Synthesis and Tuberculostatic Activity of Some 1,1-Bis-methylthio-2-nitro-ethene Derivatives

1,1-bis-methylthio-2-nitro-ethene was used as a substrate to the syntheses of new heterocyclic compounds. In the reactions, with 1-phenylpiperazine—the corresponding diaminonitroethane 1 , 1,3-diaminonitropropane, and 1,3-diaminonitropropanol—the nitromethylenotetrahydropyrimidine derivatives 2 and 3 were prepared, whereas, with o-phenylenediamine—2-nitromethyleno-benzimidazole 4 were obtained. In the condensation reactions of compounds 2 , 3 , and 4 with benzoyl isothiocyanate, the products 5 , 6 , and 7 were obtained, and afterwards two of them, 5 and 6 , were transformed into the isothiazolines 8 and 9 .

1,1-bis-(4-phenylpiperazino)-2-nitroethane ( 1 ) was exposed to the action of phenyl isothiocyanate and the derivative obtained ( 10 ) was transformed, in the reaction with phenacylbromide, in to benzoylonitrothiophene 11 . The diazo compounds 12 , 13 , and 14 were obtained in the reactions of nitromethylenotetrahydropyrimidines 2 and 3 and of 2-nitromethylenobenzimidazole 4 with benzenediazonium chloride. The derivatives obtained were tested in vitro for their tuberculostatic activity. The compounds 7 (MIC 8–32 μg/mL) and 14 (MIC 16–63 μg/mL) appeared to be the most active compounds.     

Synthesis and Reactions of New Fused Heterocycles Derived from 5-Substituted-4-Amino-3-Mercapto-(4H)-1,2,4-Triazole with Biological Interest

The reaction of thiocarbohydrazide with carboxylic acids at the melting temperature allows an improved preparation of 5-substituted-4-amino-3-mercapto 1,2,4-triazoles 1 _{a ? g} . Compound 1 _a reacted with 2-bromopropionic acid to give acid derivative 2 . The latter was reacted with a mixture of acetic anhydride and triethylamine to afford the mesoionic compound 3 . Heating of compound 3 in ethanol gave the ester derivative 4 , which on alkaline hydrolysis in methanol gave ketone derivative 5 . Substituted 1,2,4-triazolo [3,4-b]-6H-1,3,4-thiadiazine 6 _h,i and 7 were synthesized by reaction of 1 _a with acetylacetone, ethyl acetoacetate and chloroacetamide. Heterocyclic systems 8 and 9 were prepared through the reaction of 1 _a with 2,3-dichloro-1,4-naphthoquinone and 2,3-dichloroquinoxaline. In addition, thenoyl isothiocyanate, thenoyl chloride, 2-thiophenecarbaldehyde, and p-chlorophenyl isocyanate reacted with compound 1 _a to afford 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole ring system 10 , 11 , and urea derivative 12 . 1,2,4-Triazolo[3,4-b]-5H-pyrazole derivatives 14 _j,k were prepared through the reaction of compound 1 _a with 3-chloro-2,4-pentandione and ethyl-2-chloroacetoacetate. Compound 14 _j was treated with hydrazine to afford products 15 , 16 , and 17 depending on the type of hydrazine derivative and reaction conditions. Compound 19 was synthesized by refluxing of compound 14 _j with hydroxylamine hydrochloride to afford the corresponding oxime derivative 18 followed by treatment with thenoyl chloride.     

The Novel N,S-Substituted Halonitrodienes from the Reactions of Thiosubstituted Nitrodiene with Piperazine and Morpholine

The substituted 1,2-dibromomethanethio nitrodiene 2 was obtained from the addition of bromine to S-substituted nitrodien 1 in carbon tetrachloride. N, S-substituted compounds 4a–h were synthesized from the reactions of compound 2 with several substituted piperazine derivatives 3a–h in dichloromethane. N, S-substituted compounds 6 and 8 were synthesized from the reaction of 2 with morpholine ( 5 ) and thiomorpholine ( 7 ) in dichloromethane, respectively. Dibutadienyl piperazines 10 , 12 , and 14 were synthesized from the reactions of 2 with homopiperazine ( 9 ), piperazine ( 11 ), and 2,5-dimethylpiperazine ( 13 ), respectively.     

