Novel Regioselective Formation of S- and N-Hydroxyl-Alkyls of 5-(3-Chlorobenzo[b]Thien-2-yl)-3-Mercapto-4H-1,2,4-Triazole and A Facile Synthesis of Triazolo-Thiazoles and Thiazolo-Triazoles. Role of Catalyst and Microwave

Regioselective alkylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole (1) with hydroxy alkylating agents 2, 3, 13, and the 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)-glycerol (10) afforded the corresponding S-alkylated derivatives 6, 7, 11, and 14 under both conventional and microwave irradiation conditions; bentonite as a solid support gave better results, with no change in regioselectivity. A facile intramolecular dehydrative ring closure of 6, 7, 11, and 14 using K₂CO₃ in DMF afforded the corresponding fused triazolo-thiazines and thiazolo-triazole 17–19. The isopropylidenes and acetyl derivatives of the products were prepared.     

Synthesis of new thiolated acyclonucleosides with potential anti-HBV activity

Treatment of the sodium salt of compounds 1, 7 or 12 with chloroethyl methyl ether, 2-chloroethyl toluoylate or 2-(2-chloro ethoxy)ethyl acetate afforded the corresponding derivatives 2, 3, 4, 8, 9, 13 and 14. Ammonolysis of 3, 4, 9 and 14 at room temperature gave the corresponding hydroxyalkyl derivatives 5, 6, 10, 11, and 15, respectively. Alkylation of 2,4-dithiouracil gave 2,4-dialkylthio pyrimidine.     

Synthesis and antibacterial activities of new quinolone derivatives utilizing 1-azabicyclo[1.1.0]butane

The ring-opening reactions of 1-azabicyclo[1.1.0]butane 3 with thiols 6a-f gave 3-sulfenylazetidine derivatives 7a-f in 50-92% yields. Treatment of 3 with aromatic amines 11a-e and dibenzylamine 11f in the presence of Mg(ClO(4))(2) afforded the corresponding 3-aminoazetidine derivatives 12a-f in 24-53% yields. These azetidine derivatives were introduced into the C7 position of a quinolone nucleus 8 to afford the corresponding fluoroquinolones 9a-f and 13a-f in 21-83% yields. Some of them exhibited superior antibacterial activity against quinolone-susceptible MRSA in comparison with clinically used fluoroquinolones, such as levofloxacin, ciprofloxacin, and gatifloxacin.     

Derivatives of β- -fructofuranosyl α- -galactopyranoside

De-etherification of 6,6′-di-O-tritylsucrose hexa-acetate (2) with boiling, aqueous acetic acid caused 4→6 acetyl migration and gave a syrupy hexa-acetate 14, characterised as the 4,6′-dimethanesulphonate 15. Reaction of 2,3,3′4′,6-penta-O-acetylsucrose (5) with trityl chloride in pyridine gave a mixture containing the 1′,6′-diether 6 the 6′-ether 9, confirming the lower reactivity of HO-1′ to tritylation. Subsequent mesylation, detritylation, acetylation afforded the corresponding 4-methanesulphonate 8 1′,4-dimethanesulphonate 11. Reaction of these sulphonates with benzoate, azide, bromide, and chloride anions afforded derivatives of β- -fructofuranosyl α- -galactopyranoside (29) by inversion of configuration at C-4. Treatment of the 4,6′-diol 14 the 1,′4,6′-triol 5, the 4-hydroxy 1′,6′-diether 6 with sulphuryl chloride effected replacement of the free hydroxyl groups and gave the corresponding, crystalline chlorodeoxy derivatives. The same 4-chloro-4-deoxy derivative was isolated when the 4-hydroxy-1′,6′-diether 6 was treated with mesyl chloride in N,N-dimethylformamide.     

Nucleosides 7(9): synthesis, structure, and biological activity of new 6-arylidenamino-2-thio- and 2-benzylthiopyrimidine N-nucleosides

The condensation of 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidine-4-one [compound (1)] with aromatic aldehydes (2) afforded azomethine derivatives (3). The formed azomethines underwent glycosidation with α-acetobromoglucose (4) to form the corresponding pyrimidine N-glycosides (6) and not S-glycosides (5). The interaction of (3) with 1-O-acetyl-2, 3, 5-tri-O-benzoyl-β-D-ribofuranose (8) afforded the corresponding pyrimidine N-riboside (10) and not S-riboside (9). Deacetylation and debenzoylation of each of (6) and (10) by using methanolic sodium methoxide afforded the corresponding free N-nucleosides (7) and (11), respectively. Next, the reaction of 2-benzylthio-6-benzylidenaminouracil (13) with (4) and (8) did not yield the corresponding protected N-nucleosides (14) and (17), whereas it afforded (15) and (18), respectively. The latter compounds (15) and (18) were stirred in methanolic sodium methoxide to yield the corresponding free N-nucleosides (16) and (19), respectively. The structures of products have been elucidated and reported and also some of the products were screened for their antimicrobial activity. Graphical Abstract:     

