Heteroaromatic Analogues Research Articles

3-Benzylmenadiones and their Heteroaromatic Analogues Target the Apicoplast of Apicomplexa Parasites: Synthesis and Bioimaging Studies.

The apicoplast is an essential organelle for the viability of apicomplexan parasites Plasmodium falciparum or Toxoplasma gondii, which has been proposed as a suitable drug target for the development of new antiplasmodial drug-candidates. Plasmodione, an antimalarial redox-active lead drug is active at low nM concentrations on several blood stages of Plasmodiumsuch as early rings and gametocytes. Nevertheless, its precise biological targets remain unknown. Here, we described the synthesis and the evaluation of new heteroaromatic analogues of plasmodione, active on asexual blood P. falciparum stages and T. gondii tachyzoites. Using a bioimaging-based analysis, we followed the morphological alterations of T. gondii tachyzoites and revealed a specific loss of the apicoplast upon drug treatment. Lipidomic and fluxomic analyses determined that drug treatment severely impacts apicoplast-hosted FASII activity in T. gondii tachyzoites, further supporting that the apicoplast is a primary target of plasmodione analogues. To follow the drug localization, "clickable" analogues of plasmodione were designed as tools for fluorescence imaging through a Cu(I)-catalyzed azide-alkyne cycloaddition reaction. Short-time incubation of two probes with P. falciparum trophozoites and T. gondii tachyzoites showed that the clicked products localize within, or in the vicinity of, the apicoplast of both Apicomplexa parasites. In P. falciparum, the fluorescence signal was also associated with the mitochondrion, suggesting that bioactivation and activity of plasmodione and related analogues are potentially associated with these two organelles in malaria parasites.

Pinpoint-fluorinated polycyclic aromatic hydrocarbons (F-PAHs) and their heteroaromatic analogs: syntheses, reactivities, and properties

Abstract Pinpoint-fluorinated polycyclic aromatic hydrocarbons (F-PAHs) and their heteroaromatic analogs, which are regioselectively substituted by one or two fluorine atoms, were systematically synthesized by Friedel–Crafts cyclization of fluoroalkenes (2-trifluoromethyl-1-alkenes, 1,1-difluoro-1-alkenes, 1,1,2-trifluoro-1-alkenes, and 1,1-difluoroallenes) that were Al(III)-mediated, Pd(II)-catalyzed, and In(III)-catalyzed. The key feature of these reactions is ring closures that proceed via α-fluorine-stabilized CF2 cations and related species. Using an array of synthesized F-PAHs and their heteroaromatic analogs, their chemical reactivities and physical properties were investigated. (i) The reactivities of F-PAHs and their heteroaromatic analogs were used for further ring construction. (ii) The crystal structures of F-PAHs revealed that the planarity of their π-conjugated systems was not compromised because of the low steric demand of fluorine atoms. (iii) The introduction of fluorine atom(s) into PAH molecules increased their solubility in organic solvents, which was best exemplified by the high solubility of 6-fluoropicene (5.3 wt%) and 6,7-difluoropicene (5.4 wt%) in THF. (iv) One of the F-PAHs, 13-fluoropicene exhibited p-type semiconducting behavior (mobility 6.6 × 10−2 cm2/Vs by vacuum deposition; 1.3 × 10−4 cm2/Vs by spin casting using toluene as a solvent). (v) The HOMO–LUMO energy gaps of the F-PAHs were smaller than those of the corresponding fluorine-free PAH (i.e. picene) by 0.02 to 0.26 eV, and the HOMO and LUMO energy levels were lowered by 0.10 to 0.22 and 0.12 to 0.41 eV, respectively.

Dihydroazolopyrimidines: Past, Present and Perspectives in Synthesis, Green Chemistry and Drug Discovery.

Dihydroazolopyrimidines are an important class of heterocycles that are isosteric to natural purines and are therefore of great interest primarily as drug-like molecules. In contrast to the heteroaromatic analogs, synthetic approaches to these compounds were developed much later, and their chemical properties and biological activity have not been studied in detail until recently. In the review, different ways to build dihydroazolopyrimidine systems from different building blocks are described - via the initial formation of a partially hydrogenated pyrimidine ring or an azole ring, as well as a one-pot assembly of azole and azine fragments. Special attention is given to modern approaches: multicomponent reactions, green chemistry, and the use of non-classical activation methods. Information on the chemical properties of dihydroazolopyrimidines and the prospects for their use in the design of drugs of various profiles are also summarized in this review.

