Small Heterocycles Research Articles

Solid-Phase Synthesis of 2-Amino-2-thiazolines by the Cyclization of N-(2-Hydroxyethyl)thioureas Using TFA

The 2-amono-2-thiazolines have recently gained significant interest as a scaffold that is applicable to the development of bioactive compounds such as pronounced antidepressant agents, potent human nitric oxide synthase inhibitors, octopaminergic-agonists, anthelmintics, and anti-inflammatory agents. The solid phase synthesis of small heterocycles have been considerably studied because it can be applied to the rapid generation of diverse libraries of drug-like compounds. Although there are many wellestablished reports on the solution phase synthesis of 2amino-2-thiazolines scaffolds because of their valuable pharmaceutical properties, very recently we first reported a solid phase synthetic method of 2-amino-2-thiazolines from the cyclization of N-(2-hydroxyethyl)thioureas using dicyclohexylcarbodiimide (DCC). The ring closure of N-(2hydroxyethyl)thioureas can furnish different products depending on the reaction conditions and substrates such as S-cyclized, N-cyclized, or O-cyclized products. Resinbound substrates 6 were designed as precursors to generate 2-amino-2-thiazolines by the S-cyclization, which were conveniently prepared from various commercially available aminoalcohols and isothiocyanates (Scheme 1). We wish to report an alternative and more effective way into the solid phase synthesis of 2-amino-2-thiazolines, using the cyclization of N-(2-hydroxyethyl)thioureas. Scheme 2 shows the synthetic route of the 2-amino-2thiazoline scaffold. The first step in solid phase reactions was the coupling of amino alcohol onto an ArgoGel-MBCHO resin via reductive amination, followed by the protection of the free alcohol 3 with tert-butyldimethylsilyl chloride (TBSCl) according to the previous procedures. Treatment of this intermediate with isothiocyanates afforded the thioureas resin 5, and subsequent deprotection of the silylated hydroxy group with tetrabutyl ammonium fluoride in THF yielded resin 6. The intramolecular cyclization of resin 6 using dicyclohexylcarbodiimide (DCC) gave mainly the required S-cyclized 2-amino-2-thiazolines resin 7 as reported. Then we turned to release the N-(2-hydroxyethyl)thioureas from the resin 6, key intermediate in Scheme 2, by the trifluoroacetic acid (TFA) cleavage to determine the loading capacity of the both amino alcohols and isothiocyanates. The desired thiourea was not obtained but the final product 2-amino-2-thiazoline was released in high yield and purity. This is that the cyclization and cleavage reaction in TFA simultaneously occurred at the same step, thereby saving one step procedure. The results using TFA for the cyclization and cleavage are summarized in Table 1. Resin 6 derived from either aliphatic (entry 7a-b) or aryl isothiocyanates (entry 7c-7k) furnished the required Salkylation products, but aminoalcohol was limited to the primary alcohol. In summary, a solid phase synthetic method was developed for the parallel synthesis of 2-amino-2-thiazolines, using the cyclization of N-(2-hydroxyethyl)thioureas and cleavage in TFA. This synthetic methodology is ideally suited for the automated applications, because all the reactions were carried out under ambient conditions.

Potent non-nitrile dipeptidic dipeptidyl peptidase IV inhibitors

The synthesis and structure–activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with β-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2 S,3 R)-2,3-methanopyrrolidine based scaffold.

Water Lends a Hand

CHEMISTRY Although the global chirality of molecular aggregates is strongly influenced by the individual chirality of the building blocks, it is not generally a simple matter to predict one from the other. In a series of careful experiments, Johnson et al. uncover the subtle environmental factors that determine the helical handedness of rosette nanotubes assembled in solution from small organic heterocycles bearing a chiral side chain. The heterocycles (which are self-complementary toward hydrogen bonding) first form hexameric supermacrocycles, which in turn stack into a helical arrangement. Dissolution of a single enantiomer of this building block in methanol gives rise to one helical isomer, but addition of as little as 1% water to the solvent instead induces opposite helicity in the stacks. The authors show that the water-induced product is thermodynamically favored, but faces a larger kinetic barrier than its counterpart to formation in pure methanol (though aggregation in both senses appears to be accelerated in the absence of water). They further find that chiral inversion of the kinetic isomer in methanol can be catalyzed by the thermodynamic isomer. Inversion is also possible at an early stage by heating, though after 3 days the kinetic isomer becomes stereochemically locked, a result attributed in part to extensive solvation. — MSL J. Am. Chem. Soc. 129 , 5735 (2007).

