Ethylidene Derivatives Research Articles

2,1-Benzothiazine - (quinolin/thiophen)yl hydrazone frameworks as new monoamine oxidase inhibitory agents; synthesis, in vitro and in silico investigation.

Two series of new 2,1-benzothiazine derivatives have been synthesized by condensation of 4-hydrazono-1-methyl-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxide (5) with 2-chloroquinoline-3-carbaldehydes and acetylthiophenes to acquire new heteroaryl ethylidenes 7(a-f) and 9(a-k) in excellent yields. After characterization by FTIR, 1H NMR, 13C NMR and elemental analyses, the newly synthesized analogues were investigated against monoamine oxidase enzymes (MAO A and MAO B). The titled compounds exhibited activity in the lower micromolar range among which 9e was the most potent compound against MAO A with IC50 of 1.04 ± 0.01 μM whereas 9h proved to be the most potent derivative against MAO B with an IC50 value of 1.03 ± 0.17 μM. Furthermore, in vitro results were further endorsed by molecular docking studies to determine the interaction between the potent compounds and the enzyme active site. These newly synthesized compounds represent promising hits for the development of safer and potent lead molecules for therapeutic use against depression and other neurological diseases.

2-(phenylthio)ethylidene derivatives as anti-Trypanosoma cruzi compounds: Structural design, synthesis and antiparasitic activity

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi. The current chemotherapy is based on benznidazole, and, in some countries, Nifurtimox, which is effective in the acute phase of the disease, but its efficacy in the chronic phase remains controversial. It can also cause serious side effects that lead sufferers to abandon treatment. In the present work, is reported the synthesis and trypanocidal activity of new 2-(phenylthio)ethylidene thiosemicarbazones (4-15) and 1,3-thiazoles (16–26). The cyclization of thiosemicarbazones into 1,3-thiazoles presents an improvement in the cytotoxic profile for T. cruzi parasite, denoting selective compounds. Compound 18 was identified as the most promising of all compounds tested, showing an IC50 of 2.6 μM for the trypomastigote form and a non-cytotoxic effect on mouse spleen cells, reaching a selective index of 95.1. Among the 22 compounds tested, six compounds present a better trypanocidal activity, and five compounds have an equipotent activity compared to benznidazole. Flow cytometry and ultrastructural analysis were performed and indicate that compound 18 causes parasite cell death through apoptosis and acts via an autophagic pathway.

Antitumor activity of newly synthesized oxo and ethylidene derivatives of bile acids and their amides and oxazolines

Bile acid derivatives with modifications in side chain and modifications on steroid skeleton were synthetized and their antitumor activity against five human cancer cell lines was investigated. Modifications in side chain include amid group, formed in reaction with 2-amino-2-methylpropanol, and 4,4-dimethyloxazoline group, obtained after cyclization of amides. In the steroid skeleton oxo groups were introduced in position 7 (2, 2a, 2b) and 7,12 (3, 3a, 3b). Ethylidene groups were introduced regio- and stereoselectively on C-7, and/or without stereoselectivity on C-3 by Wittig reaction. By combination of these modifications, a series of 19 bile acid derivatives were synthesized. Compounds containing both C-7 ethylidene and C-12 carbonyl groups (6, 6a, 6b) shown very good antitumor activity with IC50<5µM. Altering carboxylic group to amide or oxazoline group has positive effect on cytotoxicity. Different molecular descriptors were determined in silico and after principal component analysis was found that molecular descriptor BLTF96 can be used for fast assessment of experimental cytotoxicity of bile acid derivatives.

