text] NMR, and compound 1g was further confirmed by X-ray crystallography. All of the target compounds were evaluated for their NA inhibitory activity against influenza viral neuraminidase (H1N1) in vitro, and the results showed that many compounds exhibited moderate to strong inhibitory activities against influenza viral neuraminidase (H1N1). Among them, compounds 1p, 1q and 2c showed the most potent inhibitory activities with [Formula: see text] values ranging from 10.50 to [Formula: see text]. Our structure-activity relationship analysis indicated that 2-thiazolylhydrazone is an effective scaffold for NA inhibitors and that introducing an ethoxycarbonyl group to the 5-position of thiazole ring could enhance inhibitory potency. Molecular docking was performed on the most active compounds 1p and 2c to provide more insight into their mechanism of interaction.

Copper salt-catalyzed formation of a novel series of triazole-spirodienone conjugates with potent anticancer activity.

Copper salt-catalyzed oxidative amination resulted in the formation of a novel series of triazole- spirodienone conjugates, 4-triazolyl-1-oxa-4-azaspiro[4,5]deca-6,9-dien-3,8-diones and 4-triazolyl-1-oxa-4-azaspiro[4,5]deca-6,9-dien-8-ones. A single crystal of compound 1p among them was grown and analyzed by X-ray crystallography. These compounds were evaluated for their antiproliferative activities against MDA-MB-231, HeLa, A549 and MCF-7 cell lines. Most of them showed moderate to high anticancer potency in the four cancer cell lines. The discovery of the triazole-spirodienone conjugates as cytotoxic agents against cancer cells may open up a new field in which these novel small molecules could be further explored as promising anticancer agents.

Synthesis, structure and properties of cholesterol-based A(LS)2- and A(LS)3-type gelators without hydrogen bond linkers

Dicholesteryl isophthalate (1m), dicholesteryl terephthalate (1p) and tricholesteryl trimesate (2) were synthesized as new cholesterol-based A(LS)n-type gelators (n=2 and 3) without hydrogen bond linkers. Their molecular structural details were investigated experimentally by 1H and 13C NMR, UV–vis and IR spectroscopies and theoretically by DFT calculations. Compounds 1p and 2 have relatively high degrees of symmetry and exhibit efficient gelation abilities, whereas compound 1m could not be gelated in any common organic solvents. The self-assembly behavior of the compound was largely affected by the type of solvent and the number and substitution positions of the cholesteryl groups, as revealed by scanning electron microscopy (SEM) measurements. Notably, the xerogel of 2 using benzene displayed an aggregated microfibrous strand structure that included helical fibers.

Synthesis and biological evaluation of pyrazolylthiazole carboxylic acids as potent anti-inflammatory-antimicrobial agents.

Current Letter presents design, synthesis and biological evaluation of a novel series of pyrazolylthiazole carboxylates 1a-1p and corresponding acid derivatives 2a-2p. All 32 novel compounds were tested for their in vivo anti-inflammatory activity by carrageenan-induced rat paw edema method as well as for in vitro antimicrobial activity. All the tested compounds exhibited excellent AI activity profile. Three compounds 1p (R=Cl, R(1)=Cl), 2c (R=H, R(1)=F) and 2n (R=Cl, R(1)=OCH3) were identified as potent anti-inflammatory agents exhibiting edema inhibition of 93.06-89.59% which is comparable to the reference drug indomethacin (91.32%) after 3h of carrageenan injection while most of the other compounds displayed inhibition ⩾80%. In addition, pyrazolylthiazole carboxylic acids (2a-2p) also showed good antimicrobial profile. Compound 2h (R=OCH3, R(1)=Cl) showed excellent antimicrobial activity (MIC 6.25μg/mL) against both Gram positive bacteria comparable with the reference drug ciprofloxacin (MIC 6.25μg/mL).

Symmetric Bis-chalcones as a New Type of Breast Cancer Resistance Protein Inhibitors with a Mechanism Different from That of Chromones

Potent ABCG2 inhibitors were recently identified as asymmetric chromones with different types of substituents. We here synthesized symmetric bis-chalcones that were differently substituted and screened for their ability to inhibit mitoxantrone efflux from ABCG2-transfected HEK293 cells. Potent bis-chalcone inhibitors were identified, the efficiency depending on both position of the central ketone groups and the number and positions of lateral methoxy substituents. The best derivative, namely, 1p, was selective for ABCG2 over P-glycoprotein and MRP1, appeared not to be transported by ABCG2, and was at least as active on various drug-selected cancer cells overexpressing ABCG2. Compound 1p stimulated the ABCG2 basal ATPase activity by contrast to a chromone lead that inhibited it, suggesting different mechanisms of interaction. Combination of both types of inhibitors produced synergistic effects, leading to complete inhibition at very low concentrations.

