Thiophene Analogues Research Articles

Application of directed metallation in synthesis. Part 3: Studies in the synthesis of (±)-semivioxanthin and its analogues

The synthesis of several analogues of (±)-semivioxanthin including five thiophene analogues, using directed metalation are reported. The strategy consisted of the synthesis of functionalized naphthalene or benzo[ b]thiophene as building blocks followed by annelation of the pyrone.

Solvatochromism, Crystallochromism, and Solid State Structures of Hydrophilically Functionalized Aromatic Amino Ketones Containing Furan and Thiophene Rings

[4-Di(2-acetoxyethyl)aminophenyl]-2-furylmethanone [Fur(OAc) 2 ], [4-di(2-hydroxyethyl)-aminophenyl]-2-furylmethanone [Fur(OH) 2 ], and their thiophene analogues, [4-di(2-acetoxy-ethyl)aminophenyl]-2-thienylmethanone [Thi(OAc) 2 ] and [4-di(2-hydroxyethyl)aminophenyl]-2-thienylmethanone [Thi(OH) 2 ], have been synthesized as model compounds for the study of molecular interactions in the solid-state and liquid environments with different polarity. The UV/Vis absorption spectra of these compounds have been studied in 30 solvents of different polarity and hydrogen bonding ability. The solvent dependent UV/Vis spectroscopic band shifts ν max are analyzed using the empirical Kamlet-Taft solvent parameters π* (dipolarity/polarizability), α (hydrogen bond donating capacity), and β (hydrogen bond accepting ability) in terms of the well-established linear solvation energy relationship (LSErs): ν max = (ν max ) 0 + sπ* + aα + bβ. The solvent independent coefficients s, a, and b and (ν max ) 0 have been determined. To evaluate the environmental effects for Fur(OH) 2 and Thi(OH) 2 , the UV/Vis spectroscopic behavior of these compounds was also investigated as pure crystal powders and as a guest in ormosil sol-gel glasses. The solid-state structures of the latter compounds were determined by single-crystal X-ray diffraction techniques. The X-ray investigations confirm the existence of qualitatively different intermolecular hydrogen bonds in Fur(OH) 2 and Thi(OH) 2 , which are additionally reflected by the UV/Vis reflectance absorption spectra and are related to the solvatochromism result.

Modeling the chromatographic enantioseparation of aryl- and hetarylcarbinols on ULMO, a brush-type chiral stationary phase, by 3D-QSAR techniques.

The enantiomers of a series of chiral aryl- and hetaryl-carbinols were separated on a chiral stationary phase (ULMO) based on (S,S)-3,5-dinitrobenzoylated 1,2-diphenylethane-1,2-diamine. In all cases, the homochiral analogs of (S)-1-phenylethanol (mostly also S-enantiomers) were retained more. Log alpha values were modeled with the aid of the 3D-QSAR techniques CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) as well as a descriptor based on normal mode eigenvalues (EVA). Partial least-squares analysis with two (CoMSIA) or three (CoMFA, EVA) latent variables on a set of 22 training analytes gives cross-validated correlation coefficients q(2) = 0.85-0.91 and conventional correlation coefficients r(2) = 0.94-0.99. The quantitative structure-enantioselective retention relationships derived thereby were used to predict the separation factors of the test set, containing also hetaryl-carbinols, e.g., furan and thiophene analogs, with good accuracy.