Micellization parameters (number average, aggregation number and critical micellar concentration) of bile salt 3 and 7 ethylidene derivatives: Role of the steroidal skeleton II

BackgroundBile salts are steroidal biosurfactants. Micellar systems of bile salts are not only important for solubilization of cholesterol, but they also interact with certain drugs thus changing their bioavailability. MethodsThe number-average aggregation numbers (n¯) are determined using the Moroi–Matsuoka–Sugioka thermodynamic method. Critical micellar concentrations were determined by spectrofluorometric method using pyren and by surface tension measurements. ResultsMicelles of ethylidene derivatives possess the following values for n¯: 7-Eth-D (n¯=11 (50mM)–n¯=14.8 (100mM)); 12-Ox-7-Eth-L (n¯≈8.8, without concentration dependence) and 7,12-diOx-3-Eth-Ch (n¯≈2.9, without concentration dependence). In the planes n¯–ln k and ln CMC–ln k derivative 7-Eth-D is outlier in respect to hydrophobic linear congeneric groups. ConclusionGibbs energy of formation for 7-Eth-D anion micelles in addition to the Gibbs energy of hydrophobic interactions consists excess Gibbs energy (GE) from hydrogen bond formation between building blocks of micelles. Gibbs energy of formation for 7,12-diOx-3-Eth-Ch and 12-Ox-7-Eth-L anion micelle is determined by the Gibbs energy of hydrophobic interactions. Relative increase in hydrophobicity and aggregation number for ethylidene derivatives is larger when ethylidene group is introduced from the C7 lateral side of steroidal skeleton then it is when ethylidene group is on C3 carbon. General significancePosition of outlier towards hydrophobic congeneric groups from n¯–ln k and ln CMC–ln k planes indicates the existence of excess Gibbs energy (GE) which is not of hydrophobic nature (formation of hydrogen bonds). For the bile salt micelles to have GE (formation of secondary micelles) it is necessary that steroidal skeleton possesses C3-α-(e)-OH and C12-α-(a)-OH groups.

Synthesis of arylmethylidene(ethylidene)furanones

The data on the methods of synthesizing arylmethylidene(ethylidene) derivatives of 3H-furan-2-ones and related compounds based on the heterocyclization of different acids and their functional derivatives as well as the condensation of heterocyclic compounds with carbonyl components, are systematized in the review.

Wittig reaction (with ethylidene triphenylphosphorane) of oxo-hydroxy derivatives of 5β-cholanic acid: Hydrophobicity, haemolytic potential and capacity of derived ethylidene derivatives for solubilisation of cholesterol

Bile acid salts are biosurfactants which form mixed micelles with phospholipids in vertebrates. These mixed micelles are suitable for solubilisation of cholesterol. For therapeutic purposes some bile acid salts as sodium ursocholate are used. However, bile acid anions possess low capacity for solubilisation of cholesterol. Thus, synthesis of more hydrophobic and less membranotoxic bile acid derivatives is of the great interest. In this paper Wittig reaction between ethylidene triphenylphosphorane and different bile acids oxo derivatives is examined. Wittig reaction of bile acids has not been studied much. C12 oxo group is inert in this reaction. If Wittig reaction happens on C7 oxo group stereospecifically E ethylidene stereoisomer is obtained, while the same reaction on C3 oxo group leads to more reactive not sterospecific product. In this paper stereochemical course of investigated Wittig reactions is thoroughly analysed. Hydrophobicity of derived products is determined over the temperature (T) dependence on retention coefficients (k) in reversed phase high resolution chromatography. Using method of principle components on k=f(T) matrix it is found that values of first principle components best describe hydrophobicity of analysed bile acids, while the second principal component is responsible for their hydrophilicity. By in silico molecular descriptors: valence connectivity index of order 3 (X3v) and packing density index (PDI), linear regression equations are obtained that can be used to predict hydrophobicity (over retention coefficient) of bile acids that belong to set of more congeneric groups. Membranotoxicity is determined by haemolytic potential. Monoethylidene derivatives of bile acids (in the form of anions) have lower membranotoxicity than deoxycholic acids anion. Sodium salt of deoxycholic acid 7-ethylidene derivative has 11% greater capacity for solubilisation of cholesterol monohydrate than sodium salt of deoxycholic acid.

