Bromo Atom Research Articles

MAO inhibitory activity modulation: 3-Phenylcoumarins versus 3-benzoylcoumarins

With the aim of finding the structural features for the human MAO inhibitory activity and selectivity, in the present communication we report the synthesis, pharmacological evaluation and a comparative study of a new series of 3-phenylcoumarins (compounds 1-4) and 3-benzoylcoumarins (compounds 5-8). A bromo atom and a methoxy/hydroxy substituent were introduced in these scaffolds, at six and eight positions of the coumarin moiety, respectively. The synthesized compounds 1-8 were evaluated as MAO-A and B inhibitors using R-(-)-deprenyl and iproniazide as reference compounds. The presence or absence of a carbonyl group between the coumarin and the phenyl substituent in 3 position remarks, respectively, the MAO-A or MAO-B inhibitory activity. Some of the new compounds showed MAO-B inhibitory activities in the low nanomolar range. Compound 2 (IC(50)=1.35nM) showed higher inhibitory activity than the R-(-)-deprenyl (IC(50)=19.60nM) and higher MAO-B selectivity, with more than 74,074-fold inhibition level, respecting to the MAO-A isoform.

Self-Assembled One- and Two-Dimensional Networks Based on NH2Me2[ReX5(DMF)] (X = Cl and Br) Species: Polymorphism and Supramolecular Isomerism in Re(IV) Compounds

Three mononuclear rhenium(IV) compounds of general formula NH 2 Me 2 [ReX 5 (DMF)] [NH 2 Me 2 + = dimethylammonium cation, DMF = N,N-dimethylformamide, and X = Cl (1 and 2) and Br (3)] have been prepared and characterized. In all three cases, the rhenium atom is six-coordinated by five chloro (1 and 2) or bromo (3) atoms and one oxygen atom from a DMF molecule (1―3) building a somewhat distorted octahedral surrounding. Short Re IV ―X · · · X―Re IV contacts and H-bonds occur in the crystal lattice generating novel supramolecular Re(IV) architectures. 1 and 2 are polymorphs and supramolecular isomers that exhibit supramolecular ladder-like ( 1 ) and rectangular two-dimensional grids (2), the different intermolecular X· · ·X contacts playing a structure-determining role. Noteworthy, the formation of 1 and 2 is selective and dependent on the crystallization conditions. Although compound 3 is isolated using the same crystallization conditions as 2, their crystal packing is different. The investigation of the magnetic behavior of 1―3 in the temperature range 1.9―250 K showed the occurrence of maxima of the magnetic susceptibility at 10.5 (1), 12.0 (2), and 17.0 K (3), which are the signature of significant intermolecular antiferromagnetic interactions. The short Re IV ―X· · · X―Re IV contacts provide the exchange pathway for the overall antiferromagnetic behavior observed in 1―3. The magnetostructural results of 1―3 are compared with those of the related compounds NBu 4 [ReX 5 (DMF)] [NBu 4 + = tetra-n-butylammonium cation with X = Cl (4) and Br (5)] which were reported elsewhere.

Remarkable effect of a lateral substituent on the molecular ordering of chiral liquid crystal phases: A novel bromo-containing dichiralcompound showing SmC* variants

A bromo-substituted chiral smectic liquid crystal was synthesized for the purpose of the study on the sub-phases of the chiral smectic C* (SmC* variants) using resonant X-ray scattering. The introduction of a bromo atom was found to have a significant effect on the phase sequence. The bromo-substituted compound exhibited enantiotropic smectic phases in a wide temperature range of more than 130 K, in which at least five SmC* variants appeared below the smectic A phase. On the basis of the electro-optic and dielectric measurements, each SmC* variant was identified and assigned, and the structures of which were investigated by resonant X-ray scattering.

New halogenated 3-phenylcoumarins as potent and selective MAO-B inhibitors

With the aim to find out the structural features for the MAO inhibitory activity and selectivity, in the present communication we report the synthesis and pharmacological evaluation of a new series of bromo-6-methyl-3-phenylcoumarin derivatives (with bromo atom in both different benzene rings of the skeleton) with and without different number of methoxy substituent at the 3-phenyl ring. The methoxy substituents were introduced, in this new scaffold, in the meta and/or para positions of the 3-phenyl ring. The synthesized compounds 3– 7 were evaluated as MAO-A and B inhibitors using R-(−)-deprenyl (selegiline) and iproniazide as reference inhibitors, showing, most of them, MAO-B inhibitory activities in the low nanomolar range. Compounds 4 (IC 50 = 11.05 nM), 5 (IC 50 = 3.23 nM) and 6 (IC 50 = 7.12 nM) show higher activity than selegiline (IC 50 = 19.60 nM) and higher MAO-B selectivity, with more than 9050-fold, 30,960-fold and 14,045-fold inhibition levels, with respect to the MAO-A isoform.