Synthesis and Antiproliferative Activity of New Aminoisoquinolinylurea Derivatives against Melanoma Cell Line

A series of new diarylureas possessing aminoisoquinoline scaffold was synthesized, and their in vitro antiproliferative activity against A375P human melanoma cell line was tested. Compounds 1d, 1l, 1n, 1p, 1q, and 1t showed superior potency against A375P to Sorafenib. The highest potency was shown by compound 1p possessing 3,5-bis(trifluoromethyl)phenyl terminal ring with <TEX>$IC_{50}$</TEX> value of <TEX>$0.41{\mu}M$</TEX>.

Design, synthesis and biological evaluation of cycloalkyl arylpyrimidines (CAPYs) as HIV-1 NNRTIs

A series of 18 cycloalkyl arylpyrimidines (CAPYs) were designed from lead compounds diarylpyrimidines (DAPYs), synthesized and evaluated for in vitro anti-HIV activity. Among them, the compound 1p displayed potent anti-HIV-1 activity against WT HIV-1 with an EC50 value of 0.055μM and a selectivity index (SI) >7290. The preliminary structure–activity relationship (SAR) of this new series of compounds was also investigated, which enriched the SAR of diarylpyrimidines (DAPYs).

Efficient Regioselective Three‐Component Domino Synthesis of 3‐(1,2,4‐Triazol‐5‐yl)‐1,3‐thiazolidin‐4‐ones as Potent Antifungal and Antituberculosis Agents

In research for promising antibacterial and antifungal compounds, a series of 2-aryl 3-[1,2,4]triazol-5-yl 4-thiazolidinones 1 were synthesized by a domino reaction of 5-amino-1H-[1,2,4]triazoles 3, aromatic aldehydes, and α-mercaptoacids in boiling toluene in the presence of molecular sieves 4 Å. Of the twenty novel 3-[1,2,4]triazol-5-yl 4-thiazolidinone derivatives, four compounds 2-benzo[d][1,3]dioxol-6-yl-3-[(3-morpholin-4-yl)-1H-1,2,4-triazol-5-yl)]-1,3-thiazolidin-4-one (1i), 2-(4-chlorophenyl)-5-methyl-3-[3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazol-5-yl]-1,3-thiazolidin-4-one (1p), 2-benzo[d][1,3]dioxol-6-yl-3-[3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazol-5-yl]-1,3-thiazolidin-4-one (1s), 2-benzo[d][1,3]dioxol-6-yl-5-methyl-3-[3-(4-methylpiperazin-1-yl)-1H-1,2,4-triazol-5-yl]-1,3-thiazolidin-4-one (1t) exhibited MICs of 4 µg/mL or less versus Mycobacterium tuberculosis. Moreover, these compounds were screened against Candida albicans. Compounds 1p, 1s gave MICs of 1 µg/mL or less, and were fungicidal. Finally, compound 1s was evaluated against an expanded fungal panel and showed good activity against Cryptococcus neoformans. In addition, compound 1s also appeared to be fungicidal against Aspergillus arrhizus, with MIC <1 µg/mL.

Solid state double [2 + 2] photochemical reactions in the co-crystal forms of 1,5-bis(4-pyridyl)-1,4-pentadiene-3-one: establishing mechanism using single crystal X-ray, UV and 1H NMR

Double [2 + 2] photochemical reaction of 1,5-bis(4-pyridyl)-1,4-pentadiene-3-one (1P) was observed with 100% yield in four co-crystal forms of 1P with the hydrogen bonding template molecule phloroglucinol (PG) or 5-methoxy resorcinol (MR). The crystal structure of compound 1P does not have the required geometry to produce the double [2 + 2] reaction product, but it gives a single [2 + 2] reaction product with 15% yield upon time restricted irradiation. All the reactions in co-crystals of 1P resulted in the stereospecific exo–exotetrapyridyl tricyclo[6.2.0.03,6]-decane. 1H NMR and the UV-vis spectroscopic studies clearly established a stepwise mechanism for this reaction through the formation of monocyclobutane intermediate. One co-crystal form of 1P with PG and another co-crystal form of 1P with resorcinol were found to be unreactive due to different reasons. Furthermore the mechanochemical grinding products of 1P with RN or MR have exhibited similar structural and reactivity correlations with those crystallized from solution.

