Pendant Aryl Ring Research Articles

Coumarin containing hetero[5/6]helical donor–acceptor molecules: Synthesis, photophysical properties and DFT studies

Coumarin containing hetero[5/6]helical derivatives with alkoxy substituent on coumarin ring were designed, synthesized and studied for their photophysical properties. Along with type of extended helical core around coumarin moiety, substitution on pendent aryl ring was also found to have significant effect on photophysical properties. Hetero [5]helical coumarin with furan ring in helical core and cyano substituted pendant aryl ring, compound 20a exhibited good quantum yield with blue fluorescence in both solid and solution state as compared to corresponding nitro analogue. For nitro substituted pendant aryl ring, phenanthrene moiety in helical core in compound 15b was found to play key role to show yellow fluorescence in hetero[6]helical coumarin. All the compounds were studied by DFT calculations for various structural as well as electronic parameters. TD-DFT calculations were studied for all the compounds to calculate various electronic parameters associated with excited state and correlated with the observed photophysical properties.

Synthetic Kavalactone Analogues with Increased Potency and Selective Anthelmintic Activity against Larvae of Haemonchus contortus In Vitro.

Kava extract, an aqueous rhizome emulsion of the plant Piper methysticum, has been used for centuries by Pacific Islanders as a ceremonial beverage, and has been sold as an anxiolytic agent for some decades. Kavalactones are a major constituent of kava extract. In a previous investigation, we had identified three kavalactones that inhibit larval development of Haemonchus contortus in an in vitro-bioassay. In the present study, we synthesized two kavalactones, desmethoxyyangonin and yangonin, as well as 17 analogues thereof, and evaluated their anthelmintic activities using the same bioassay as employed previously. Structure activity relationship (SAR) studies showed that a 4-substituent on the pendant aryl ring was required for activity. In particular, compounds with 4-trifluoromethoxy, 4-difluoromethoxy, 4-phenoxy, and 4-N-morpholine substitutions had anthelmintic activities (IC50 values in the range of 1.9 to 8.9 µM) that were greater than either of the parent natural products—desmethoxyyangonin (IC50 of 37.1 µM) and yangonin (IC50 of 15.0 µM). The synthesized analogues did not exhibit toxicity on HepG2 human hepatoma cells in vitro at concentrations of up to 40 µM. These findings confirm the previously-identified kavalactone scaffold as a promising chemotype for new anthelmintics and provide a basis for a detailed SAR investigation focused on developing a novel anthelmintic agent.

Chemoselective Trifluoroethylation Reactions of Quinazolinones and Identification of Photostability.

Herein, we report chemoselective trifluoroethylation routes of unmasked 2-arylquinazolin-4(3 H)-ones using mesityl(2,2,2-trifluoroethyl)iodonium triflate at room temperature. Homologous C-, O-, and N-functionalized subclasses are accessed in a straightforward manner with a wide substrate scope. These chemoselective branching events are driven by Pd-catalyzed ortho-selective C-H activation at the pendant aryl ring and base-promoted reactivity modulation of the amide group, leveraging the intrinsic directing capability and competing pronucleophilicity of the quinazolin-4(3 H)-one framework. Furthermore, outstanding photostability of the quinazolin-4(3 H)-one family associated with nonradiative decay is presented.

Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat.

A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.

Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization

The discovery of 3-methoxy-9-(3′,4′,5′-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents. A series of twenty-two new benzosuberene-based analogues of KGP18 was designed and synthesized. These compounds vary in their methoxylation pattern and separately incorporate trifluoromethyl groups around the pendant aryl ring for the evaluation of the effect of functional group modifications on the fused six-membered aromatic ring. In addition, the 8,9-saturated congener of KGP18 has been synthesized to assess the necessity of unsaturation at the carbon atom bearing the pendant aryl ring. Six of the molecules from this benzosuberene-series of compounds were active (IC50 < 5μM) as inhibitors of tubulin polymerization while four analogues were comparable (IC50 approximately 1μM) in their tubulin inhibitory activity to CA4 and KGP18. The potency of a bis-trifluoromethyl analogue 74 and the unsaturated KGP18 derivative 73 as inhibitors of tubulin assembly along with their moderate cytotoxicity suggested the potential utility of these compounds as vascular disrupting agents (VDAs) to selectively target microvessels feeding tumors. Accordingly, water-soluble and DMSO-soluble phosphate prodrug salts of each were synthesized for preliminary in vivo studies to assess their potential efficacy as VDAs.