A new entry into cis-3-amino-2-methylpyrrolidines viaring expansion of 2-(2-hydroxyethyl)-3-methylaziridines

3-Amino-2-methylpyrrolidines were prepared via a novel protocol, involving the reductive ring closure and O-deprotection of gamma-acetoxy-alpha-chloroketimines towards 2-(2-hydroxyethyl)-3-methylaziridines, followed by ring expansion of the latter into 3-bromopyrrolidines via intermediate bicyclic aziridinium salts and consecutive nucleophilic displacement of the bromo atom by azide towards 3-azidopyrrolidines. A final reduction of the azide moiety furnished 3-amino-2-methylpyrrolidines in high yields. Thus, a new formal synthesis of the antipsychotic emonapride was developed through preparation and further aroylation of cis-3-amino-1-benzyl-2-methylpyrrolidine.

New insights into the antioxidant activity of hydroxycinnamic acids: Synthesis and physicochemical characterization of novel halogenated derivatives

An interdisciplinary research project was developed combining the synthesis of a series of hydroxycinnamic acid derivatives and the evaluation of their physicochemical parameters (namely redox potentials and partition coefficients), along with the corresponding antioxidant activity. A structure–property–activity relationship (SPAR) approach was then applied aiming at establishing a putative relation between the physicochemical parameters of the compounds under study and their antioxidant activity. The results gathered allow concluding that the redox potentials could contribute to the understanding of the antioxidant activity and that the presence of an electron withdrawing group (EWG) of halogen type, namely a bromo atom, in an ortho position to a phenolic group of the cinnamic scaffold does not influence the antioxidant activity. On the other hand after the introduction of this type of substituent a significant increase on the lipophilicity of cinnamic derivatives was observed, which is a feature of extreme importance in the development of novel lipophilic antioxidants. The SPAR results revealed a relation between the redox potentials and the antioxidant activity of hydroxycinnamic acids and derivatives. The data obtained operate as a positive reinforce of the tendency to use redox properties as a guideline of the rational design of this type of compounds.

Synthesis and anti‐staphylococcal activity of new halogenated pyrroles related to Pyrrolomycins F

Abstractmagnified imageThe chemical synthesis of new halogenated pyrroles related to pyrrolomycins F is described and the anti‐staphylococcal activity compared. The replacement of 4′‐bromo atom of parent compounds with two chloro atoms at 3′ and 5′ position increase the antibacterial activity against a reference strain of S. aureus.

Synthesis and radiosensitizing properties of brominated tetrapyridine porphyrins

Brominated derivatives of tetrapyridinium copper porphyrin were prepared via bromination of the β-positions (pyrrole rings) and/or the peripheral alkyl side-chains attached to the pyridine moieties. The radiosensitizing properties of these new cationic, brominated porphyrins were tested on MDA-MB-231 breast cancer cells in vitro using a 60 Co source or an X-ray irradiator. The non-brominated porphyrin and the porphyrin containing bromines at β-positions only were devoid of any radiosensitizing activity. However, a pronounced radiosensitizing effect was observed with the porphyrin containing bromo atoms at both β-positions and the peripheral side-chains. A similar radiosensitizing effect was detected for different radiation energies, suggesting that high energy photons could be used to treat tumors in conjunction with this novel brominated, porphyrin-based radiosensitizer.

Novel Synthesis of cis-3,5-Disubstituted Morpholine Derivatives

1-tert-Butyl-2-(allyloxymethyl)aziridine has been transformed for the first time diastereoselectively into cis-3,5-di(bromomethyl)-4-tert-butylmorpholine via an electrophile-induced ring closure using bromine in dichloromethane. The latter morpholine has been used as a substrate for the synthesis of the corresponding 3,5-di(methoxymethyl)morpholine and 3,5-di(cyanomethyl)morpholine upon nucleophilic displacement of both bromo atoms. Further evaluation of this protocol toward the synthesis of 4-arylmethyl- and 4-alkylmethyl-3,5-di(bromomethyl)morpholines showed that the premised cyclization of the corresponding 2-(allyloxymethyl)aziridines into 3,5-di(bromomethyl)morpholines only proceeded well for the N-neopentylmorpholine, which was subsequently transformed into a 3-oxa-7-thia-9-azabicyclo[3.3.1]nonane derivative. Also, in some other cases, the desired 3,5-di(bromomethyl)morpholines were isolated in low yields and transformed into the corresponding 3,5-di(cyanomethyl)morpholines.