3-BocNH-ABNO-catalyzed aerobic oxidation of alcohol at room temperature and atmospheric pressure

A transition-metal-free catalytic system has been developed for selective transformation of alcohol to aldehydes or ketones. The reactions were performed with 3-(tert-butoxycarbonylamino)-9-azabicyclo[3.3.1]nonane N-oxyl (3-BocNH-ABNO) as the catalyst, NaNO2 as the co-catalyst, molecular oxygen as the terminal oxidant, and AcOH as the solvent under room temperature. This catalytic system exhibited broad functional group tolerance. A series of alcohol substrates, including primary and secondary benzylic alcohols, heteroaromatic analogues, primary and secondary aliphatic alcohols, could be converted into their corresponding aldehydes and ketones in good conversions and selectivities.

Piperazine as an Inexpensive and Efficient Ligand for Pd-Catalyzed Homocoupling Reactions to Synthesize Bipyridines and Their Analogues.

The synthesis of bipyridines, especially 2, 2'-bipyridines, remains challenging because the catalytic cycle can be inhibited due to coordination of bipyridine to transition metal. Thus, the development of efficient methods for the synthesis of bipyridines is highly desirable. In the present work, we presented a promising approach for preparation of bipyridines via a Pd-catalyzed reductive homocoupling reaction with simple piperazine as a ligand. Simple and inexpensive piperazine was used as a ligand for Pd-catalyzed homocoupling reaction. The combination of Pd(OAc)2 and piperazine in dimethylformamide (DMF) was observed to form an excellent catalyst and efficiently catalyzed the homocoupling of azaarenyl halides, in which DMF was used as the solvent without excess reductants although stoichiometric reductant was generally required to generate the low-oxidation-state active metal species in the catalytic cycles. In this case, good to excellent yields of bipyridines and their (hetero) aromatic analogues were obtained in the presence of 2.5 mol% of Pd(OAc)2 and 5 mol% of piperazine, using K3PO4 as a base in DMF at 140°C. According to the results, piperazine as an inexpensive and efficient ligand was used in the Pd(OAc)2-catalyzed homocoupling reaction of heteroaryl and aryl halides. The coupling reaction was operationally simple and displayed good substrate compatibility.

From Acenaphthenes to (+)-Delavatine A: Visible-Light-Induced Ring Closure of Methyl (α-Naphthyl) Acrylates.

Disclosed herein is a visible light mediated cyclization of methyl (α-naphthyl) acrylates and heteroaromatic analogues yielding substituted acenaphthenes and azaacenaphthenes. This highly functional-group-tolerant transformation was put to the test in an enantioselective formal synthesis of delavatine A. Mechanistic details were elucidated by DFT-calculations revealing an unusual intramolecular H-transfer mediated by a primary amine. The generality of this transformation enables a novel synthetic strategy of five membered ring annulation at an advanced stage, allowing reliance upon naphthalene chemistry up to the point of acenaphthene construction.

Excited state transformations of heterostilbenes: Pathways to polycyclic skeleta

For the past 40 years M. Šindler-Kulyk's group has been studying, among other things, excited state reactivity of various heteroaromatic analogues of o -vinylstilbenes, o -vinylstyryl- and o -phenylenedivinylene-aromatic heterocycles, simply called o -vinyl-heterostilbenes and di-heterostilbenes. A concise overview of this vast research is presented. To date furan, pyrrole, sydnone, thiophene, oxazole, and most lately pyridine nuclei were incorporated into the basic stilbene-type skeleton. The photochemistry of these compounds is of great importance as it gives a pathway to new polycyclic products that are taxing or even impossible to obtain via ground state synthetic organic chemistry approaches. It is also an interesting subject because of illustration of diverse photoproducts formed by introducing different substituents into the system, thereby changing the conformation and electronic distribution in the molecule. Star representatives of the group of polycycles that were obtained are the benzobicyclo[3.2.1]octadiene photoproducts, which might show promising biological activity.