Synthesis of structurally diverse benzosuberene analogues and their biological evaluation as anti-cancer agents

Diversely functionalized, fused aryl–alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure–activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton’s reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0μM) and strongly cytotoxic against selected human cancer cell lines (for example, GI50=5.47nM against NCI-H460 cells with fluoro-benzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18 (referred to as KGP265, compound 44) and a water-soluble serinamide salt (compound 48) of KGP156 were also synthesized and evaluated in this study.

Novel tetrahydropyrido[3,2-c]pyrroles as 5-HT7 antagonists

The synthesis and SAR for a novel series of tetrahydropyrido[3,2-c]pyrroles is described. Optimization of the pendant aryl ring lead to high binding affinity at the 5-HT7 receptor when small lipophilic groups were placed in the para position. Modification of the N-benzyl group and secondary amine were not well tolerated. A representative set of compounds was shown to be functional antagonists of the 5-HT7 receptor.

Synthesis and Pharmacological Characterization of Novel Druglike Corticotropin-Releasing Factor 1 Antagonists

To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.

Pyrimidine benzamide-based thrombopoietin receptor agonists

A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.

Coupling of Arylamines with Coordinated Arylazopyrimidines in Palladium(II) Complexes

2-(Arylazo)pyrimidine (1) reacts with palladium chloride and gives Pd(aapm)Cl2 (2) which undergoes a palladium(II)-mediated novel carbon−nitrogen bond formation reaction of the aromatic amines to the ortho-C−H function of the pendant aryl ring in the coordinated 2-(arylazo)pyrimidine. The reactant, Pd(papm)Cl2 (2a) and the product, Pd(papm-N-C6H4-OCH3-p)Cl (5a) have been characterised by X-ray crystal structure. The coupled products exhibit low energy transitions (NIR region) unlike the parent complex, Pd(aapm)Cl2. The cyclic voltammogram shows an oxidation couple at positive potential to SCE. The EHMO calculation suggests that the spectral feature in Pd(aapm)Cl2 (2) is due to the MLCT [d(Pd)⇄π*(azo)] whereas in Pd(aapm-N-C6H4-X-p)Cl (3−6) the transition at the NIR region is due to the intravalence charge transfer (IVCT) transition.

Coupling of o and/or m-substituted arylamines with the ortho-C–H function of the pendant aryl ring in coordinated arylazopyrimidinepalladium(II) complexes. Spectral and electrochemical characterisation of the products

2-(Arylazo)pyrimidines (aapm) are N,N′-chelators which form palladium(II) complexes, Pd(aapm)Cl2(1). The reaction of Pd(aapm)Cl2(1) with arylamines (ArNH2) yields Pd(aapm-N-Ar)Cl, (2)–(7), complexes of the tridentate N,N′,N″-donor system in which arylamines are fused to the ortho C–H function of the pendant aryl ring in the coordinated 2-(arylazo)pyrimidine, leading to the C–N coupled product. Pd(aapm-N-Ar)Cl, complexes (2)–(7), exhibit a broad intense absorption band in n.i.r. region (870–920 nm), while the parent complex, Pd(aapm)Cl2, shows an intense absorption at 425 nm. Cyclic voltammograms of (2)–(7) exhibit an oxidation couple at positive potential to s.c.e. together with three reductions at negative side. The oxidation may involve conversion of the chelated azoarylamine to semibenzoquinone azoarylamine fragment. The reduction is due to the accommodation of electrons in the azoimine function. The absorption spectra in the n.i.r. region may be regarded as HOMO → LUMO intravalence charge transfer (i.v.c.t.) transitions.

Chemistry of azopyrimidines. Part IV. Aromatic hydroxylation in palladium(II)-arylazopyrimidines

2-(Arylazo)pyrimidines (aapm) are N,N′-chelating ligands and synthesise orange-red complexes of composition [Pd(aapm)Cl2],1, with Pd(MeCN)2Cl2 in MeCN. The complex hascis-PdCl2 configuration [v(Pd-Cl): 340, 360 cm−1]. The treatment of Tollen’s reagent (‘AgOH’) leads to chelatative hydroxylation in the pendant aryl ring, affording a green phenolato complex, Pd(aapmO)Cl,5 (aapmO is deprotonated 2-((8-hydroxo)arylazo)pyrimidine). The reaction is also carried out by controlled addition of dilute sodium hydroxide in air or by the addition of PhIO/m-chloroperbenzoic acid to a MeCN suspension of the complex. A single Pd-Cl stretch at 360 cm−1 supports the composition of phenolato complex. Unlike Pd(aapm)Cl2 the hydroxylated product, Pd(aapmO)Cl, has a structured intense absorption in the visible region near 670 nm. The Pd-Cl bond in Pd(aapmO)Cl is highly sensitive to nucleophilic substitution and slowly hydrolyses in aqueous medium.