Anionic ring‐opening polymerization of small phosphorus heterocycles and their borane adducts: An ab initio investigation

AbstractThe kinetics and thermodynamics of anionic ring‐opening reactions of phosphiranes, phosphetanes, and phospholanes and their borane adducts have been studied by high‐level ab initio procedures. For the free heterocycles, model propagation reactions involving nucleophilic attack by Me2P− at the ring α‐carbon were found to be feasible for the three‐ and four‐membered rings, but not for the five‐membered ring. For the borane adducts, nucleophilic attack by Me2(BH3)P− was only facile for the three‐membered ring, despite an increased thermodynamic tendency toward ring opening for the borane adducts of both the three‐ and four‐membered rings. The formation constants of the borane adducts of methylphosphirane and methylphosphetane were K = 2.6 × 1013 L mol−1 and K = 1.2 × 1020 L mol−1, respectively. A Marcus analysis of the ring‐opening reactions of methylphosphirane, methylphosphetane, and their borane adducts showed that the release of ring strain and an “additional factor'' contribute to rate enhancement compared with their strain‐free analogues. The additional factor was larger for the three‐membered rings than for the four‐membered rings and was larger in the free heterocycles than in their borane adducts. The additional factor is complex in origin and appears to reflect an increase in the separation between the bonding and antibonding orbitals of the breaking bond on going from the three‐membered rings to the four‐membered rings, and on going from the free heterocycles to the borane adducts. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:118–128, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20323

Millimetre wave spectroscopy of PANHs: phenanthridine

The pure rotational spectrum of phenanthridine (C(13)H(9)N), a small polycyclic aromatic nitrogen heterocycle (PANH), has been measured from 48 to 85 GHz employing Stark modulated millimetre wave absorption spectroscopy of a supersonic rotationally cold molecular beam. Initial survey search scans were guided by rotational constants obtained through quantum chemical calculations performed at the B3LYP/cc-pVTZ level of theory. Close agreement--to well within 1%--is found between the calculated equilibrium and experimentally derived ground state rotational constants. From the moments of inertia a substantial negative inertial defect of Delta = -0.4688(44) amu Angstroms(2) is obtained which can be explained by the presence of several energetically low-lying out-of-plane vibrational modes. Corresponding density functional theory calculations of harmonic fundamental frequencies indeed yield four such low frequency modes with values as low as 96 cm(-1). The data presented here will also be useful for deep radio astronomical searches for PANHs employing large radio telescopes.

Diastereoselective Multicomponent Synthesis of Dihydropyridones with an Isocyanide Functionality

[Structure: see text] In a search for new multicomponent strategies leading to valuable small heterocycles, a new highly diastereoselective four-component reaction (4CR) was found in which a phosphonate, nitriles, aldehydes, and isocyanoacetates combine to afford functionalized 3-isocyano-3,4-dihydro-2-pyridones. In this strategy, initially a 1-azadiene is generated, which is trapped in the same pot by an isocyanoacetate as the fourth component. Multicomponent reactions (MCRs) that lead to heterocycles containing isocyano substituents are unprecedented and offer many possibilities for further differentiation.

Spontaneity in the patellamide biosynthetic pathway

Post-translationally modified ribosomal peptides are unusual natural products and many have potent biological activity. The biosynthetic processes involved in their formation have been delineated for some, but the patellamides represent a unique group of these metabolites with a combination of a macrocycle, small heterocycles and d-stereocentres. The genes encoding for the patellamides show very low homology to known biosynthetic genes and there appear to be no explicit genes for the macrocyclisation and epimerisation steps. Using a combination of literature data and large-scale molecular dynamics calculations with explicit solvent, we propose that the macrocyclisation and epimerisation steps are spontaneous and interdependent and a feature of the structure of the linear peptide. Our study suggests the steps in the biosynthetic route are heterocyclisation, macrocyclisation, followed by epimerisation and finally dehydrogenation. This study is presented as testable hypothesis based on literature and theoretical data to be verified by future detailed experimental investigations.

