Basic Heterocycles Research Articles

Simplified aminocoumarin analogues as anticancer agents: Amino isosteric replacement in the noviose moiety resulted in substantial enhancement of antiproliferative activity

Abstract Simplified aminocoumarin analogues, either noviosylated or simple basic heterocycle attached 3-amido-coumarin compounds, are known to be promising anticancer agents targeting the C-terminal ATP-binding site of Hsp90. In this study, 3′-amino isosteric replacement in the noviose moiety of two known noviose containing Hsp90 C-terminal inhibitors was synthetically realized for the first time. In vitro evaluation of these compounds suggested that the introduction of a basic amino group into the noviose subunit resulted in significant improvement of their cytotoxicities.

Exploring the Anticancer Activity of Functionalized Isoindigos: Synthesis, Drug‐like Potential, Mode of Action and Effect on Tumor‐Induced Xenografts

Meisoindigo has been used as an indirubin substitute for the treatment of chronic myeloid leukemia (CML) for several years. In view of its poor solubility and erratic absorption, several investigations have focused on developing analogues with more desirable physicochemical profiles. Here, we investigated the structure-activity relationship (SAR) of meisoindigo with respect to its antiproliferative activity on leukemic K562 cells and found that appending a phenalkyl side chain onto the lactam NH resulted in analogues that retained good activity. Furthermore, analogues in which the phenyl ring was substituted with a basic heterocycle were significantly more soluble than meisoindigo while retaining acceptable antiproliferative profiles. The most promising analogue (E)-1-(2-(4-methylpiperazin-1-yl)ethyl)-[3,3'-biindolinylidene]-2,2'-dione (5-4) is more potent than meisoindigo across a panel of malignant cells, with at least 40 times greater solubility than meisoindigo, little or no tendency to aggregate in solution and capable of significantly extending the lifespans of animals with K562 induced xenografts. Mechanistically, it induced apoptotic cell death and disrupted the progression of K562 cells from the G(1) to G(2) phase. Taken together, our findings highlighted the feasibility of addressing the physicochemical deficits of the isoindigo scaffold by systematic modifications which was achieved without overt loss of growth inhibitory activity.

Heterobiaryl and heterobiaryl ether derived M 5 positive allosteric modulators

This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M 5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G q mAChR M 1, M 3, M 5 PAM. An iterative parallel synthesis approach was employed to incorporate basic heterocycles to improve physiochemical properties.

Small, non-peptide C5a receptor antagonists: Part 2

Starting from 2, several highly potent C5a receptor antagonists were synthesised through α-amide substitution. Attempts to increase the polarity of these compounds through the introduction of basic centres or incorporation into weakly basic heterocycles is described.

Mononuclear and dinuclear iron thiocyanate and selenocyanate complexes of tris-pyrazolylmethane ligands

Treatment of Fe(NCE) 2 (E = S or Se) with 1 equiv. of tris-(3,5-dimethylpyrazol-1-yl)methane (tpm′) yields dimeric [{Fe(NCE)(μ-NCE)(tpm′)} 2]. These dimers are cleaved in MeCN solution, yielding isolable [Fe(NCE) 2(tpm′)(NCMe)], whose solvent ligands can be substituted by moderately basic heterocycle donors to give [Fe(NCE) 2(tpm′)(py)], [Fe(NCS) 2(tpm′)(im)] or [{Fe(NCE) 2(tpm′)} 2(μ-4,4′-bipy)]. The monodentate heterocycles in the latter compounds are readily lost in most solvents, regenerating the dimeric starting materials. [Fe(NCS) 2(tpm′)(py)] was also prepared by reacting [Fe(NCS) 2(py) 4] with tpm′. The mononuclear compounds are all high-spin between 5 and 300 K, despite mostly having regular coordination geometries and tpm′ ligand conformations that should in principal favour spin-crossover. Analogous products containing unsubstituted tris-(pyrazol-1-yl)methane (tpm) could not be isolated, but the crystal structure of the double salt [Fe(tpm) 2][Fe(NCS) 5(py)], containing a new iron(III) anion, is described.

Reactivity of substituted seven-membered heterocyclic sulfones: Spectroelectrochemical study and theoretical modeling

The redox behaviour of four arylidene substituted derivatives of dibenz-[b,e]-thiepin-5,5-dioxide-11-one was investigated in aprotic media by cyclic voltammetry coupled with spectral EPR and UV–vis–absorption techniques. The results point out that the predominant chemical reaction following the electron transfer (ET) is the cleavage of the C–SO 2 bond (characteristic for the basic heterocycle) and not isomerization and/or coupling reactions (characteristic for the aryl vinyl sulfones). The solvent dependent semiempirical modeling performed in the frame of AMSOL programme package evidences as more probable the cleavage of the C–SO 2 bond in the phenyl vinyl derivatives 1 and 2 after the second ET, and explains satisfactorily the different behaviour of compounds 3 and 4, determined by the presence of the phenolic OH group.

Synthesis of fluorescein derivatives containing metal-coordinating heterocycles

Fluorescein derivatives that contain Lewis basic heterocycles have been synthesized by concise reaction sequences. The preparation of these compounds proceeds by functionalization of an electron-rich aromatic precursor and subsequent condensation to form the fluorophore. These compounds are envisioned as components of metal-based sensors.

Synthesis and structure-activity relationships of novel arylpiperazines as potent and selective agonists of the melanocortin subtype-4 receptor.