Design and Synthesis of Potent Inhibitors of Plasmepsin I and II: X-ray Crystal Structure of Inhibitor in Complex with Plasmepsin II

New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting K(i) values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 microM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II.

Organic high-spin systems of oligoarylamines: Properties of tetraaryl-m-phenylendiamine oligocations as examined by electron transfer stopped-flow method

Abstract Three types of N,N,N′,N′-tetraaryl-1,3-phenylenediamines with bromo atoms as protecting groups were designed and synthesized. Electrochemical and novel electron transfer stopped-flow (ETSF) methods were invoked for characterizing the absorption spectra of the corresponding short-lived mono- and dicationic states. Useful molecular design rules for stabilizing the dicationic states of N,N,N′,N′-tetraaryl-1,3-phenylenediamines as precursors for positively charged high-spin systems were elucidated. An extended system, 3,3′-bis(diphenylamino)triphenylamine in the tricationic state with four bromo groups was also examined, being confirmed to give a ground-state triplet dication by ESR spectroscopy.

Perfluorocyclobutane-Based Polyester(arylene ether)s for Applications in Integrated Optics

Novel ester-containing aryl trifluorovinyl ether monomers and the resulting perfluorocyclobutane aromatic ether polymers have been synthesized and characterized to exhibit desirable properties for low optical loss waveguide applications. The monomers were prepared via a very mild esterification between the intermediate 4-trifluorovinyloxybenzoic acid and diphenol/triphenol using N,N‘-dicyclohexylcarbodiimide as the activating agent for carboxylic acid and 4-(dimethylamino)pyridinium 4-toluenesulfonate as the catalyst. Chloro and bromo atoms are incorporated into trifunctional trifluorovinyl aryl ether monomers to achieve good tunability in refractive index without introducing additional optical loss. Polymerization of the monomers proceeded in melt or solution to form perfluorocyclobutane-containing prepolymers with good processability. The combination of desirable optical polymer properties, such as thermal stability (Tg: 38−350 °C), solvent resistance, tunable refractive index (n: 1.447−1.546 at 1310 nm), and low optical loss (as low as 0.26 dB/cm at 1310 nm) can be achieved through the copolymerization of highly fluorinated and flexible difunctional monomers with chloro/bromo-containing rigid trifunctional monomers.

Facile Routes to Alkoxymaleimides/Maleic Anhydrides

New routes to alkoxymaleic anhydrides 1a/b have been described in good yields via base-induced chemoselective vinylic substitution of bromo atom in bromomaleimide 4 with alkanols, and base-induced oxa-Micahel addition of alkanols to dialkyl acetylenedicarboxylates 8a/b as key steps. An unusual acyl exchange in the conversion of 6a/b to 1a/b under very simple and mild reaction conditions is noteworthy.

Benzimidazole derivatives. 3. 3D-QSAR/CoMFA model and computational simulation for the recognition of 5-HT(4) receptor antagonists.

A three-dimensional quantitative structure-affinity relationship study (3D-QSAR), using the comparative molecular field analysis (CoMFA) method, and subsequent computational simulation of ligand recognition have been successfully applied to explain the binding affinities for the 5-HT(4) receptor (5-HT(4)R) of a series of benzimidazole-4-carboxamides and carboxylates derivatives 1-24. The K(i) values of these compounds are in the range from 0.11 to 10 000 nM. The derived 3D-QSAR model shows high predictive ability (q(2) = 0.789 and r(2) = 0.997). Steric (contribution of 43.5%) and electrostatic (50.3%) fields and solvation energy (6.1%) of this novel class of 5-HT(4)R antagonists are relevant descriptors for structure-activity relationships. Computational simulation of the complexes between the benzimidazole-4-carboxamide UCM-21195 (5) and the carboxylate UCM-26995 (21) and a 3D model of the transmembrane domain of the 5-HT(4)R, constructed using the reported crystal structure of rhodopsin, have allowed us to define the molecular details of the ligand-receptor interaction that includes (i) the ionic interaction between the NH group of the protonated piperidine of the ligand and the carboxylate group of Asp(3.32), (ii) the hydrogen bond between the carbonyl oxygen of the ligand and the hydroxyl group of Ser(5.43), (iii) the hydrogen bond between the NH group of Asn(6.55) and the aromatic ring of carboxamides or the ether oxygen of carboxylates, (iv) the interaction of the electron-rich clouds of the aromatic ring of Phe(6.51) and the electron-poor hydrogens of the carbon atoms adjacent to the protonated piperidine nitrogen of the ligand, and (v) the pi-sigma stacking interaction between the benzimidazole system of the ligand and the benzene ring of Tyr(5.38). Moreover, the noticeable increase in potency at the 5-HT(4)R sites, by the introduction of a chloro or bromo atom at the 6-position of the aromatic ring, is attributed to the additional electrostatic and van der Waals interaction of the halogen atom in a small cavity located between transmembrane domains 5 and 6.