Chemistry of Phosphorus Ylides. Part 37. The Reaction of Phosphonium Ylides with Indoles and Naphthofurans. Synthesis of Phosphanylidenes, Pyrans, Cyclobutenes, and Pyridazine as Antitumor Agents

The reaction of the stabilized phosphonium ylides 2a, 2b with indolinones 1a, 1b and naphthofuranone 13 afforded the corresponding propylidene and ethylidene derivatives 4a, 4b, 4c, 4d and 14a, 14b. On the other hand, the active phosphacumulenes 5a, 5b react with compounds 4a, 4b, 4c, 4d by [4 + 2]‐cycloaddition to give the stable phosphanylidene indole pyranones 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h. Although compounds 14a, 14b afforded the naphthofuropyrans 16a, 16b, 16c, 16d and triphenylphosphane. Moreover, the phosphallene ylide 7 react with compounds 4a, 4b, 4c, 4d and 14a, 14b to give phosphanylidenecyclobuteneindoline 9a, 9b, 9c, 9d and naphthalenones 18a, 18b, respectively. In addition, the naphthofuropyridazine 21 was obtained from the reaction of the hydrazone 19 and the phosphacumulene 5a. The antitumor activity of some of the new compounds was evaluated, in vitro, against colon and hepatocellular carcinoma cell lines. They showed values closed to that recorded by the reference drug Doxorubicin.

Use of 2-aminoprop-1-ene-1,1,3-tricarbonitrile for the synthesis of tetrahydronaphthalene, hexahydroisoquinoline and hexahydrocinnoline derivatives with potential antitumor activities

The aim of the work was to synthesize heterocyclic compounds from 2-aminoprop-1-ene-1,1,3-tricarbonitrile and to study their antitumor activities. The title reagent reacted with cyclohexanone to give the ethylidene derivative 2. The reactivity of the latter product towards different chemical reagents was studied to give tetrahydronaphthalene, hexahydroisoquinoline and hexahydrocinnoline derivatives. The newly synthesized products were screened as antitumor agents on the in vitro growth of three human tumor cell lines representing different tumor types, namely, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268). It was found that some of these compounds showed inhibitory effects on the three cell lines, indicating their potential use in the development of oncology products.

An efficient approach towards the convergent synthesis of "fully-carbohydrate" mannodendrimers.

Glycosylation of sugar trityl ethers with sugar 1,2-O-(1-cyano)ethylidene derivatives (the trityl-cyanoethylidene condensation) has been applied to the synthesis of highly branched (dendritic) mannooligosaccharides incorporating a Manalpha1-->3(Manalpha1-->6)Man structural motif. The convergent synthetic strategy used to assemble these oligosaccharides was based on the use of glycosyl acceptors and/or a glycosyl donor already bearing this structural motif. The former were represented by mono- and ditrityl ethers of ManalphaOMe, Manalpha1-->3ManalphaOMe, and Manalpha1-->3(Manalpha1-->6)ManalphaX, where X=OMe or SEt. The pivotal glycosyl donor was the peracetylated 1,2-O-(1-cyano)ethylidene-3,6-di-O-(alpha-D-mannopyranosyl)-beta-D-mannopyranose (1), prepared by orthogonal Helferich glycosylation of the known 1,2-O-(1-cyano)ethylidene-beta-D-mannopyranose with tetra-O-acetyl-alpha-D-mannopyranosyl bromide followed by O-acetylation. Glycosylation of acetates of methyl 6-O-trityl-alpha-D-mannopyranoside and methyl 3,6-di-O-trityl-alpha-D-mannopyranoside with one equivalent of the donor 1 gave rise to the isomeric tetrasaccharide derivatives, Manalpha1-->3(Manalpha1-->6)Manalpha1-->6ManalphaOMe and Manalpha1-->3(Manalpha1-->6)Manalpha1-->3ManalphaOMe, respectively. The latter derivative was further mannosylated at the remaining 6-O-trityl acceptor site to give the protected pentasaccharide Manalpha1-->3(Manalpha1-->6)Manalpha1-->3(Manalpha1-->6)ManalphaOMe. The isomeric pentasaccharide, Manalpha1-->3(Manalpha1-->6)Manalpha1-->6(Manalpha1-->3)ManalphaOMe, was prepared by reaction of 1 with the 6-O-trityl derivative of (Manalpha1-->3)ManalphaOMe. In a similar fashion, 6'- and 6"-O-trityl derivatives of the branched trisaccharide Manalpha1-->3(Manalpha1-->6)ManalphaOMe served as precursors for two isomeric mannohexaosides. The 3,6-di-O-trityl ether of ManalphaOMe and the 6',6"-di-O-trityl ether of Manalpha1-->3(Manalpha1-->6)ManalphaX (X=OMe or SEt) were efficiently bis-glycosylated with the donor 1 to give the corresponding protected mannoheptaoside and mannononaoside. The yields of these glycosylations with the donor 1 ranged from 50 to 66 %. Final deprotection of all the oligosaccharides was straightforward and afforded the target products in high yields. Both the acylated and deprotected products were characterized, and the intersaccharide connectivities were elucidated by extensive one- and two-dimensional NMR spectroscopy. The described blockwise convergent approach allows assembly of a variety of 3,6-branched mannooligosaccharides.