Novel drug designing approach for dual inhibitors as anti-inflammatory agents: implication of pyridine template

Compounds incorporating thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest, owing to the therapeutic utility of the template as useful drug molecular scaffolding. We report the synthesis and pharmacological evaluation of thiophenes substituted with 4-methanesulfonyl benzoyl moiety at the fifth position of the ring, as possible anti-inflammatory lead candidates. The aryl sulfonyl methyl thiophene analogs AP29, AP82, and AP37, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, exhibited moderate to good activity at a dose level of 100mg/kg body weight P.o compared to Ibuprofen. In a five day formalin induced rat paw edema, a chronic in vivo anti-inflammatory model, candidates AP29, AP82, and AP37 inhibited the disease progression by 53%, 34%, and 65%, respectively on the fifth day, at a dose level of 100 mg/kg body weight P.o compared to Rofecoxib, Ibuprofen, and Dexamethasone at therapeutic doses which gave a protection of 53.8%, 81.5%, and 81.5%, respectively. The replacement of the 4-methanesulfonyl benzoyl moiety in AP82 with the pyridine template, 3,5-dimethyl-4-methoxy-2-pyridyl function, gave rise to AP84, which was less active in the acute model, but gave 54% and 75% protection both during the first day and fifth day, respectively, in the chronic model. A dual mechanism of action is proposed for AP84, a non-steroidal drug which has exhibited remarkable activity when compared to the steroid dexamethasone. These results open up new avenues in designing novel anti-inflammatory drugs as dual inhibitors with the incorporation of a pyridine template as part of the pharmacophore.

Purines, pyrimidines, and related fused systems. 20. Heterocyclizations of 6-alkynyl-1,3-dimethyllumazines. Synthesis of pyrrole and thiophene analogs of some natural pteridines

Sonogashira cross-coupling of 6-chloro-1,3-dimethyllumazine with terminal alkynes gave 6-alkynyl derivatives in good yields. Oxidative amination of the latter with primary alkylamines was accompanied by the pyrrole-ring closure to form 1-R"-2-R-6,8-dimethylpyrrolo[3,2-g]pteridine-5,7(6H,8H)-diones. The addition of bromine to 6-alkynyllumazines afforded the corresponding dibromoalkenes whose treatment with sodium trithiocarbonate gave rise to 2-R-6,8-dimethylthieno[3,2-g]pteridine-5,7(6H,8H)-diones. The latter compounds are close analogs of the metabolite of molybdenum cofactor (molybdopterine).

Stannous chloride-mediated reductive cyclization-rearrangement of nitroarenyl ketones.

Cyclization products are produced in excellent yields from using standard reaction conditions for nitroarene reduction to aminoarene with SnCl2. Thus, 4-methyl-2-(2-nitrobenzyl)-2H-1,4-benzothiazin-3(4H)-one (2b) upon treatment with SnCl2 in ethanol did not produce the expected aniline derivative. Instead, 6-methyl-11a, 12-dihydro-6H-quino[3,2-b][1,4]benzothiazine (3) was produced in excellent yield, presumably via novel Sn (IV)-mediated amidine formation from the initial aniline reduction product. Under identical reaction conditions, 2-(2-nitrophenyl)-thiochroman-4-one (6) produces ethyl 5,11-dihydrodibenzo[b,e][1,4]thiazepin-11-ylacetate (7). A novel semipinacol rearrangement is proposed to account for this extensive skeletal rearrangement. Aniline derivative (14) (from 6 treated with FeSO4.7H2O) forms 12-ethoxy-11,12-dihydro-6H-6,12-methanodibenzo[b,f][1,5]thiazocine (15) upon treatment with SnCl2 in ethanol. Thiophene analogues of 6 and 14 (18 and 19, respectively) react similarly, forming the analogous thiazepine (20) and cyclic N,O-acetals (21), respectively.

Photophysical studies of mixed furan, pyrrole, and thiophene-containing oligomers with three and five rings

The photophysics of several oligomers containing mixed furan, pyrrole, and thiophene heterocyclic systems is reported. The mixed systems contain three rings and five rings of the heterocycles. Comprehensive spectroscopic and photophysical data were obtained and all of the rate constants kF, kIC, and kISC were evaluated. The lowest singlet excited state is of (1)B-like origin in any solvent. It is possible to have a reasonable understanding of the photophysics of the mixed ring systems compared to all the thiophene analogs if it is considered that some π–electron decoupling occurs at the site of the pyrrole or furan substitution, although this cannot be the total answer, as is discussed.