Propagation Mechanisms in Ring-Opening Polymerization of Small Phosphorus Heterocycles: Toward Free-Radical Polymerization of Phosphines?

The mechanism and kinetics of the propagation step in the radical ring-opening polymerization of methylphosphirane, -phosphetane, and -phospholane, and also phenylphosphetane, were studied via high-level ab initio calculations. It was found that radical ring-opening polymerization should occur via attack of the carbon-centered propagating radical at the phosphorus center of the ring. This is a facile process (with reaction rates of the order of 104−106 L mol-1 s-1 at 298.15 K), driven by the creation of a transition structure that resembles a (relatively stable) stretched phosphoranyl radical. The reaction is fastest for the four-membered phosphetanes, reflecting the best compromise between the strain in the transition structure and the strain released by the partially broken ring bond. Though slightly slower, radical ring opening of the three-membered phosphirane should also occur, but the reaction of the five-membered phospholane is not thermodynamically favorable. On the basis of the calculations for t...

Inhibitors of Apoptosis in Lymphocytes: Synthesis and Biological Evaluation of Compounds Related to Pifithrin-α

The chemoprotection of cells from apoptosis induced by toxins or ionizing radiation could be important for biodefense and in the treatment of acute injuries. We describe a series of small heterocycles, including fused benzothiazoles, benzimidazoles, and related compounds, that abrogate thymocyte apoptosis induced by dexamethasone and gamma-irradiation. To optimize the protective activity of the previously reported pifithrin-alpha (PFT-alpha, 1), various derivatives and analogues of this and the corresponding ring-closed imidazobenzothiazole (IBT, 39) were synthesized. The aromatic analogues of 39 were more protective than 39, while the aromatic analogues of 1 were not active. Compound 19 containing a pyrrolidinyl substituent on the phenyl ring provided potent antiapoptotic activity (EC50 of 1.31 microM compared to 4.16 microM for 1). Modification of aromatic 39 with a pyrrolidinyl para substituent (compound 60) enhanced the activity, lowering the EC50 to 0.35 microM. Also, 60 provided significant protection against gamma-irradiation-induced apoptosis, as expected. Compounds 19 and 60 may be promising for potential clinical development.

Improvement of the impedance measurement reliability by some new experimental and data treatment procedures applied to the behavior of copper in neutral chloride solutions containing small heterocycle molecules

The electrochemical behavior of copper in chloride solutions containing 0.001 M concentrations of small five- and six-ring member heterocyclic molecules was investigated by means of impedance spectroscopy. The investigation was performed by a new technique based on a broadband multisine excitation. This method allows for a quantification and separation of the measurement and stohastic nonlinear noises and for an estimation of the bias non-linear contribution. It as well reduces the perturbation brought to studied system by the measurement process itself. The measurement data for some experimental conditions was quantified by fitting into a equivalent circuit corresponding to a physical model both of them developed earlier. In general, the experimental results obtained show that the number of atoms in the heterocyclic ring and the molecular conformation have a significant influence on the electrochemical response of copper in the investigated environments.

QSAR studies on some thiophene analogs as anti-inflammatory agents: enhancement of activity by electronic parameters and its utilization for chemical lead optimization

Small molecule heterocycle is an integral part of new drug discovery in anti-inflammatory research. In our previous papers we reported the synthesis of thiophene analogs substituted at the fifth position with α-oximino propionic ester moiety and the fact that such new chemical entities exhibit anti-inflammatory activity in male/female Sprague–Dawley rats. In this paper we report the quantitative structure activity relationship (QSAR) studies of a series of 43 thiophene analogs. The analogs when subjected to cluster analysis technique led to the formation of four homogeneous groups. The cluster analysis technique grouped the 2-anilino-5-substituted-4-methyl-thiophene-3-carboxylic acid methyl esters as one homogeneous group. The clusters were individually taken up for a Hansch type of QSAR study with 10 molecular descriptors. The QSAR equations generated were cross validated by the leave out one method. The studies gave an insight into the dominant role played by electronic properties like energy of the lowest unoccupied molecular orbital ( E LUMO) and dipole moment (dipole) in modulating the anti-inflammatory activity. From the QSAR studies a three point pharmacophore has been established for designing novel anti-inflammatory molecules.