Regioisomeric Formation of the Linear 1,2,4-Triazolo[4′,3′: 2,3][1,2,4]Triazino[5,6-b]Indole from 3-Hydrazino-1,2,4-Triazino[5,6-b]Indole Derivatives

Oxidative cyclisation of the ethylidene derivatives of 5-allyl-3-hydrazino-1,2,4-triazino[5,6-b]indole (7) and 8-bromo-3-hydrazino-5H-1,2,4-triazino[5,6-b]indole (8) gave regioselectively the linear isomers, 10-allyl-3-methyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indole (15) and 7-bromo-3-methyl-10H-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino-[5,6-b]indole (16), respectively. They were also obtained by the dehydrative cyclisation of 5 and 6 respectively with acetic acid as well as by the condensation of the N-allyl- (22) or 5-bromo-isatin (23) with 3,4-diamino-5-methyl-4H-1,2,4-triazole (24). The corresponding allyl derivatives 17 and 18 were also synthesised. Some sugar derivatives of 5 were prepared.

New Trifluoromethyl Substituted 1,2,3-Triazoles Linked toD-Galactose andD-Gulose

The title compounds were synthesized by 1,3-dipolar cycloaddition of 3,3,3-trifluoropropinyl benzene (2) to the azido sugars 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl azide (1), 6-O-acetyl-4-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloroethylidene)-β-D-gulopyranosyl azide (6), 6-azido-6-deoxy-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (12), and methyl 6-azido-4-O-cyclohexylcarbamoyl-6-deoxy-2,3-O-(2,2,2-trichloroethylidene)-β-D-gulopyranoside (16), respectively. Because of the dissymmetry of the dipolarophile 2, always two regioisomeric products were obtained, the nucleoside-analogous compounds 3/4 (from 1) and 7/8 (from 6), respectively, and the reversed nucleosides 13/14 (from 12) and 17/18 (from 16), respectively. Protecting group chemistry like transesterification, deacetalation, hydrodechlorination is demonstrated in some cases. Thus, the trichloroethylidene derivatives 7, 8, 17, and 18 were converted into the corresponding ethylidene derivatives (9, 10, 19, 20) by treatment with tributylstannane/AIBN. An X-ray analysis is given for the 1-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-4-trifluoromethyl-5-phenyl-1,2,3-triazole (4) and for the 1-[6-O-acetyl-4-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloroethylidene)-β-D-gulopyranosyl]-4-trifluoromethyl-5-phenyl-1,2,3-triazole (7).