Synthesis and cytotoxicity evaluation of thiophene analogues of 1-methyl-2,3-bis(hydroxymethyl)benzo[ g]indole bis[ N-(2-propyl)carbamate

The cytotoxicity of the bis[ N-(2-propyl)carbamates] 2 and 3 which are linked to thieno[ i, j- g]indole scaffolds through methylene bridges were studied as thiophene analogues of prototype 1. Compounds 2 and 3 were evaluated in vitro against 60 human–tumor cell lines derived from nine cancer-cell types and demonstrated, for compound 3 not only strong growth-inhibitory activities against leukemia cancer cells, but also fairly good activities against the growth of certain renal and ovarian cancer cell lines. Compound 2, the thieno[2,3- g]indole bis-carbamate, possessed only significant (MG-MID log 10 GI 50=−4.89) and selective cytoxicity against NCI–HOP92 (non-small cell lung), MALME 3M (melanoma) and IGROV 1 (ovarian) cancer cell with log 10 GI 50 values of −5.66, −5.48 and −5.47, respectively.

Synthesis and In Vitro Antitumor Activity of Thiophene Analogues of 5-Chloro-5,8-dideazafolic Acid and 2-Methyl-2-desamino-5-chloro-5,8-dideazafolic Acid

N-[5-[ N-(2-Amino-5-chloro-3,4-dihydro-4-oxoquinazolin-6-yl)methylamino]-2-thenoyl]- l-glutamic acid ( 6 ) and N-[5-[ N-(5-chloro-3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)methylamino]-2-thenoyl]- l-glutamic acid ( 7 ), the first reported thiophene analogues of 5-chloro-5,8-dideazafolic acid, were synthesized and tested as inhibitors of tumor cell growth in culture. 4-Chloro-5-methylisatin ( 10 ) was converted stepwise to methyl 2-amino-5-methyl-6-chlorobenzoate ( 22) and 2-amino-5-chloro-3,4-dihydro-6-methyl-4-oxoquinazoline ( 19 ). Pivaloylation of the 2-amino group, followed by NBS bromination, condensation with di- tert-butyl N-(5-amino-2-thenoyl)- l-glutamate ( 28 ), and stepwise cleavage of the protecting groups with ammonia and TFA yielded 6 . Treatment of 9 with acetic anhydride afforded 2,6-dimethyl-5-chlorobenz[1,3- d]oxazin-4-one ( 31 ), which on reaction with ammonia, NaOH was converted to 2,6-dimethyl-5-chloro-3,4-dihydroquinazolin-4-one ( 33 ). Bromination of 33 , followed by condensation with 28 and ester cleavage with TFA, yielded 7 . The IC 50 of 6 and 7 against CCRF-CEM human leukemic lymphoblasts was 1.8±0.1 and 2.1±0.8 μM, respectively.

SYNTHESIS AND STUDY OF THE ANTIAGGREGANT AND HYPOTENSIVE PROPERTIES OF N-BENZYL-3,3- DIMETHYL-1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES

As is known, N-benzyl-1,2,3,4-tetrahydroisoquinoline derivatives are capable of influencing the blood coagulation process [1, 2]; tiklyd, representing a thiophene analog of N-benzylisoquinoline, is a selective antiaggregant with respect to thrombocytes [3, 4]. While compounds of the 1-benzylisoquinoline series were reported to exhibit hypotensive properties [3 – 8], this activity was not studied for 2-benzylisoquinolines (i.e., N-derivatives of the heterocycle). A comparison between properties of the two groups of isoquinoline derivatives would elucidate the dependence of their pharmacological properties on the position of the benzyl radical in the molecule. N-Benzylisoquinolines (IIIa – IIIg) were synthesized via reduction of the corresponding amides (IIa – IIg) with lithium aluminum hydride. The initial amides were obtained via benzoylation of compound I in the presence of triethylamine [9]:

Photostability of electro-optic polymers possessing chromophores with efficient amino donors and cyano-containing acceptors

The photostability of various electro-optic active guest–host polymers, doped with chromophores that possess very efficient cyano-containing acceptors and dialkyamino- or diarylamino-benzenes, and also their extended thiophene analogs as bridging structures, has been investigated over a broad wavelength range in the near infrared and the visible. A variation of over 2 orders of magnitude was found in the probability that an absorbed photon will lead to a photodegraded chromophore. The most photostable chromophore contained a tricyanovinyl acceptor and a diarylaminobenzene bridge unit.