N,S-, S-, S,S-, <S═O-, and < SO2-Substituted Dienes from Halo-1,3-Butadienes

Mono(thio)substituted dienes 1 gave 3a–g , 5 , and 7 with piperazine derivatives in dichloromethane. Hexachlorobutadiene 14 in a water-ethanol mixture in the presence of sodium hydroxide reacted with thiol 15 to give the mono(thio)substituted thioether 16 and di(thio)substituted thioether 17 . 18 was obtained from the reaction of 16 with m-CPBA in chloroform. 9 was obtained from the reaction of l,2,3,4,4-pentachloro-(1-2-hydroxyethylthio)-1,3- butadiene 8 with 47% HI, and 11 was synthesized from the reaction of 8 with concentrated H₂SO₄ and KBr. Compounds 9 and 11 gave in the reaction with m-CPBA in chloroform 10 , 12 , and 13 , respectively.     

Mono-Heteroatom Effects on Singlet–Triplet Energy Gaps of Divalent Five-Membered Ring XC3H3C (X = CH,N, P,and As)

Heteroatom effects were investigated on singlet–triplet energy gaps of divalent five-membered ring XC ₃ H ₃ C, 1 _X and 2 _X (X = CH, N, P, and As) at B3LYP/6-311++G?? level. All triplet states of 1 _X and 2 _X are more stable than the related singlet state. Δ G _{s ? t} between singlet and triplet states of 1 _X and 2 _X were changed in the order (in kcal/mol): 1 _As (14.43) > 1 _P (10.07) > 1 _CH (9.60) > 1 _N (8.50) and 2 _N (11.56) > 2 _CH (9.60) > 2 _P (3.07) > 2 _As (2.13).     

Synthesis of Two Tetrasaccharides Related to the O-Antigen from Azospirillum brasilense S17 and Azospirillum lipoferum SR65

Synthesis of two isomeric tetrasaccharides, β-D-Glup-(1→2)-α-L-Rhap-(1→3)-α-L- Rhap-(1→2)-α-L-Rhap (I) and β-D-Glup-(1→3)-α-L-Rhap-(1→3)-α-L-Rhap-(1→3)-α-L-Rhap (II), the repeating units from the lipopolysaccharides of the nitrogen-fixing bacterium Azospirillum brasilense S17 and Azospirillum lipoferum SR65, was achieved via assembly of the building blocks 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl trichloroacetimidate (2), p-methoxyphenyl 3,4-di-O-benzoyl-α-L-rhamnopyranoside (3), 3-O-allyloxycarbonyl-2,4-di-O-benzoyl-α-L-rhamnopyranosyl trichloroacetimidate (6), 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl trichloroacetimidate (8), and p-methoxy phenyl 2,4-di-O-benzoyl-α-L-rhamnopyranoside (14). Condensation of 3 with 6 or 8 provided the disaccharides 9 or 11, respectively. Deallyloxycarbonylation of 11 gave the disaccharide aceptor 12, while removal of the p-methoxyphenyl group in 9 followed by trichloroacetimidation of the anomeric hydroxyl group afforded the disaccharide donor 10. Meanwhile, disaccharide donor 16 and acceptor 18 were prepared from 6, 8, and 14 similarly. Finally, condensation of 10 with 12 or 16 with 18, followed by deprotection, gave the target tetrasaccharides I or II, respectively.     

Identification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC-MS/MS

The in vitro microsomal metabolism of JWH-015, a ligand that exhibits a high binding affinity at the peripheral cannabinoid receptor CB₂, has been studied. A total of 22 metabolites were identified and structurally characterized. The metabolites are products of: 1) monohydroxylation on the naphthalene ring (m/z 344, M20 and M21), indole ring (m/z 344, M17 and M18), or the N-alkyl group (m/z 344, M14); 2) arene oxidation leading to dihydrodiols (m/z 362, M12 and M15); 3) dihydroxylation on the naphthalene ring (m/z 360, M7) or indole ring (m/z 360, M13), resulting from a combination of monohydroxylations on both the naphthalene and indole rings (m/z 360, M16), or a combination of monohydroxylations on the naphthalene ring and on the N-propyl group (m/z 360, M9); 4) trihydroxylation (m/z 378, M1, M3, M4, M6, and M10); 5) N-dealkylation (m/z 286, M19); 6) N-dealkylation and monohydroxylation on the naphthalene ring (m/z 302, M11); 7) N-dealkylation and dihydrodiol formation from arene oxidation (m/z 320, M2 and M5); 8) dehydrogenation after monohydroxylation on the N-alkyl group (m/z 326, M22); 9) dehydrogenation and monohydroxylation on the indole ring (m/z 342, M8).     