Nucleophilic Addition of 1-Acetylindole Enolates to Pyridinium Salts. Stereoselective Formal Synthesis of (±)-Geissoschizine and (±)-Akagerine via 1,4-Dihydropyridines

Addition of the enolate derived from 1-acetylindole (3) to pyridinium salt 4b followed by acid-induced cyclization of the resulting 1,4-dihydropyridine 5b in the presence of lithium iodide gives tetracyclic 3,7-methano[1,4]diazonino[1,2-a]indole 6b, which has subsequently been elaborated into the (E)-ethylidene derivative 7b. From this compound is reported a stereocontrolled route to (±)-geissoschizine, involving closure of C ring by Pummerer reaction, methanolysis of the resulting pentacyclic lactam 12, and desulfurization. A similar synthetic sequence starting from the enolate of 3 and 2-fluoropyridinium salt 15b gives access to the pentacyclic dilactam 2, which had previously been converted to (±)-akagerine through opening of the piperidone (D) ring.

Acyclo C-Nucleoside Analogs. Regioselective Annellation of a Triazole Ring to 5-Methyl-1,2,4-Triazino[5,6-b]Indole and Formation of Certain 3-Poly Hydroxyalkyl Derivatives

ABSTRACT Cyclodehydrogenation of the ethylidene derivative of (5-methyl-1,2,4-triazino[5,6-b]indol-3-yl)hydrazine (1) gave the angular isomer, 1,10-dimethyl-1,2,4-triazolo[3′,4′:3,4][1,2,4]triazino[5,6-b]indole (4). The linear isomer, 3,10-dimethyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indole (7) could be prepared regioselectively by the cyclodehydration of the acetyl derivative of 1. The cyclodehydrogenation was extended to the monosaccharide derivatives of 1. The role of the N-methyl group on the site of annellation has been discussed.

1-(3,5-O-Alkylidene-2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracils

1-(2,3-O-Cyclohexylidene-4-C-hydroxymethyl-α-L-lyxofuranosyl)uracil (1) was converted in seven steps into 1-(2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil (8) and further into 1-(2-deoxy-4-C-hydroxymethyl-3,5-O-isopropylidene-α-L-threo-pentofuranosyl)uracil (9). Successive benzoylation, removal of the isopropylidene group, reaction with acetaldehyde diethyl acetal, and debenzoylation afforded (R)- and (S)-1-(2-deoxy-3,5-O-ethylidene-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil (10a and 10b, respectively). Reaction of 1-(2-deoxy-4-C-triphenylmethyloxymethyl-α-L-threo-pentofuranosyl)uracil (14) with dichloromethane under conditions of phase transfer, followed by detritylation, afforded 1-(2-deoxy-4-C-hydroxymethyl-3,5-O-methylidene-α-L-threo- pentofuranosyl)uracil (15). Compound 14 was obtained from the derivative 8 by partial silylation, tritylation and desilylation. The absolute configuration of the isomeric ethylidene derivatives 10a and 10b was determined by NMR spectroscopy and the population of the deoxypentofuranose ring conformers was derived from the vicinal coupling constants J(H,H). The obtained results were compared with energy calculations. Neither of the prepared nucleoside analogues was active in vitro against HIV-1 and HIV-2.

α,α‐Disubstituted Allyl Sulfones: An approach to the synthesis of vinyl‐branched pheromone analogues

AbstractThe two‐step alkylation of phenyl prop‐2‐enyl sulfone (1) with protected ω‐bromoalkanols and 1‐iodoalkanes (→3; see Scheme 1) followed by a Pd‐catalyzed desulfonylation with LiBH4 affords a 96:4 mixture of vinylbranched, protected alcohols and corresponding ethylidene‐branched isomers (see Scheme 2; 4 and 5, respectively). By utilizing the large difference in reactivity of mono‐ and trisubstituted CC bonds towards singlet oxygen, the ethylidene derivatives are easily removed from the mixture by photo‐oxygenation. The vinyl‐branched compounds are inert to this reaction and can be conveniently isolated in highly pure form (99.5%) and ca. 45% overall yield.