Synthesis of glycosides of 3-deoxy-4-thiopentopyranosid-2-uloses and their reduction products: 3-deoxy-4-thiopentopyranosides

Michael addition of common thiols to the enone system of (2S)-2-benzyloxy-2H-pyran-3(6H)-one (1) afforded the corresponding 3-deoxy-4-thiopentopyranosid-2-ulose derivatives (2-4). The reaction was highly diastereoselective, and the addition was governed by the quasiaxially disposed 2-benzyloxy substituent of the starting pyranone. As expected from the enantiomeric excess of 1 (ee > 86%) the corresponding thiouloses 2-4 exhibited the same optical purity. However, the enantiomerically pure thioulose 5 was obtained by reaction of 1 with the chiral thiol, N-(tert-butoxycarbonyl)-L-cysteine methyl ester. The thio derivative 7 was also synthesized by reaction of 6 (enantiomer of 1) with the same chiral thiol. Alternatively, 4-thiopent-2-uloses 9-12 were prepared in high optical purity by 1,4-addition of thiols to (2S)-[(S)-2'-octyloxy]dihydropyranone 8. Similarly, reaction of 13 (enantiomer of 8) with benzenemethanethiol afforded 14 (enantiomer of 10). This way, the stereocontrol exerted by the anomeric center on the starting dihydropyranone led to 4-thiopentuloses of the D and L series. Sodium borohydride reduction of the carbonyl function of uloses 10 and 12 gave the corresponding 3-deoxy-4-thiopentopyranosid-2-uloses (16-19). The diastereomers having the beta-D-threo configuration (16, 18) slightly predominated over the beta-D-erythro (17, 19) analogues. However, the reduction of the enantiomeric pyranones 10 and 14 with K-Selectride was highly diastereofacial selective in favor of the beta-D- and beta-L-threo isomers 16 and 20, respectively.     

Synthesis of base substituted 2-hydroxy-3-(purin-9-yl)-propanoic acids and 4-(purin-9-yl)-3-butenoic acids

Alkylation of 6-chloropurine and 2-amino-6-chloropurine with bromoacetaldehyde diethyl acetal afforded 6-chloro-9-(2,2-diethoxyethyl)purine (3a) and its 2-amino congener (3b). Treatment of compounds 3 with primary and secondary amines gave the N6-substituted adenines (5a-5c) and 2,6-diaminopurines (5d-5f). Hydrolysis of 3 resulted in hypoxanthine (6a) and guanine (6b) derivatives, while their reaction with thiourea led to 6-sulfanylpurine (7a) and 2-amino-6-sulfanylpurine (7b) compounds. Treatment with diluted acid followed by potassium cyanide treatment and acid hydrolysis afforded 6-substituted 3-(purin-9-yl)- and 3-(2-aminopurin-9-yl)-2-hydroxypropanoic acids (8-10). Reaction of compounds 3 with malonic acid in aqueous solution gave exclusively the product of isomerisation, 6-substituted 4-(purin-9-yl)-3-butenoic acids (15).     

Synthesis, characterization and antiamoebic activity of 1-(thiazolo[4,5-b]quinoxaline-2-yl)-3-phenyl-2-pyrazoline derivatives

A new series of 1-N-thiocarboxamide-3-phenyl-2-pyrazolines 1-6 was synthesized by cyclization of different Mannich bases with unsubstituted thiosemicarbazide. The reaction of cyclized pyrazoline derivatives 1-6 with 2,3-dichloroquinoxaline afforded the title compounds 7-12. The structures of the new compounds were confirmed by elemental analyses as well as (1)H, (13)C NMR, IR and electronic spectral data. The HM1:IMSS strain of Entamoeba histolytica parasite was cultured in vitro and the sensitivity of the parasite to the synthesized compounds was evaluated using the microdilution method. Among all the pyrazoline derivatives 1-6, none was found to be a better inhibitor as compared to the reference drug, metronidazole. The quinoxaline derivatives, 9, 11 and 12 were found to be potent inhibitors of E. histolytica.     

Synthesis and biological evaluation of new 3-substituted indole derivatives as potential anti-inflammatory and analgesic agents

Treatment of 3-cyanoacetyl indole 1 with the diazonium salts of 3-phenyl-5-aminopyrazole and 2-aminobenzimidazole afforded the corresponding hydrazones 4 and 5. 3-Cyanoacetyl indole reacted with phenylisothiocyanate to give the corresponding thioacetanilide derivative 7. Treatment of 7 with hydrazonoyl chlorides afforded the corresponding 1,3,4-thiadiazole derivatives 8a-f and 9. Also, the thioacetanilide reacted with alpha-haloketones to afford thiophene derivatives 10a,b (tenidap analogues), or thiazolidin-4-one derivative 11. The newly synthesized compounds were found to possess potential anti-inflammatory and analgesic activities.     