P‐Toluenesulfonylmethyl Isocyanide: A Versatile Synthon in Organic Chemistry

AbstractFor Abstract see ChemInform Abstract in Full Text.

Neuropeptide Y Y 5 receptors inhibit kindling acquisition in rats

Neuropeptide Y inhibits neuronal excitability and seizures in various experimental models. This peptide delays kindling epileptogenesis but the receptors involved in this action are unknown. We have studied the role of Y 5 receptors in kindling using the selective antagonist GW438014A (IC50=210 nM), a small heterocycle molecule that crosses the blood–brain barrier, and the selective peptide agonist Ala 31Aib 34 NPY (IC50=6.0 nM). Intraperitoneal injection of GW438014A (10 mg/kg), 30 min before the beginning of a rapid-kindling protocol, significantly accelerated the rate of kindling acquisition as compared to vehicle-injected rats. Thus, the number of electrical stimuli required to reach stages 3 and 4–5 of kindling were reduced by 50% and 25%, respectively. The average afterdischarge duration in the stimulated hippocampus was prolonged by 2-fold. Conversely, kindling rate was delayed by intracerebroventricular administration of 24 nmol Ala 31Aib 32 NPY. Thus, the number of stimuli necessary to reach stages 2 and 3 of kindling was increased by 3- and 4-fold, respectively. During the stimulation protocol (40 stimuli) none of the rats treated with the Y 5 agonist showed stages 4–5 seizures. Twenty-four hours after the last kindling stimulation, thus during the re-test session, Y 5 agonist- or antagonist-treated rats had stages 4–5 seizures as their controls. In rats treated with both the antagonist and the agonist, kindling rate was similar to vehicle-injected rats. These data indicate that Y 5 receptors mediate inhibitory effects of NPY in kindling and display anticonvulsant rather then antiepileptogenic effects upon agonist stimulation.

P-Toluenesulfonylmethyl Isocyanide: A Versatile Synthon in Organic Chemistry

TosMIC, a versatile synthon in organic chemistry, has been extensively used for the synthesis of a wide variety of small, medium and large ring heterocycles. It has immense implications in the synthesis of nitriles, aldehydes, ketones, alkanes, cyclophanes and large number of natural products. Several drug intermediates and pharmacologically active compounds have been synthesized from TosMIC. In addition, chiral TosMIC analogs have been synthesized and employed for synthesis of optically active compounds.

Proflavine acts as a Rev inhibitor by targeting the high-affinity Rev binding site of the Rev responsive element of HIV-1.

Rev is an essential regulatory HIV-1 protein that binds the Rev responsive element (RRE) within the env gene of the HIV-1 RNA genome, activating the switch between viral latency and active viral replication. Previously, we have shown that selective incorporation of the fluorescent probe 2-aminopurine (2-AP) into a truncated form of the RRE sequence (RRE-IIB) allowed the binding of an arginine-rich peptide derived from Rev and aminoglycosides to be characterized directly by fluorescence methods. Using these fluorescence and nuclear magnetic resonance (NMR) methods, proflavine has been identified, through a limited screen of selected small heterocyclic compounds, as a specific and high-affinity RRE-IIB binder which inhibits the interaction of the Rev peptide with RRE-IIB. Direct and competitive 2-AP fluorescence binding assays reveal that there are at least two classes of proflavine binding sites on RRE-IIB: a high-affinity site that competes with the Rev peptide for binding to RRE-IIB (K(D) approximately 0.1 +/- 0.05 microM) and a weaker binding site(s) (K(D) approximately 1.1 +/- 0.05 microM). Titrations of RRE-IIB with proflavine, monitored using (1)H NMR, demonstrate that the high-affinity proflavine binding interaction occurs with a 2:1 (proflavine:RRE-IIB) stoichiometry, and NOEs observed in the NOESY spectrum of the 2:1 proflavine.RRE-IIB complex indicate that the two proflavine molecules bind specifically and close to each other within a single binding site. NOESY data further indicate that formation of the 2:1 proflavine.RRE-IIB complex stabilizes base pairing and stacking within the internal purine-rich bulge of RRE-IIB in a manner analogous to what has been observed in the Rev peptide.RRE-IIB complex. The observation that proflavine competes with Rev for binding to RRE-IIB by binding as a dimer to a single high-affinity site opens the possibility for rational drug design based on linking and modifying it and related compounds.

