- 2-Aminoimidazole amino acids as inhibitors of the binuclear manganese metalloenzyme human arginase i
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Arginase, a key metalloenzyme of the urea cycle that converts l-arginine into l-ornithine and urea, is presently considered a pharmaceutical target for the management of diseases associated with aberrant l-arginine homeostasis, such as asthma, cardiovascular diseases, and erectile dysfunction. We now report the design, synthesis, and evaluation of a series of 2-aminoimidazole amino acid inhibitors in which the 2-aminoimidazole moiety serves as a guanidine mimetic. These compounds represent a new class of arginase inhibitors. The most potent inhibitor identified in this study, 2-(S)-amino-5-(2-aminoimidazol-1-yl) pentanoic acid (A1P, 10), binds to human arginase I with Kd = 2 μM and significantly attenuates airways hyperresponsiveness in a murine model of allergic airways inflammation. These findings suggest that 2-aminoimidazole amino acids represent new leads for the development of arginase inhibitors with promising pharmacological profiles.
- Ilies, Monica,Di Costanzo, Luigi,North, Michelle L.,Scott, Jeremy A.,Christianson, David W.
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Read Online
- A continuous reaction network that produces RNA precursors
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Continuous reaction networks, which do not rely on purification or timely additions of reagents, serve as models for chemical evolution and have been demonstrated for compounds thought to have played important roles for the origins of life such as amino acids, hydroxy acids, and sugars. Step-by-step chemical protocols for ribonucleotide synthesis are known, but demonstrating their synthesis in the context of continuous reaction networks remains a major challenge. Herein, compounds proposed to be important for prebiotic RNA synthesis, including glycolaldehyde, cyanamide, 2-aminooxazole, and 2-aminoimidazole, are generated from a continuous reaction network, starting from an aqueous mixture of NaCl, NH4Cl, phosphate, and HCN as the only carbon source. No well-timed addition of any other reagents is required. The reaction network is driven by a combination of γ radiolysis and dry-down. γ Radiolysis results in a complex mixture of organics, including the glycolaldehyde-derived glyceronitrile and cyanamide. This mixture is then dried down, generating free glycolaldehyde that then reacts with cyanamide/NH3 to furnish a combination of 2-aminooxazole and 2-aminoimidazole. This continuous reaction network models how precursors for generating RNA and other classes of compounds may arise spontaneously from a complex mixture that originates from simple reagents.
- Adam, Zachary R.,Ali, Sarfaraz,Cleaves, H. James,Fahrenbach, Albert C.,Tran, Quoc Phuong,Yi, Ruiqin,Yoda, Isao
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Read Online
- Photoredox chemistry in the synthesis of 2-aminoazoles implicated in prebiotic nucleic acid synthesis
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Prebiotically plausible ferrocyanide-ferricyanide photoredox cycling oxidatively converts thiourea to cyanamide, whilst HCN is reductively homologated to intermediates which either react directly with the cyanamide giving 2-aminoazoles, or have the potential to do so upon loss of HCN from the system. Thiourea itself is produced by heating ammonium thiocyanate, a product of the reaction of HCN and hydrogen sulfide under UV irradiation. This journal is
- Liu, Ziwei,Wu, Long-Fei,Bond, Andrew D.,Sutherland, John D.
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supporting information
p. 13563 - 13566
(2020/11/17)
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- Synthesis and Antitrypanosomal Activity of 1,4-Disubstituted Triazole Compounds Based on a 2-Nitroimidazole Scaffold: a Structure-Activity Relationship Study
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Chagas disease affects 6–8 million people worldwide, remaining a public health concern. Toxicity, several adverse effects and inefficiency in the chronic stage of the disease are the major challenges regarding the available treatment protocols. This work involved the synthesis of twenty-two 1,4-disubstituted-1,2,3-triazole analogues of benznidazole (BZN), by using a click chemistry strategy. Analogues were obtained in moderate to good yields (40-97 %). Antitrypanosomal activity was evaluated against the amastigote forms of Trypanosoma cruzi. Compound 8 a (4-(2-nitro-1H-imidazol-1-yl)methyl)-1-phenyl-1H-1,2,3-triazole) without substituents on phenyl ring showed similar biological activity to BZN (IC50=3.0 μM, SI>65.3), with an IC50=3.1 μM and SI>64.5. Compound 8 o (3,4-di-OCH3?Ph) with IC50 = 0.65 μM was five-fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound 8 v (3-NO2, 4-CH3?Ph) with IC50=1.2 μM and relevant SI>166.7, also exhibited higher activity than BZN. SAR analysis exhibited a pattern regarding antitrypanosomal activity relative to BZN, in compounds with electron-withdrawing groups (Hammett σ+) at position 3, and electron-donating groups (Hammett σ-) at position 4, as observed in 8 o and 8 v. Further research might explore in vivo antitrypanosomal activity of promising analogues 8 a, 8 o, and 8 v. Overall, this study indicates that approaches such as the bioisosteric replacement of amide group by 1,2,3-triazole ring, the use of click chemistry as a synthesis strategy, and design tools like Craig-plot and Topliss tree are promising alternatives to drug discovery.