A new alkaloid from Portulaca oleracea L. and its antiacetylcholinesterase activity

A new alkaloid, (10E, 12E)-9-ureidooctadeca-10, 12-dienoic acid, named oleraurea (1) and 10 known compounds, p-hydroxybenzaldehyde (2), p-hydroxybenzoic acid (3), p-hydroxyacetophenone (4), benzamide (5), (E)-p-coumaramide (6), (E)-ferulamide (7), soyalkaloid A (8), β-carboline-3-carboxylic acid (9), 2, 3, 4, 9-tetrahydro-1H-pyrido [3, 4-b] indole-3-carboxylic acid (10), (1S, 3S)-1-methyl-1, 2, 3, 4-tetrahydro-β-carboline-3-carboxylic acid (11) were obtained from Portulaca oleracea L., in which, compounds 4, 5, 8–11 were isolated from the plant for the first time. The structure of the compound 1 was identified using spectroscopic methods including 1D and 2D NMR, HR-ESI-TOF-MS. The compounds 1, 5–11 presented anticholinesterase activities, but the P. oleracea extract (POE) presented very low anticholinesterase activity.     

Investigation of the Addition of Benzenethiol to p-Chlorophenylphenylacetylene

The addition of benzenethiol to p-chlorophenylphenylacetylene results in the formation of a mixture of two pairs of diastereomeric (E)- and (Z)-1-p-chlorophenyl-2-phenyl-1-phenylthioethylenes (1 and 2) and (E)- and (Z)-1-p-chlorophenyl-2-phenyl-2-phenylthioethylenes (3 and 4). The configurations of these compounds have been established by ¹ H NMR studies, by their preparation from benzyl p-chlorophenyl ketone and p-chloro-benzylphenyl ketone, and by the oxidation of the thioethylenes 1, 2, 3, and 4 to the corresponding sulphonylethylenes 5, 6, 7, and 8, respectively.     

Synthesis and Antibacterial Activity of Substituted Thiosemicarbazides and of 1,3,4-Thiadiazole or 1,2,4-Triazole Derivatives

The synthesized series of new thiosemicarbazide derivatives ( 1 , 6–10 ) in reactions with carbon disulphide produced, according to the reaction conditions, the dithioacids ( 4 , 30 ) or the 5-substituted 1,3,4-thiadiazolo-2-thiol derivatives ( 2 , 27 ). The dithioacids were cyclized, in the reaction with hydrazine, into the 4-ami-no-1,2,4-triazolo-2-thiol derivatives ( 5 , 31 ). One of these compounds ( 31 ) was transformed into the 1,2,4-triazolo-1,3,4-thiadiazine derivative ( 33 ). The compo-unds 6–9 were also exposed to the condensation with aldehydes. 4-phenylpipera-zinocarbothiohydrazide ( 6 ) was exposed to the action of isothiocyanates, which gave the compounds 16–20 , and these cyclized to the 1,3,4-thiadiazoloamino derivatives ( 21–23 ).

The susceptibility of aerobic and anaerobic bacteria to some of the new derivatives were tested. The anaerobes were the most susceptible at concentrations in ranges less than 6.2 to 100 μg/mL to derivative: 9 (64% were susceptible), 1 , 13 (for 60%), and 7 (for 56%).     