Synthesis and Cytotoxic Evaluation of α‐Methylene‐γ‐butyrolactone Bearing Naphthalene and Naphtho[2,1‐b]furan Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Aminoketone, oxazole and thiazole synthesis. Part 15.1 2-[4-(4-halobenzenesulphonyl)-phenyl]-5-aryloxazoles

Acylaminoacylation of aromatic hydrocarbons (benzene, toluene, meta-xylene, mesitylene) with 2-(4-benzenesulfonyl-(4-halophenyl))-5-oxazolones in the presence of anhydrous aluminum chloride leads to 2-aza-1,4-diones 5 which cyclize under the action of phosphorus oxychloride yielding the corresponding 2-(4-(4-halobenzenesulphonyl)-phenyl)-5-aryloxazoles 6. The para- halogens are chloro or bromo atoms. Electronic absorption, vibrational, 1 H-NMR and 13C-NMR spectral data are presented. The UV and NMR spectra provide evidence for the non-coplanarity of the oxazole and mesityl rings.

Synthesis and cytotoxic evaluation of α-methylene-γ-butyrolactone bearing naphthalene and naphtho[2,1- b]furan derivatives

Naphthalene α-methylene-γ-butyrolactones exhibits a unique cytotoxicity profile. They are highly cytostatic for leukaemia cancer cells but are not cytocidal. For almost all the solid tumours tested, they are both cytostatic and cytocidal. Substitution of a bromo atom on either naphthalene or both naphthalene and γ-phenyl moiety of the lactone enhanced potency while retaining the same cytotoxicity profile. The tricyclic naphtho[2,1- b]furan derivatives, prepared from 2-hydroxy-1-naphthaldehyde in an efficient pathway, also possess the same cytotoxicity profile.

Complexes of copper(II) dihalide with 2,2′-dipyridylamine. X-ray diffraction structures of the [dibromo-bis(dipyam)copper(II)]–water (1:2) and di[chloro-bis(dipyam)copper(II)]diiodide–acetonitrile (1:2) complexes

The formation of complexes between copper(II) halides and 2,2′-dipyridylamine (dipyam) has been studied systematically. Only complexes with a 1:1 and 1:2 metal-to-ligand ratio are formed. Some mixed chloro–iodide and halide–PF 6 compounds have also been isolated. The X-ray diffraction structures of the [Cu(dipyam) 2Br 2] · 2H 2O ( I) and the [Cu(dipyam) 2Cl] 2I 2 · 2CH 3CN ( II) complexes are reported. I is a rare example of an octahedral coordination among the copper(II) halide complexes of dipyam. The two bromo atoms, which occupy the apical positions, are H-bonded to the water molecules of crystallization. II is a dimer, where each copper forms a cationic chloro-complex of approximately trigonal bipyramidal geometry, the dimerization being due to hydrogen bonds formed by the NH group of one of the two dipyams coordinated to each metal atom with the chlorine atom of the centrosymmetric cationic complex. The iodide anions are hydrogen-bonded to the NH groups of the dipyams not involved in the dimerization.

Synthesis of novel nucleosides of 4-oxoquinoline-3-carboxylic acid analogues

A series of new ribonucleosides 1a–d having 4-oxoquinoline-3-carboxylic acid substituted with a chloro or bromo atom in the aromatic ring, as the nitrogen base, was synthesized and examined for anti-HIV activity. Compounds 1a and 1c showed a modest inhibition activity on HIV-1 reverse transcriptase, inhibiting 10% of the enzyme activity at the concentration of 100 μM. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 197–202, 1999

Radiosynthesis of new radio neurotensin (8-13) analogues

Two types of radiolabelled neurotensin(8-13) analogues have been synthesised. For radioiodination 2- and 4-bromophenyl-acetyl and 2- and 4-bromobenzoyl Arg8 substituted neurotensin(8-13) were used as substrates for radiolabelling carried out by the Cu1+ assisted non-isotopic nucleophilic exchange with a labelling yield ranging from 55 to 85% depending on the position of the bromo atom in the phenyl ring. For labelling with 111In, DTPA was substituted as chelating group on the Arg8 position of neurotensin(8-13). Labelling was achieved in kit-conditions with a yield of 98%. The non carrier added peptide analogue was recovered by HPLC with a purity >99% and a specific activity of at least 370 TBq/mmol. The inhibition constant values for the binding of [3H]neurotensin to guinea pig fore brain membranes were of the order of 7.5 nM for the halophenyl compounds and 6.5 nM for the DTPA substituted analogue. © 1998 John Wiley & Sons, Ltd.