Transformation of the hydrazones of 6-chloro-3-(l-threo-2,3,4-trihydroxy-1-oxobutyl)-2-quinoxalinone into other heterocyclic compounds

The difference in reactivity of the two amino groups in 4-chloro-o-phenylene-diamine allowed it to react with l-threo-2,3-hexodiulosono-1,4-lactone to give, after further reaction with various hydrazines, 6-chloro-3-(1-substituted-hydrazono-l-threo-2,3,4-trihydroxybutyl)-2-quinoxalinones (5-14), whose structures were deduced from their reactions, as well as from mass spectrometry of the (p-nitrophenyl)-hydrazone. Elimination of one mole of water per mole from these hydrazones gave the 1-aryl-6-chloro-3-(l-threo-glycerol-1-yl)flavazoles; the mass spectrum of one of these flavazoles is discussed. Elimination of two moles of water per mole from the hydrazones (5, 7, and 8) occurred with simultaneous cyclization to give 3-[l-aryl-5- (hydroxymethyl)pyrazol-3-yl]-6-chloro-2-quinoxalinones. whose acetylation gave the corresponding- monoacetyl derivatives (that could also be obtained by the action of boiling acetic anhydride on the starting hydrazones). Periodate oxidation of the hydrazones and the flavazole derivatives afforded the corresponding aldehydes (that could react with hydrazines).     

Synthesis and anti-HBV activity of thiouracils linked via S and N-1 to the 5-position of methyl beta-D-ribofuranoside

Reverse nucleoside derivatives of 2-(methylsulfanyl)uracils 6a-d were prepared by treating of the sodium salt of 2-(methylsulfanyl)uracils (5a-d) with methyl 2,3-O-isopropylidene-5-O-p-toluenesulfonyl-beta-D-ribofuranoside (2). The alkylation of 2-thiouracils 4a-d with methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-D-ribofuranoside (3) afforded the corresponding S-ribofuranoside derivatives 8a-d. Deisopropylidenation of 6a-d and 8a-d afforded the corresponding deprotected derivatives 7a-d and 9a-d, respectively. The Anti-HBV activity of selected compounds was studied.     

Synthesis of AZT analogues: 7-(3-azido-2-hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-,7-(3-triazolyl-2-hydroxypropyl)theophylline

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph3P/Py/NH4OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N1-propargyl thymine (6) afforded the regioisomeric triazole 7.     

Application of α- and β-naphthoflavones as monooxygenase inhibitors of Absidia coerulea KCh 93, Syncephalastrum racemosum KCh 105 and Chaetomium sp. KCh 6651 in transformation of 17α-methyltestosterone

In this work, 17α-methyltestosterone was effectively hydroxylated by Absidia coerulea KCh 93, Syncephalastrum racemosum KCh 105 and Chaetomium sp. KCh 6651. A. coerulea KCh 93 afforded 6β-, 12β-, 7α-, 11α-, 15α-hydroxy derivatives with 44%, 29%, 6%, 5% and 9% yields, respectively. S. racemosum KCh 105 afforded 7α-, 15α- and 11α-hydroxy derivatives with yields of 45%, 19% and 17%, respectively. Chaetomium sp. KCh 6651 afforded 15α-, 11α-, 7α-, 6β-, 9α-, 14α-hydroxy and 6β,14α-dihydroxy derivatives with yields of 31%, 20%, 16%, 7%, 5%, 7% and 4%, respectively. 14α-Hydroxy and 6β,14α-dihydroxy derivatives were determined as new compounds. Effect of various sources of nitrogen and carbon in the media on biotransformations were tested, however did not affect the degree of substrate conversion or the composition of the products formed. The addition of α- or β-naphthoflavones inhibited 17α-methyltestosterone hydroxylation but did not change the percentage composition of the resulting products.     

Reaction of sugars with 2-hydrazinopyridine, precursors for seco C-nucleosides of 1,2,4-triazolo[4,3-a]pyridine

Reaction of 2-hydrazinopyridine (1) with D-xylose, D-galactose, D-glucose and D-fructose afforded the corresponding hydrazones mainly in the acyclic forms 2, 3, 6 and 11 with minor amounts of the cyclic structures. Oxidative cyclization of the hydrazones with bromine in methanol resulted in the formation of the 3-(polyhydroxyalkyl)-1,2,4-triazolo[4,3-a]pyridine derivatives 13-15 whose acetylation afforded the acetylated derivatives 16-18. Assignment of 1D and 2D NMR spectral data in addition to 15N NMR experiments led to complete characterization of the products.     