The Synthesis of Some New Quinazolone Derivatives of Potential Biological Activity

The refluxing of 3-amino-6,8-dibromo-2-thioxo-2,3-dihydro-1H-quinazolin-4-one (5) with ethyl chloroformate and/or ethyl chloroacetate afforded compounds 6 and 7 . The reaction of 5 with ethyl bromobutyrate, chloroacetyl chloride, phenacyl chloride, and phenyl isocyanate yielded compounds 8 , 9 , 11 , and 12 . The coupling of 5 with (2,3,4,6-tetra-O-acetyl-α -D-gluopyranosyl)bromide( ABG ) in DMF at r.t. gave 3-amino-6,8-dibromo-2-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyl)thioxo-2,3-dihydro-1H-quinazolin-4-one ( 14 ). The deblocking of 14 in sodium methoxide gave 5 . 3-Amino-6,8-dibromo-2-methylthio-3H-quinazolin-4-one ( 16 ) was prepared by stirring 5 with methyl iodide in methanol. The treatment of 16 with hydrazine hydrate afforded 4 . The condensation of 4 with aldehydes furnished 3,5-dibromo-2-arylaminobenzoic acid hydrazide ( 18a–c ). The refluxing of 18a with acetic anhydride gave 3-(benzylideneamino)-6,8-dibromo-2-methyl-3H-quinazolin-4-one ( 19 ). Hydrazones 20a–f were prepared by the condensation of 4 with pentoses and/or hexoses. The acetylation of ( 20a–f ) with acetic anhydride gave the acetyl derivatives 21a–f .     

NMR and X-Ray Diffraction Study of Some Inositol Derivatives 1

Abstract

We have determined the preferred conformers in solution by a detailed NMR analysis using COSY and HETCOR experiments of three inositol isomers: myo (1), scyllo (2) and epi (3) plus sixteen derivatives of myo-inositol: 1,2,3,4,5,6-hexa-O-acetyl-myo-inositol (4), 1,2,-O-isopropylidene-myo-inositol (5), 1,2:4,5-di-O-isopropylidene-myo-inositol (6), 3,4,5,6-tetra-O-acetyl-1,2-O-isopropylidene-myo-inositol (7), 3,4,5,6-tetra-O-acetyl-myo-inositol (8), 1,2-O-isopropylidene-3,6-di-O-tosyl-myo-inositol (9), 1,2-O-isopropylidene-3,4,6-tri-O-tosyl-myo-inositol (10), 1,2:4,5-di-O-isopropylidene-3-O-tosyl-myo-inositol (11), 3,6-di-O-benzyl, 1,2:4,5-di-O-isopropylidene-myo-inositol (12), 3,6-di-O-benzyl-1,2-O-isopropylidene-myo-inositol (13), 3,6-di-O-benzyl-myo-inositol (14), 1,2-O-cyclohexylidene-myo-inositol (15), 1,2:4,5-di-O-cyclohexylidene-myo-inositol (16), 1,2:5,6-di-O-cyclohexylidene-myo-inositol (17), 1,3,5-O-(orthoformate)-myo-inositol (18) and 2-benzyl-1,3,5-O-(orthoformate)-myo-inositol (19). The X-ray diffraction structure of compounds 2, 6-8, 18 and 19 are reported.

     

Stereoselective epoxidation of 2-arylidene-1-indanones and 2-arylidene-1-benzosuberones

Summary Oxidation of the (E) and (Z) isomers of 2-arylidene-1-indanones (1) and 2-arylidene-1-benzosuberones (4) by alkaline hydrogen peroxide (methodi) afforded the spiroepoxidestrans-2a–g andtrans-5a–g from both isomers as sole products in high yields. On the other hand, dimethyldioxirane epoxidation(methodii) of the (E) isomers1a–g and4a–g gave the correspondingtrans spiroepoxides in good yields, whereas the (Z) isomers1a,c,e and4a,c,e led to thecis spiroepoxides in moderate yields. Dimethyldioxirane oxidation (methodii) of (Z)-1c and (Z)-4c,e gave diones3c and6c,e as by-products as well. Epoxidation of (Z)-1a,c,e and (Z)-4a,c,e bym-chloroperoxybenzoic acid (methodiii) resulted inca. 6:1 mixtures ofcis-2a,c,e andtrans-2a,c,e orcis-5a,c,e andtrans-5a,c,e spiroepoxides.Dedicated to Prof.W. Fleischhacker on the occasion of his 65^th birthday     