Synthesis of (24R)-11α-(4-carboxybutyryloxy)-24,25-dihydroxyvitamin D3: a novel haptenic derivative producing antibodies of high affinity for (24R)-24,25-dihydroxyvitamin D3

The measurement of serum/plasma (24R)-24,25-dihydroxyvitamin D31a levels, which is one of the major metabolites of vitamin D31b, is important to clarify its physiological significance. To obtain highly specific antibodies to compound 1a which are useful for development of immunoassays, a novel haptenic derivative, (24R)-11α-(4-carboxybutyryloxy)-24,25-dihydroxyvitamin D32 was synthesized in 21 steps from a [17(20)Z]-ethylidene derivative 3 of 11α-hydroxydehydroepiandrosterone. The preparation of an immunogenic conjugate of the hapten 2 with bovine serum albumin and the properties of the resulting antibodies are also described briefly.

Regioisomeric Formation of Acenaphtho[1,2-e][1,2,4]triazolo[3,4-c][1,2,4]triazines and Their Acyclic C-Nucleoside Analogues

Abstract The oxidative cyclization of the ethylidene derivative of 3-hydrazinoacenaphtho[1,2-e][1,2,4]triazine (2) gave regioselectively the angular isomer 1-methylacenaphtho[1,2-e][1,2,4]triazolo[3,4-c][1,2,4]triazine (5). Its linear isomer 10-methylacenaphtho[1,2-e][1,2,4]triazolo[4,3-b][1,2,4]triazine (4) was synthesized by the condensation of acenaphthenequinone (6) with 3,4-diamino-5-methyl-4H-1,2,4-triazole. Condensation of 2 with a number of monosaccharides afforded the respective hydrazones 9 whose oxidative cyclization gave the corresponding 1-(polyhydroxyalkyl)acenaphtho[1,2-e][1,2,4]triazolo[3,4-c][1,2,4]triazine (10). Acetylation of 9 and 10 gave 3-[N-acetyl-N′-(polyacetoxyalkylidene)hydrazino]acenaphtho[1,2-e][1,2,4]triazine (11) and 1-(polyacetoxyalkyl)acenaphtho[1,2-e][1,2,4]triazolo[3,4-c][1,2,4]triazine (13) respectively. Periodate oxidation of 9e gave 3-(2-oxoethylidenehydrazino)acenaphtho[1,2-e][1,2,4]triazine (14).

Versatile synthesis of alicyclic and acyclic compounds with alternate and remote C-methyl substitution patterns via asymmetric sequential olefination and ene reactions

Treatment of enantiomerically pure alkyl cyclohexane ethylidene derivatives with 2,3-di-O-benzyl D-and L-glyceraldehyde and related aldehydes in the presence of Lewis acids leads to enantiomerically pure or enriched branched alkylcyclohexenes. These can be oxidized to acyclic motifs with a predetermined C-methyl substitution pattern.

Steric factors in the azidolysis–thermolysis of some 5-tosyloxymethylbi-cyclo[2.2.2]oct-2-enes to yield 4-azatetracyclo[4.4.0.0.0]decanes

Azidolysis of C-19 diastereoisomer tosylesters of morphine derivatives possessing a bridged ring C has been studied and 4-azatetracyclo[4.4.02,4.03,8]decanes 6b, 6d and 6f were formed via the substitution and subsequent intramolecular cyclization of the (R)-C-19 tosylesters 4b, 4d and 4f, and primarily the ethylidene derivatives 7a, 7b and 7c were obtained from (S)-C-19 tosylesters 4c, 4e and 4g. According to our experience the course of the reaction depends on the configuration of the C-19 centre of chirality and on the spatial requirement of the substitutent on C-6

ChemInform Abstract: Synthesis and Structural Elucidation of 19‐Norpregnane Derivatives with Nitrogen‐Containing Four‐Membered Rings in 14,15‐Position.

AbstractThe introduction of a C2 side chain in the 17‐position of the azetidino‐estratrienol (I) leads to the ethylidene derivative (V) which is converted to the steroid (X) via the intermediates (VI), (VII) (VIII).