New Heteroaromatic Derivatives of the Anthelmintic Cyclooctadepsipeptide PF1022A by Click-Chemistry

The cyclooctadepsipeptide PF1022A (1) and its semisynthetic, commercial analogue emodepside (2) have been established as excellent anthelmintics with resistance breaking properties. For a second generation anthelmintic cyclooctadepsipeptide with improved activity for instance against human worm infections new derivatives are required. We detail here for the first time the synthesis of phenylheteroaromatic analogues of PF1022A prepared by efficient click-reactions. Keywords: Anthelmintic, click-chemistry, cyclodep, heteroaromatic analogues, PF1022A, sipeptide.

ChemInform Abstract: Synthesis of Functionalized 2‐Trifluoromethylquinolines and Their Heteroaromatic Analogues.

Abstractby cyclization of electron‐rich anilines with heterocyclic CF3‐containing amines

Smooth Photocatalyzed Benzylation of Electrophilic Olefins via Decarboxylation of Arylacetic Acids.

Arylacetic acids were used as sources of benzyl radicals under tetrabutylammonium decatungstate photocatalyzed conditions for the benzylation of electron-poor olefins. The reaction proceeds smoothly in a mixed aqueous medium (MeCN/H2O 2/1) in the presence of NaHCO3, NaClO4, and an electron transfer agent (biphenyl). The reaction tolerates a wide variety of functional groups on the aromatic ring (whether electron donating or electron withdrawing) and can be extended to heteroaromatic analogues. The olefins have the double role of radical trap and electron acceptor. The present approach can also be extended to arylpropionic acids (including the nonsteroidal anti-inflammatory drugs ibuprofen and flurbiprofen), as well as mandelic acid derivatives.

SYNTHESIS OF ISATOIC ANHYDRIDE DERIVATIVES

Isatoic anhydride (1 H -benzo[ d ][1,3]oxazine-2,4-dione) and its derivatives are convenient building blocks for the synthesis of various nitrogen-containing heterocyclic structures, such as quinazolines, quinazolones, quinazolinediones, benzodiazepines, quinolinones, and tryptanthrin derivatives. The following methods have been applied to the construction of benzo[ d ][1,3]oxazine-2,4-dione ring: cyclization of anthranilic acids, catalytic carbonylation of substituted anilines, transformation of phthalic anhydride derivatives, oxidation of isatin derivatives, and oxidation of indoles with Oxone. This microreview covers data from the last 10 years regarding the synthesis of 1 H -benzo[ d ][1,3]oxazine-2,4-dione derivatives without considering the preparation of its heteroaromatic analogs. How to Cite Bogdanov, A. V.; Mironov, V. F. Chem. Heterocycl. Compd. 2016 , 52 , 90. [ Khim. Geterotsikl. Soedin. 2016 , 52 , 90.] For this article in the English edition see DOI 10.1007/s10593-016-1837-3

Synthesis of Functionalized 2‐Trifluoromethylquinolines and their Heteroaromatic Analogues

AbstractElectron‐rich anilines and amino heterocycles were converted in one step into N‐protected functionalized aminoethyl 2‐trifluoromethylquinolines and their heteroaromatic analogues. The N‐carbamate protecting group can be easily cleaved under acidic conditions to give the corresponding amines.

Synthesis and antimicrobial activity of new 3,5-diarylidene-4-piperidone derivatives

Three series of heteroaromatic analogs (twenty seven compounds) with monoketone linkers have been synthesized and evaluated for their antimicrobial activity against six microbial strains. Among them, 3,5-dibenzylidene-1-(3,5-dichloro-2-hydroxyphenylsulfonyl)piperidin-4-one 5e showed best antifungal activity against Aspergillus niger and Aspergillus fumigatus. Structural elucidation of the synthesized compounds was determined on the basis of various spectroscopic methods.

ChemInform Abstract: Mechanistic Insights into the Post‐Cyclization Isomerization in Gold‐Catalyzed 7‐exo‐Dig‐Hydroarylations.

AbstractThe gold catalyzed intramolecular hydroarylation of biphenyls and heteroaromatic analogs proceeds in the presence of a base to give the corresponding cyclization products with an exocyclic double bond.