Studies on Pyrazine Derivatives,XLIV: Synthesis and Tuberculostatic Activity of 4-Substituted 3,4,5,6-Tetrahydro-2H-[1,2′]-Bis-Pyrazine Derivatives

2-chloro-3-cyanopyrazine was a substrate in the syntheses of some potentially tuberculostatic pyrazine derivatives. This compound, upon action of secondary amines, pyrazine derivatives 1-phenyl-, 1-piperonyl-, 1-(4-fluorophenyl)-, 1-(2-pyridil)-, and 1-benzylpiperazine, gave the corresponding nitriles ( 1a–e ). Compounds 1c , d , e were changed into the amidoximes ( 2c , d , e ) by hydroxylamine action. Derivatives 1a–e were transformed into the corresponding thioamides ( 3a–e ) when treated with ammonium polysulphide. Two of these, thioamides, 3a and 3b , in the cyclization reactions with ethylenediamine gave the imidazolines ( 4a , b ) with phenacyl bromide—the thiazole derivatives ( 5a , b ). The compounds obtained were tested in vitro for their tuberculostatic activity. The tuberculostatic activity of compound 5b was the highest: MIC 3.1–7.8 μ g/mL.     

A new 9,10-dihydrophenanthrene from Dendrobium moniliforme

A new 9,10-dihydrophenanthrene,1,5-dihydroxy-3,4,7-trimethoxy-9,10-dihydrophenanthrene (1) was isolated and identified from the whole plants of Dendrobium moniliforme, as well as 24 known compounds including hircinol (2), (2R^*,3S^*)-3-hydroxymethyl-9-methoxy-2-(4′-hydroxy-3′,5′-dimethoxyphenyl)-2,3,6,7-tetrahydro-phenanthro[4,3-b]furan-5,11-diol (3), diospyrosin (4), aloifol I (5), moscatilin (6), 3,4′-dihydroxy-3′,4,5-trimethoxybibenzyl (7), gigantol (8), 3,3′-dihydroxy-4,5-dimethoxybibenzyl (9), longicornuol A (10), N-trans-cinnamoyltyramine (11), paprazine (12), N-trans-feruloyl 3′-O-methyldopamine (13), moupinamide (14), dihydroconiferyl dihydro-p-coumarate (15), dihydrosinapyl dihydro-p-coumarate (16), 3-isopropyl-5-acetoxycyclohexene-2-one-1 (17), p-hydroxybenzaldehyde (18), vanillin (19), p-hydroxyphenylpropionic acid (20), vanillic acid (21), protocatechuic acid (22), (+)-syringaresinol (23), β-sitosterol (24) and daucosterol (25). Compounds 3, 4, 13, 16, 17 and 20 were isolated from the Dendrobium genus for the first time, and compounds 2, 5, 7, 9–12, 14, 15, 18, 21 and 22 were originally obtained from D. moniliforme.     

Chemical composition and antioxidant activity of aerial parts of Ferula longipes Coss. ex Bonnier and Maury

This is the first study on the phytochemistry and antioxidant activity of Ferula longipes Coss. ex Bonnier and Maury (Apiaceae). A new flavonoid quercetin-3-O-α-L-rhamnopyranoside-7-O-ß-D-[2-O-caffeoyl]-glucopyranoside (1), along with 10 known compounds kaempferol-3-O-α-L-rhamnopyranoside (2), quercetin-3-O-α-L-rhamnopyranoside (3), kaempferol-3-O-ß-D-glucopyranoside-7-O-α-L-rhamnopyranoside (4), isorhamnetin-3-O-α-L-rhamnopyranoside-7-O-ß-D-glucopyranoside (5), quercetin-3-O-α-L-rhamnopyranoside-7-O-ß-D-glucopyranoside (6), isorhamnetin-3,7-di-O-β-D-glucopyranoside (7), apigenin (8), apigenin-7-O-ß-D-glucopyranoside (9), 3,5-dicaffeoylquinic acid (10), deltoin (11) were isolated from the aerial parts of Ferula longipes Coss. Structures elucidation was performed by comprehensive 1D and 2D NMR analyses, mass spectrometry and by comparison with literature data. The compounds 1, 3, 4, 6, 7 and 10 were evaluated for their antioxidant activity, compound 1 exhibited the best antiradical activity potential and showed IC₅₀ and A_0.5 values 5.70, 7.25, 5.00, and 2.63 μg/mL towards DPPH free radical-scavenging, ABTS, CUPRAC, and reducing power assays, respectively compared with BHA, BHT and ascorbic acid which were used as positive controls.     