Sacrificial spacer and non-covalent routes toward the molecular imprinting of “poorly-functionalized” N-heterocycles

A comparison of three different methods for the imprinting of small aromatic heterocycles containing only a single nitrogen atom, for the preparation of specific analytical phases, was carried out. A conventional non-covalent approach to the imprinting of pyridine using methacrylic acid as the functional monomer was compared with two sacrificial spacer methods, in which heterocycles were imprinted as covalent template analogues. The results of binding experiments showed that discrimination based on ligand size was possible when polymers were prepared using a silyl ester-based template. The most selective polymer was able to bind pyridine in preference to quinoline or acridine which is opposite to the trend predicted by the p K HB values for the three ligands. Curve fitting of the isotherm for pyridine binding to this polymer to the Langmuir model gave an approximate K d of 1.1±0.1 mM and a binding site concentration of 57±2 mmol g −1. Acridine binding did not show saturation behaviour and was non-specific and cooperative in nature.

Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist.

Numerous reports have implicated theY5 receptor as the 'feeding' receptor mediating the orexigenic action of neuropeptide Y (NPY). This notion is supported by the correlation between the in vitro functional and binding activities of different peptide agonists and their potent stimulation of food intake in rodents. We have discovered a series of small molecule heterocycles with high affinity, selectivity, and functional antagonism for Y5 receptors. Intraperitoneal (i.p.) administration of GW438014A into rodents, resulted in a potent reduction of NPY-induced and normal overnight food intake. Brain levels of GW438014A were detected well in excess of its binding IC(50) for up to 3 h post-dosing. Daily (i.p., BID, 10 mg/kg) administration of this compound to Zucker Fatty rats for a period of 4 days resulted in a marked decrease in the rate of weight gain and a reduction in fat mass. No effect on food intake was observed following oral administration of GW438014A (25-100 mg/kg), consistent with the poor oral bioavailability (<3%) and low brain levels observed.

Defects in the silver halide photographic process

The imaging efficiency of today's photographic film and paper is influenced in a variety of ways. Among them, the incorporation of dopants is widely used to increase efficiency, control contrast or improve imaging deficiencies such as reciprocity law failure. Transition metal-organic ligand dopants are attractive because the organic ligand influences the photographic properties. Experimental studies have shown that many of these dopants incorporate well into the silver halide microcrystal even with large organic ligands. In this paper, experimental and computational results are presented on a variety of Ir-OL dopants in AgCl where OL is a small nitrogen and/or sulfur-containing heterocycle. Electron paramagnetic resonance methods provide information about the electronic structure, electron trapping properties and the stability of the electron trap state. These results are complemented by ab initio studies that give information about the optimum structure, charge compensation and the possibility of electron and hole trapping.

Synthesis and Evaluation of Efavirenz (Sustiva TM) Analogues as HIV-1 Reverse Transcriptase Inhibitors: Replacement of the Cyclopropylacetylene Side Chain

Two series of efavirenz analogues have been developed: one in which the cyclopropane ring has been replaced by small heterocycles and another in which the entire acetylenic side chain has been replaced by alkyloxy groups. Several members of both series show equivalent potency to efavirenz against both wild-type virus and the key K103N mutant.

ChemInform Abstract: Palladium Catalyzed Tandem Cyclization—Anion Capture. Part 5. Cascade Hydrostannylation‐bis‐cyclization‐intramolecular Anion Capture. Synthesis of Bridged‐ and Spiro‐cyclic Small and Macrocyclic Heterocycles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.