Unambiguous Assignment of the 1H- and 13C-NMR Spectra of Propafenone and a Thiophene Analogue

Full and unambiguous asssignment of all 1H- and 13C-NMR resonances of the free bases as well as the hydrochloride salts of the antiarrhythmic agent propafenone and a thiophene analogue in different solutions (DMSO-d6, CDCl3) is reported.

Synthesis of expanded calix[ n]pyrroles and their furan or thiophene analogues

meso-Dialkylporphyrinogen-like mixed cyclic oligomers containing furans, pyrroles and thiophenes have been synthesized by ‘3+1’, ‘3+2’ and ‘3+ketone’ approaches. Condensation of 2,5-bis[1-methyl-1(1 H-pyrrol-2-yl)-ethyl]furan with 2,5-bis[(α-hydroxy-α,α-dimethyl)furan or 2,5-bis[(α-hydroxy-α,α-dimethyl)thiophene resulted in the formation of the mixture of cyclic tetramer, cyclic octamer and cyclic hexamer possessing different numbers of furans (thiophenes) and pyrroles. The major product was found to be the cyclic tetramer in ‘3+1’ condensation while cyclic pentamer was the major product in ‘3+2’ condensation. Appreciable amounts of cyclic decamer was isolated in ‘3+2’ condensation. The formation of furan–pyrrole alternating cyclic hexamer in ‘3+1’ condensation indicates acid-catalyzed, reversible cleavage of the starting material during the reaction. In the same analogy, cyclic dodecamer was synthesized by ‘4+2’ approach. Synthesis of cyclic dodecamer and cyclic pentadecamer was also achieved by condensing 2,5-bis[1-methyl-1(1 H-pyrrol-2-yl)-ethyl]furan with ketones. The effect of catalysts, temperature, templates, solvent and concentration was examined and no appreciable changes in the product distribution were found.

CoMFA-SIMCA Model for antichagasic nitrofurazone derivatives

The physico-chemical properties of some 5-nitro-2-furaldehyde semicarbazones (nitrofurazones) and thiophene analogues were compared with their in vitro and in vivo trypanocidal activity against Trypanosoma cruzi (Tulahuen strain). 3D-QSAR models were obtained by applying the SIMCA methodology to the electrostatic and steric fields (CoMFA fields) of the molecules. Nitrofurazones bearing N4 substituents, which cover a range of 14–17 Å from the nitro group with a thickness of about 6 Å when considering the extended conformer, produced complete survival in infected mice. The in vitro model allows larger N4 substituents than the SURVival model, but they must not bear positive centres in the region 15–16 Å from the nitro group. Moreover, the in vitro model is in agreement with the active site of trypanothione reductase (TR). Both models can be of use in the design of novel drugs bearing an amide-like group at a distance of 7–9 Å from an easily reducible group.

Synthesis of novel sulfonyl-substituted pyrrole chromophores for second-order nonlinear optics

The first synthesis of sulfonyl-substituted pyrrole chromophores 1–4 and their UV–vis absorptions, second-order nonlinear optical properties and thermal stability are described and compared with those of the benzene, thiophene and furan analogues 5–9.

Synthesis of a thiophene analogue of kuanoniamine A

Synthesis of 9-methoxycarbonyl-7H-[1]benzothieno[4,5,6-ij][2,7]naphthyridin-7-one (3)—an analogue of kuanoniamine A (1)—via hetero Diels–Alder reaction of crotonaldehyde N,N-dimethylhydrazone with 2-methoxycarbonylbenzo[b]thiophene-4,7-dione and subsequent annelation, is described. The Diels–Alder reaction produced only the adduct with the desired regiochemistry, the structure of which was verified by 2D-NMR experiments.