The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K(i) = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K(i) = 6600 nM). Sulfonamide 39 (K(i) = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K(i) = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K(i) = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.

Development of QSARs to investigate the bacterial toxicity and biotransformation potential of aromatic heterocylic compounds

A series of aromatic heterocyclic and hydrocarbon compounds were tested for toxicity and biotransformation potential against two contrasting lux-marked whole-cell microbial biosensors. Toxicity was determined by inhibition of light output of a Pseudomonas fluorescens construct that expresses lux constitutively. Biotransformation was tested by increase in light output of P. fluorescens HK44 (pUTK21), which expresses lux when in the presence of a metabolic intermediate (salicylate). The data were then modelled against physical/chemical properties of the compounds tested to see if quantitative structure–activity relationships (QSARs) could be derived. Toxicity was found to be accurately predicted by log K ow ( R 2=0.95, Q 2=0.88), with the basic (pyridine-ring containing) heterocycles modelled separately. The biotransformation data were best modelled using lowest unoccupied molecular orbital (LUMO) energies ( R 2=0.90, Q 2=0.87).

The calculation of sensitometric properties of 1,2,4-triazolo[1,5-a]pyrimidines

Quantitative structure–property relationships were proposed by using artificial neural networks and information received from 13C NMR spectra. The suitability of 1,2,4-triazolo[1,5-a]pyrimidines as stabilizers in photographic silver halide materials was determined from their chemical structures. For the numeric coding of the chemical structures of differently substituted 1,2,4-triazolo[1,5-a]pyrimidines 1–44 only information available from their 13C NMR spectra was used. Even an assignment of the 13C NMR chemical shift values to the carbons was not necessary. The best results were achieved by combination of the 13C NMR chemical shifts of carbons of the basic heterocycle and the relative fog Drel using a feed-forward two-layer neural network. For some compounds with a good stabilizing effect the calculated results strongly differ from experimental values giving indication of a mechanism which is not covered by the 13C NMR chemical shifts.

LIFE-THREATENING ASTHMA

This article focuses on various issues related to acute, life-threatening episodes of asthma. The areas discussed include epidemiology, clinical assessment, pharmacologic treatment with bronchodilators and anti-inflammatory agents, endotracheal intubation, mechanical ventilation, adjunctive and nonconventional therapy used in the management of the mechanically ventilated asthmatic, and the prognosis of patients who require mechanical ventilation, including both short-term morbidity and long-term outlook.

Preparation ofN-Arylated Heterocycles by Nucleophilic Aromatic Substitution

Abstract Nucleophilic aromatic substitution of fluorobenzoates and fluorophenylnitriles with weakly basic heterocycles readily occur. This synthetic methodology is utillized to produce potent angiotensin-II antagonists.

6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure-activity relationships.

Starting from the recently reported nonpeptidic angiotensin II (AII) receptor antagonists DuP753 (1) and Exp 7711 (2), we have designed and investigated novel substituted benzimidazoles. Systemic variation of several substituents at the benzimidazole ring positions 4-7 led to the finding that substitution in position 6 with acylamino groups results in highly active AII antagonists. Compounds with 6-membered lactam or sultam substituents in position 6 of benzimidazole showed receptor activities in the low nanomolar range but were only weakly active when given orally to rats. In contrast, analogous substitution of the benzimidazole moiety with basic heterocycles resulted in potent AII antagonists which were also well absorbed after oral application. The most active compound of this series, 33 (BIBR 277), was selected as a candidate for clinical development. On the basis of molecular modeling studies a binding model of this new class of AII antagonists to the AT1 receptor is proposed.

Short syntheses of 1,2,3,5‐tetrahydro‐5‐oxopyrrolo‐[1,2‐a]quinoline‐4‐carboxylic acid and 1,2,3,4‐tetrahydro‐6H‐6‐oxopyrido[1,2‐a]quinoline‐5‐carboxylic acid derivatives

AbstractShort and efficient syntheses of 7‐fluoro‐8‐(4‐methylpiperazin‐1‐yl)‐1,2,3,5‐tetrahydro‐5‐oxopyrrolo[1,2‐a]‐quinoline‐4‐carboxylic acid and 8‐fluoro‐9‐(4‐methylpiperazin‐1‐yl)‐1,2,3,4‐tetrahydro‐6H‐6‐oxopyrido[1,2‐a]‐quinoline‐5‐carboxylic acid are described. Both basic heterocycles were synthesized in two steps by the condensation of a benzoylacetate with an imino ether followed by an intramolecular nucleophilic displacement cyclization reaction.

Benzo [b] tellurophènes substitues en position 3

Abstract3‐substituted benzo (b) tellurophenes can be obtained through Wittig or Wittig‐Horner reaction on 2 H‐benzo (b) tellurophene‐3‐one (telluroindoxyl). This reaction shows a partial isomerisation specific of the tellurium series, due to breaking of Te‐CH2 bond. The products so obtained can lead to various mono 3‐substituted derivatives (CH3, CHO, CH2OH, COOH, COOCH3, CN, CONH2).Reaction of triphenylphosphin/TeX4 on the same substrate leads to 3‐chloro and 3‐bromo benzo (b) tellurophenes, which could not be obtained by halogenation of the basic heterocycle. Acetylation of benzo (b) tellurophene with Ac2O/CF3COOH leads to a mixture 76/24 of 2‐acetyl and 3‐acetylbenzo (b) tellurophenes, which could be separated through thin‐layer chromatography.