Mechanistic Insights into the Post‐Cyclization Isomerization in Gold‐Catalyzed 7‐exo‐dig‐Hydroarylations

The subsequent double-bond isomerization in the synthesis of dibenzocycloheptenes and their heteroaromatic analogues was investigated. In the case of biphenyls, a basic additive completely prevented an isomerization to the thermodynamic product. With electron-rich intramolecular heteroaromatic nucleophiles, the isomerization was still observed, but the kinetic product can be obtained by careful control of the reaction times in most cases. Mechanistic studies demonstrated that a slow isomerization is also possible with the gold catalyst at elevated temperatures, but much faster isomerization rates were observed with acidic additives. An observed initiation period for the gold-catalyzed isomerization indicates that not the homogenous catalyst, but a decomposition product of it may be the catalytically active species.

Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-cancer agents.

Heteroaromatic analogs of DMU-212 (8-15) have been synthesized and evaluated for their anti-cancer activity against a panel of 60 human cancer cell lines. These novel analogs contain a trans-3,4,5-trimethoxystyryl moiety attached to the C2 position of indole, benzofuran, benzothiazole or benzothiophene ring (8, 11, 13 and 14, respectively) and showed potent growth inhibition in 85% of the cancer cell lines examined, with GI50 values <1 μM. Interestingly, trans-3,4- and trans-3,5-dimethoxystyryl DMU-212 analogs 9, 10, 12 and 15 exhibited significantly less growth inhibition than their 3,4,5-trimethoxystyryl counterparts, suggesting that the trans-3,4,5-trimethoxystyryl moiety is an essential structural element for the potent anti-cancer activity of these heterocyclic DMU-212 analogs. Molecular modeling studies showed that the four most active compounds (8, 11, 13 and 14) all bind to the colchicine binding site on tubulin, and that their binding modes are similar to that of DMU-212.

ChemInform Abstract: An Efficient Gold‐Catalyzed Domino Process for the Construction of Tetracyclic Ketoethers.

AbstractThe oxidative domino cyclization/cycloaddition of enyne aldehydes and ketones (I) as well as related substrates (III) afford tetracyclic ketoethers (II) and heteroaromatic analogues (IV) by using pyridine N‐oxides as external oxidants.

Design, synthesis, and evaluation of novel heteroaromatic analogs of curcumin as anti-cancer agents

To improve the potential of curcumin to treat advanced hormone-refractory prostate cancer, three series (A–C) of heteroaromatic analogs (thirty two compounds) with different monoketone linkers have been synthesized and evaluated for cytotoxicity against two human androgen-independent prostate cancer cell lines (PC-3 and DU-145). Among them, thirty analogs are more potent than curcumin against PC-3 cells, and twenty one analogs are more cytotoxic towards DU-145 cells relative to curcumin. The most potent compounds (44, 45, 51, and 52) also showed impressive cytotoxicity against three other metastatic cancer cell lines (MDA-MB-231, HeLa, and A549), with IC50 values ranging from 50 nM to 390 nM. All four most potent analogs exhibited no apparent cytotoxicity towards the MCF-10A normal mammary epithelial cells. Taken together, selective enhancement of cell death in prostate cancer cell lines and other aggressive cancer cell lines suggests that nitrogen-containing heteroaromatic rings are promising bioisosteres of the substituted phenyl ring in curcumin.

ChemInform Abstract: Synthesis of Amino‐Substituted Indanes and Tetralins via Consecutive Multibond‐Forming Tandem Processes.

AbstractDifferent indanes, tetralins and similarly their heteroaromatic analogues can be synthesized via two one‐pot tandem syntheses starting from alkyne‐derived allylic alcohols.

Synthesis of indole analogues of the natural schweinfurthins.

An interest in the schweinfurthins, natural stilbenes with significant antiproliferative activity, has prompted efforts to prepare a set of indole analogues. To approach the desired compounds through a Horner-Wadsworth-Emmons condensation, new indole derivatives bearing a phosphonomethyl substituent in the B-ring were required. The parent indole system with the necessary substitution pattern was obtained through Stobbe condensation and cyclization. A prenyl substituent was incorporated at the C3 position of a 4,6-disubstituted indole through a highly regioselective electrophilic aromatic substitution reaction, while metalation and alkylation provided the C2-prenylated indole. After introduction of the phosphonate group through classical reactions, the new indole phosphonates were found to undergo the desired condensation with nonracemic aldehydes representing the schweinfurthin left half. This approach provides facile access to new heteroaromatic analogues of the natural schweinfurthins and should be applicable to many other natural stilbenes as well.