Photocycloaddition of acetylselenophene to double bond containing substrates

Upon direct irradiation with light of wavelength between 290 and 320 nm, 2-acetylselenophene in the presence of olefinic substrates exhibits three types of behavior. Namely, it undergoes [2+2] cycloaddition reactions involving the CC bond of the olefinic compound and the acetyl-substituted selenophene CC bond, oxetane formation involving the carbonyl group present in the selenophene moiety and the CC bond of the olefinic compound. Third, but not less important, it acts as a photosensitizer. This versatile behavior is discussed and compared with that of several thiophene analogs.

Thiophene analogs of naphthoxazines and 2-aminotetralins: bioisosteres with improved relative oral bioavailability, as compared to 5-OH-DPAT

In the present study, a series of thiophene analogs of 2-aminotetralins and hexahydronaphthoxazines were studied in vivo for their ability to decrease striatal dopamine release, their effects on locomotor activity, and their behavioral characteristics in reserpinized rats, in order to investigate whether a thiophene moiety can act as a bioisostere for the phenol moiety. In general, the new compounds showed lower in vivo activities than 5-hydroxy-2-( N, N,-di- n-propylamino)tetralin (5-OH-DPAT). However, the introduction of the thiophene moiety gave a significant improvement of the relative oral bioavailability, compared to 5-OH-DPAT. Our results suggest that the thiophene moiety can act as a bioisostere for a phenol group in hydroxylated 2-aminotetralins. For the thianaphthoxazines it was not possible to discriminate between bioisosterism for a phenyl or a phenol moiety. The tetrahydrobenzo[ b]thiophenes could be used as lead compounds for the development of novel dopamine receptor ligands with improved relative oral bioavailability.

Thiazole and Thiophene Analogues of Donor−Acceptor Stilbenes: Molecular Hyperpolarizabilities and Structure−Property Relationships

We calculate the first hyperpolarizability (β) of several thiazole and thiophene analogues of donor−acceptor stilbene compounds using the ZINDO (sum-over-states) formalism. Because of the inherent dipolar nature of thiazole, in which C2 is electron-poor and C5 is electron-rich, the relative orientation of the thiazole subunit in the dipolar chromophore dramatically affects the nonlinear optical properties. In the “mismatched” case, the dipole of the thiazole ring opposes the molecular dipole created by the donor−acceptor substituents, while in the “matched” case, the dipole of the thiazole ring reinforces the molecular dipole. The hyperpolarizability of the “mismatched” monothiazole 2 (βμ = 68 × 10-30 cm5 esu-1) exceeds that of stilbene 1 (βμ = 34 × 10-30 cm5 esu-1) but is smaller than that of monothiophene 4 (βμ = 90 × 10-30 cm5 esu-1). By contrast, the hyperpolarizability of the “matched” monothiazole 3 (βμ = 177 × 10-30 cm5 esu-1) exceeds not only that of the “mismatched” monothiazole 2, but also that ...

Preparation of benzene, furan, and thiophene analogs of duocarmycin SA employing a newly-devised phenol-forming reaction.

Five A-ring analogs of duocarmycin SA 9a-e were synthesized in racemic form modifying our second synthetic route toward duocarmycin SA. The problem encountered at the crucial phenol forming step to secure 17a, b from 16a, b under the conventionally used Kuwajima conditions was overcome by devising a more convenient method: simple heating of 16a-c in benzene in the presence of bis(triphenylphosphine)palladium(II) chloride (10 mol%), cesium carbonate (3 eq), and triphenylphosphine (0.3 eq) gave 17a-c in high yields of 86-91%. The intermediates 17a-e were readily led to the A-ring analogs (+/-)-9a-e almost according to the reported route.