- Assun??o, Elvis L. F.,Carvalho, Diego B.,das Neves, Amarith R.,Kawasoko Shiguemotto, Cristiane Y.,Portapilla, Gisele B.,de Albuquerque, Sergio,Baroni, Adriano C. M.
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p. 2019 - 2028
(2020/09/21)
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- Rational design of nickel catalysts containing N-acylated imidazolin-2-imine ligand for ethylene copolymerization with polar monomer
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By taking advantage of electronic influence of ligand design, the novel neutral nickel complexes bearing strong electron-donating N-acylated imidazolin-2-imine ligand were synthesized and characterized. The nickel catalysts conducted ethylene polymerization with high activity and good thermal stability, affording semicrystalline polyethylene with short chain branches (32–46/1000 C atoms). The complex Ni2 bearing adamantyl substituent on the imidazoline ligand showed higher activity than phenyl substituted complex Ni1, and highest activity was observed at 60 °C (up to ~106 g?mol?1?h?1). Most importantly, the catalysts were also effective for the copolymerization of ethylene and 5-hexenyl acetate with moderate activity (~105 g?mol?1?h?1). The microstructure analyses by the 13C NMR spectroscopy indicated that the 5-hexenyl acetate was successfully incorporated into the polyethylene main chain with reasonable comonomer content.
- Li, Yanqing,Cheng, Hailong,Xiao, Ru,Cai, Zhengguo
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p. 117 - 123
(2020/02/04)
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- Keto-imidazoline-2-imine ligand [N,O] bidentate nickel and palladium complex as well as preparation method and application thereof
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The invention relates to a keto-imidazoline-2-imine [N,O] bidentate nickel and palladium complex as well as a preparation method and application thereof. The preparation method comprises the followingsteps: reacting a keto-imidazoline-2-imine ligand with a hydrogen withdrawing reagent and a metal precursor in sequence to prepare a keto-imidazoline-2-imine [N,O] bidentate nickel and palladium complex; and the structural formula of the prepared complex is one of formulas shown in the specification. The complex and a cocatalyst form a catalyst composition, the complex or the catalyst compositionis used for catalyzing homopolymerization or copolymerization of olefin monomers, and the specific process is as follows: under the protection of nitrogen, firstly dissolving the complex or the catalyst composition in a solvent, then adding an olefin monomer, and conducting reacting for a period of time at a certain temperature and under a certain pressure to prepare the olefin polymer. The complex and the catalyst composition provided by the invention have relatively high catalytic activity, high tolerance to polar monomers and relatively low application cost.
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Paragraph 0082; 0086; 0094; 0098; 0106; 0110; 0118; 0122
(2019/11/13)
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- PHARMACEUTICAL COMPOUNDS FOR TREATMENT OF MEDICAL DISORDERS
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Complement Factor D inhibitors, pharmaceutical compositions, and uses thereof, as well as processes for their manufacture are provided. The compounds provided include Formula I, Formula II, Formula III, and Formula IV or a pharmaceutically acceptable salt, prodrug, isotopic analog, N-oxide, or isolated isomer thereof, optionally in a pharmaceutically acceptable composition. The inhibitors described herein target Factor D and inhibit or regulate the complement cascade.
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Page/Page column 497-498
(2018/09/21)
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- Common and Potentially Prebiotic Origin for Precursors of Nucleotide Synthesis and Activation
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We have recently shown that 2-aminoimidazole is a superior nucleotide activating group for nonenzymatic RNA copying. Here we describe a prebiotic synthesis of 2-aminoimidazole that shares a common mechanistic pathway with that of 2-aminooxazole, a previously described key intermediate in prebiotic nucleotide synthesis. In the presence of glycolaldehyde, cyanamide, phosphate and ammonium ion, both 2-aminoimidazole and 2-aminooxazole are produced, with higher concentrations of ammonium ion and acidic pH favoring the former. Given a 1:1 mixture of 2-aminoimidazole and 2-aminooxazole, glyceraldehyde preferentially reacts and cyclizes with the latter, forming a mixture of pentose aminooxazolines, and leaving free 2-aminoimidazole available for nucleotide activation. The common synthetic origin of 2-aminoimidazole and 2-aminooxazole and their distinct reactivities are suggestive of a reaction network that could lead to both the synthesis of RNA monomers and to their subsequent chemical activation.