Novel Ti−O−Ti Bonding Species Constructed in a Metal−Oxide Cluster: Reaction Products of Bis(oxalato)oxotitanate(IV) with the Dimeric, 1,2-Dititanium(IV)-Substituted Keggin Polyoxotungstate

The preparation and structural characterization of a novel Ti-O-Ti bonding complex constructed in a dilacunary alpha-Keggin polyoxometalate (POM), [[{Ti(ox)(H2O)}4(mu-O)3](alpha-PW10O37)](7-) (H2ox = oxalic acid) (1a), are described. The water-soluble, crystalline complex with a formula of K6H[1a].0.5KCl.10H2O (1p) was prepared as the bulk sample in 28.0% (0.51 g scale) yield in a 1:4 molar-ratio reaction of the dititanium(IV)-substituted, dimeric form of an alpha-Keggin POM, K10[(alpha-1,2-PW10Ti2O39)2].18H2O, with the titanium(IV) source K2[TiO(ox)2].2H2O in HCl-acidic solution (pH 0.08). Prior to formation of 1p, the KCl-free crystalline compound (1c) obtained was characterized with X-ray crystallography. The compound 1p was unequivocally characterized with complete elemental analysis, thermogravimetric and differential thermal analyses (TG/DTA), FTIR, and solution (31P, 183W, and 13C) NMR spectroscopy. The molecular structure of 1a was determined. The POM 1a in the solid state was composed of the four octahedral Ti groups (four guests), i.e., the two Ti-O-Ti groups linked with the mu-O atom, incorporated to the two adjacent, octahedral vacant sites (two hosts) in the dilacunary Keggin POM. The formation of 1a, as well as the recently found POM [{Ti(ox)(H2O)}2(mu-O)](alpha-PW11O39)](5-) (2a), was strongly dependent on the reaction with [TiO(ox)2](2-), i.e., the anionic titanium(IV) complex as the titanium(IV) source. The POM 1a is contrasted to most titanium(IV)-substituted POMs consisting of a combination of a monolacunary site (one host) and an octahedral Ti group (one guest) and also contrasted to 2a as a combination of a monolacunary site (one host) and two octahedral Ti groups or a Ti-O-Ti group (two guests).

CoMFA Study of Piperidine Analogues of Cocaine at the Dopamine Transporter: Exploring the Binding Mode of the 3α-Substituent of the Piperidine Ring Using Pharmacophore-Based Flexible Alignment

A 3D-QSAR CoMFA study of piperidine-based analogues of cocaine with flexible 3 alpha-substituents is described. A series of pharmacophore models were generated based on three representative compounds 1p, 2i, and 3c using the Genetic Algorithm Similarity Program (GASP) method. The flexible superposition of all studied compounds was performed for each pharmacophore model using the FlexS algorithm and the three-dimensional structure of 2i as a template. All sets of the overlaid structures with the top-ranked conformers were used for CoMFA modeling. Two best initial CoMFA models were selected and further optimized by identifying the best-fitting conformer of each compound. Compared with the initial models, the conventional correlation coefficients r(2) for the optimized models 1 and 2 were improved from 0.90 and 0.837 to 0.997 and 0.993, respectively. The leave-one-out cross-validated coefficients q(2) for the optimized models 1 and 2 were improved from 0.515 and 0.296 to 0.828 and 0.849, respectively. The results of the two CoMFA models suggest that both steric and electrostatic interactions play important roles in the binding of the 3 alpha-substituents of the piperidine-based analogues of cocaine. The contributions from steric and electrostatic fields for model 1 were 0.621 and 0.379, respectively. The contributions from steric and electrostatic fields for model 2 were 0.493 and 0.507, respectively. The two highly predictive CoMFA models indicate that the 3 alpha-substituent has two possible binding modes at the DAT. The CoMFA contour maps provide a visual representation of prospective binding modes of the 3 alpha-substituent of the piperidine-based analogues of cocaine and can be used to design novel DAT inhibitors that may be useful for the treatment of cocaine abuse and certain neurological disorders.

Oxidative cyclization of some 1-Aryl-5-(tetrazol-5-ylmethyl)pyrrolidin-2-ones and of a related piperidin-2-one. Preparation of fused tetracyclic tetrazolobenzodiazepinone derivatives

In contrast to compounds of type 1a, compounds 1c–1i, when treated with lead(IV) acetate or cerium(IV) ammonium nitrate, underwent oxidative cyclizations to afford the corresponding compounds of type 3 with both oxidants, while oxidation of compound 1p afforded compound 2a (m = n = 1).