Glycosylation of 4‐Aryl‐1‐thioxo[1,2,4] triazolo[4,3‐a] quinazolin‐5(4H)‐one

Reaction of 4‐aryl‐1‐thioxo [1,2,4] triazolo [4,3‐a] quinazolin‐5 (4H)‐ones (2a,b) with acetylated glycosyl bromides 3a–c under alkaline conditions afforded the corresponding S‐glycoside derivatives 4, 5 and N‐glycoside derivatives 6, 7. Oxidation of S‐glycosyl derivatives 4, 5 with m‐chloroperbenzoic acid yielded the corresponding sulphones 8, 9, whereas the N‐glycosyl derivatives 6, 7 yielded 1‐oxo derivatives 10, 11. However their O‐deacetylation with sodium methoxide in methanol caused cleavage of the S‐glycosyl residue and gave N ²‐glycosylated analogues 12, 13, 14 and 15.     

New Synthesis of 1,4 Benzodiazepine-2,5-diones by Means of HCL Gas Catalyst

A new synthesis of 1,4- benzodiazepinediones 4 , particularly 1,4-dihydro1H-1,4-benzodiazepine-2,5-dione, 4c key intermediate of metabolites cyclopenin 9 , cyclopenol 10 , cyclopeptine 11 and dehydrocyclopeptine 12 , was achieved by action of dry HCl gas in DMF on compound 3 prepared from anthranilic acid derivative 1 and amino ester 2 .     

A criterion for the confluence of two seams of conical intersection in triatomic molecules

It is shown that the cross product t ^{I J} (R _x )≡g ^{I J} (R _x )×h ^{I J} (R _x ), where g _τ ^{I J} (R)=(c ^I (R _x )−c ^J (c ^I (R _x )+c ^J (R _x )), h _τ ^{I J} (R)=c ^I (R _x )^† c ^J (R _x ), τ is an internal nuclear coordinate, the c ^I (R) satisfy [H(R)−E _I (R)]c ^I (R)=0 and H(R) is the electronic Hamiltonian matrix, is a unique property of a conical intersection at R _x . t ^{I J} (R _x )=0 when R _x is located at the intersection of two (or more) seams of conical intersection. This criterion for an intersection of two seams of conical intersection has important implications for algorithms that seek to locate such points. Here it␣is␣used to analyze the trifurcation of a generic C_2v ^2S+1 A−^2S+1 B seam of conical intersection, analogous to those recently found in AlH₂ and CH₂. Received: 31 July 1997 / Accepted: 27 August 1997     

Zur Kenntnis organischerLewis-Säuren, 36.Cis—trans-Gleichgewichte und Konformationen von 2,(x)-Dialkyl-1-dicyanomethylencyclohexanen. Wahlweise einfache Darstellung dercis- odertrans-Formen

Knoevenagel condensation of malononitrile withcis- andtrans-2,5-dimethylcyclohexanone (1 c and1 t, respectively) leads to2 c and2 t, respectively, and withtrans-1-decalone to4 t. The equilibria2 c2 t and4 c4 t have been determined as well as, by means of 270-MHz-¹H-NMR, the conformations of these four compounds. The dicyanomethylene group is found to induce axial positions of neighbouring alkyl residues on the cyclohexane ring (or when this is impossible, as in the case of4 t, the twist form of the cyclohexane ring). This results in a strong predominance of thecis isomers in the equilibria2 c2 t and4 c4 t whereas thetrans isomers strongly predominate in the equilibria among the starting ketones. This situation allows the optional preparation of2 c or2 t, and of4 c or4 t, from the more stable starting ketone (or ketone mixture). The free conformational energy of the distorted twist form of4 t amounts to 17 kJ/mol.

Herrn Prof. Dr.E. Ziegler, Graz, zum 70. Geburtstag in aufrichtiger Verbundenheit gewidmet.