- Fahrenbach, Albert C.,Giurgiu, Constantin,Tam, Chun Pong,Li, Li,Hongo, Yayoi,Aono, Masashi,Szostak, Jack W.
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supporting information
p. 8780 - 8783
(2017/07/12)
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- Enhanced nonenzymatic RNA copying with 2-aminoimidazole activated nucleotides
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Achieving efficient nonenzymatic replication of RNA is an important step toward the synthesis of self-replicating protocells that may mimic early forms of life. Despite recent progress, the nonenzymatic copying of templates containing mixed sequences remains slow and inefficient. Here we demonstrate that activating nucleotides with 2-aminoimidazole results in superior reaction kinetics and improved yields of primer extension reaction products. This new leaving group significantly accelerates monomer addition as well as trimer-assisted RNA primer extension, allowing efficient copying of a variety of short RNA templates with mixed sequences.
- Li, Li,Prywes, Noam,Tam, Chun Pong,Oflaherty, Derek K.,Lelyveld, Victor S.,Izgu, Enver Cagri,Pal, Ayan,Szostak, Jack W.
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supporting information
p. 1810 - 1813
(2017/02/15)
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- RNA cleavage catalyzed by amphoteric bis(acyl)guanidinium derivatives
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Described herein are two series (twelve compounds each) of very closely related guanidinium-based receptors and their ability to catalyze hydrolytic cleavage of a unique RNA substrate - oligo-dT flanked trans-Activation Responsive region of the HIV-1 mRNA, TAR RNA. The significant difference in activities of otherwise very similar compounds is discussed, and direct and indirect evidences supporting our interpretation are presented. The results indicate that improvements in catalytic efficiency could be achieved with little modification of the structure of a relatively weak catalyst, and that a crucial feature could be a finely calibrated interplay between anion-binding and proton-donating abilities. Copyright
- Goebel, Michael W.,Roussev, Christo D.,Scheffer, Ute
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p. 215 - 227
(2014/03/21)
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- Polymethylhydrosiloxane derived palladium nanoparticles for chemo- and regioselective hydrogenation of aliphatic and aromatic nitro compounds in water
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Chemo- and regioselective hydrogenation of a wide range of aliphatic, unsaturated, aromatic and heteroaromatic nitro compounds into their corresponding amines has been achieved with highly efficient polysiloxane-stabilised "Pd" nanoparticles on NAP-magnesium oxide supports using an environmentally friendly hydrogenating agent, polymethylhydrosiloxane [PMHS] in water. Highly stable and active Pd nanoparticles were prepared by the reduction of NAP-Mg-PdCl4 with PMHS, which serves as a reducing agent as well as a capping agent. The well-dispersed palladium nanoparticles on NAP-MgO catalysts also exhibit excellent regioselectivity in the hydrogenation of dinitrobenzenes to the corresponding nitroanilines. The catalyst has high durability against sintering during the hydrogenation reaction and can be reused with no loss in its activity. This journal is the Partner Organisations 2014.
- Damodara, Dandu,Arundhathi, Racha,Ramesh Babu, T. Venkata,Legan, Margaret K.,Kumpaty, Hephzibah J.,Likhar, Pravin R.
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p. 22567 - 22574
(2014/06/23)
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- Assembly of the bis(imidazolyl)propene core of nagelamides c and s by double grignard reaction
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As characteristic structural elements of several of the nonmonomeric pyrrole-imidazole alkaloids, l, l-bis(imidazolyl)propenes were assembled in a facile manner by double Grignard reaction of metalated imidazoles with saturated esters, followed by dehydration. The presence of nitrile functions or acryl esters in the electrophile component leads to competing reactions, whereas propargyl esters are tolerated. Introduction of 2-amino groups was possible via the corresponding dimethylsulfamoyl-protected 2-azidoimidazoles, which had to be deprotected prior to hydrogenation. NOESY-based analysis revealed preferred orientation of the imidazole 5positions towards the propenyl chain.
- Jacobi, Nicolas,Lindel, Thomas
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scheme or table
p. 5415 - 5425
(2010/11/18)
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- BICYCLIC PYRIMIDINONES AND USES THEREOF
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The present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. Further provided is a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. A pharmaceutical composition or medicament comprising a compoundof Formula I is also provided.
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Page/Page column 114
(2008/12/06)
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- IMPROVED LINKERS FOR ANCHORING TARGETING LIGANDS
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An improved linker which lacks chiral centers between a hydrophobic anchor for coupling to lipid-based particles and a targeting agent has suitable hydrophobic/hydrophilic properties for use in vivo.
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Page/Page column 11; 13
(2008/12/06)
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- Chemokine receptor binding heterocyclic compounds with enhanced efficacy
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The invention relates to heterocyclic compounds consisting of a core nitrogen atom surrounded by three pendant groups, wherein two of the three pendant groups are preferably benzimidazolyl methyl and tetrahydroquinolyl, and the third pendant group contains N and optionally contains additional rings. The compounds bind to chemokine receptors, including CXCR4 and CCR5, and demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
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Page/Page column 29-30
(2010/02/03)
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- Integrin receptor antagonists
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This invention relates to novel heterocycles including 3-?1-?3-(imidazolin-2-ylamino)propyl!indazol-5-ylcarbonylamino!-2-(benzyloxycarbonylamino)propionic acid, which are useful as antagonists of the αv β3 integrin and related cell surface adhesive protein receptors, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion, the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
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- Benzodiazepine derivatives
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Compounds of Formula (I), and salts and prodrugs thereof, wherein said formula, R 1 represents certain optionally substituted alkyl or C 3-7 cycloalkyl; R 2 represents (II) or (III), where m is 0, 1, 2 or 3; R 9 is H or C 1-6 alkyl; R 10 is imidazolyl, triazolyl or tetrazolyl, and R 11 is H, C 1-6 alkyl or halo; R 3 is C 1-6 alkyl, halo or NR 6 R 7 ; R 4 is C 1-7 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkylC 1-4 alkyl, C 6-10 bicycloalkyl, optionally substituted aryl, or NR 12 R 13 ; R 5 is H or C 1-4 alkyl; n is 0, 1, 2 or 3; which are CCK and/or gastrin antagonists useful in therapy.
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- Method for inhibiting advanced glycosylation of proteins using aminosubstituted imidazoles
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The present invention relates to compositions and methods for inhibiting nonenzymatic cross-linking (protein aging), Accordingly, a composition is disclosed which comprises 2-aminoimidazoles capable of inhibiting the formation of advanced glycosylation endproducts of target proteins by reacting with the carbonyl moiety of the early glycosylation product of such target proteins formed by their initial glycosylation, The method comprises contacting the target protein with the composition, Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated.
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- Polyazaheterocycle compounds
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A polyazaheterocycle compound of the formula: STR1 or a pharmaceutically acceptable salt thereof, wherein each symbol is as defined in the specification. Said compounds exhibit calcium antagonistic and/or calcium agonistic activities.
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- Products of the Reductions of 2-Nitroimidazoles
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Reductions under neutral conditions of misonidazole (1-(2'-hydroxy-3'-methoxypropyl)-2-nitroimidazole) and 1-methyl-2-nitroimidazole have been studied with radiation chemical, electrochemical, and chemical (zinc/ammonium chloride) techniques.Major products accounting for 70-80percent of the reduction mixture have been identified as the cis:trans isomers of 4 (1-substituted 2-amino-4,5-dihydro-4,5-dihydroxyimidazolium ions).These have been independently synthesized by the reaction of glyoxal and the appropriate guanidinium ion.Their presence after nitroreduction has been established by 1H NMR and by spectroscopic analysis in which 4 is converted into glyoxal bis-oxime.The ability of misonidazole reduction mixtures to form glyoxal derivatives has been noted previously, even in vivo; the presence of the cyclic 4 accounts for this.The four-electron-reduced product, a 2-(hydroxylamino)imidazole, is the precursor of 4.The hydroxylamine is unstable at pH 7, but it can be observed in acid where decomposition also gives 4 but in a much slower reaction.Nitroreduction or hydroxylamine decomposition in pH 7 phosphate gives two additional products which have been identified on the basis of their 1H NMR spectra as cis:trans isomers of monophosphate esters of 4.The reaction leading to these may model the DNA binding which is observed with reduced misonidazole.Azomycin (2-nitroimidazole) has been investigated by the radiation chemical technique.At pH 7 the isomers of 4 are formed, but they are minor products.The major product (70percent) is 2-aminoimidazole.
- Clelland, Robert A. Mc,Panicucci, Rick,Rauth, A. Michael
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p. 4308 - 4314
(2007/10/02)
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- N-Aryl-N'-imidazol-2-ylureas
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N-aryl-N'-imidazol-2-ylureas useful for their antihypertensive, antidiarrheal, anti-irritable bowel syndrome, and anti-secretory activities.
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- PHARMACOLOGICALLY ACTIVE THIOUREA AND UREA COMPOUNDS
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The compounds are substituted thioalkyl-, aminoalkyl-and oxyalkyl-thioureas and ureas which are inhibitors of histamine activity.
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