Synthetic mucin fragments: methyl 3-O-(2-acetamido-2-deoxy-beta-D-galactopyranosyl-beta-D- 3-O-(2-acetamido-2-deoxy-3-O-beta-D-galactopyranosyl- beta-D-glucopyranosyl)-beta-D-galactoyranoside. pyranosyl)-beta-D-galactopyranoside

Methyl 2,4,6-tri-O-benzyl-beta-D-galactopyranoside (5) was obtained crystalline by way of its 3-O-allyl derivative, which was in turn obtained by ring-opening of a presumed 3,4-O-stannylene derivative of methyl beta-D-galactopyranoside, followed by benzylation. Condensation of 5 with 2-methyl-(2-acetamido-3,4,6-tri-O-acetyl-1,2-dideoxy-beta-D-glucopyra no)-[2,1-d]-2-oxazoline in 1,2-dichloroethane in the presence of p-toluenesulfonic acid afforded the disaccharide derivative methyl 3-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D-glucopyranosyl)-2, 4,6-tri-O-benzyl-beta-D-galactopyranoside (6) Deacetylation of 6 in methanolic sodium methoxide afforded the disaccharide derivative 7, which was acetalated with alpha, alpha-dimethoxytoluene to afford the 4',6'-O-benzylidene acetal (10). Catalytic hydrogenolysis of the benzyl groups of 7 afforded the title disaccharide 8. Glycosylation of 10 with 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide in 1:1 benzene-nitromethane in the presence of mercuric cyanide gave the fully protected trisaccharide derivative 12. Systematic removal of the protecting groups of 12 then furnished the title trisaccharide 14. The structures of 5, 8, and 14 were all confirmed by 13C-n.m.r. spectroscopy. The 13C-n.m.r. chemical shifts for methyl alpha- and beta-D-galactopyranoside, and also those of their 3-O-allyl derivatives, are recorded, for the sake of comparison, in conjunction with those of compound 5.     

Synthesis of 2,6-di(acylamino)-2,6-dideoxy-3-O-(d-2-propanoyl-l-alanyl-d-isoglutamine)-d-glucopyranoses

Five 2,6-di(acylamino)-2,6-dideoxy-3-O-(d-2-propanoyl-l-alanyl-d-isoglutamine)-d-glucopyranoses (lipophilic, muramoyl dipeptide analogs) were synthesized from benzyl 2-(benzyloxycarbonylamino)-3-O-(d-1-carboxyethyl)-2-deoxy-5,6-O-isopropylidene-β-dglucopyranoside (1). Methanesulfonylation of 3, derived from the methyl ester of 1 by O-deisopropylidenation, gave the 6-methanesulfonate (4). (Tetrahydropyran-2-yl)ation of 4 gave benzyl 2-(benzyloxycarbonylamino)-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-6-O-(methylsulfonyl)-5-O-(tetrahydropyran-2-yl)-β-d- glucofuranoside, which was treated with sodium azide to give the corresponding 6-azido derivative (6). Condensation of benzyl 6-amino-2-(benzyloxycarbonyl-amino)-2,6-dideoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-5-O-(tetrahydropyran-2-yl)-β-d-glucofuranoside, derived from 6 by reduction, with the activated esters of octanoic, hexadecanoic, and eicosanoic acid gave the corresponding 6-N-fatty acyl derivatives (8–10). Coupling of the 2-amino derivatives, obtained from compounds 8, 9, and 10 by catalytic reduction, with the activated esters of the fatty acids, gave the 2,6-(diacylamino)-2,6-dideoxy derivatives (11–15). Condensation of the acids, formed from 11–15 by de-esterification, with the benzyl ester of l-alanyl-d-isoglutamine, and subsequent hydrolysis, afforded benzyl 2,6-di(acylamino)-2,6-dideoxy-3-O-(d-2-propanoyl-l-alanyl-d-isoglutamine benzyl ester)-β-d-glucofuranosides. Hydrogenation of the dipeptide derivatives thus obtained gave the five lipophilic analogs of 6-amino-6-deoxymuramoyl dipeptide, respectively, in good yields.     

Synthesis of Base Substituted 2-Hydroxy-3-(purin-9-yl)-propanoic Acids and 4-(Purin-9-yl)-3-butenoic Acids

Abstract

Alkylation of 6-chloropurine and 2-amino-6-chloropurine with bromoacetaldehyde diethyl acetal afforded 6-chloro-9-(2,2-diethoxyethyl)purine (3a) and its 2-amino congener (3b). Treatment of compounds 3 with primary and secondary amines gave the N⁶-substituted adenines (5a–5c) and 2,6-diaminopurines (5d–5f). Hydrolysis of 3 resulted in hypoxanthine (6a) and guanine (6b) derivatives, while their reaction with thiourea led to 6-sulfanylpurine (7a) and 2-amino-6-sulfanylpurine (7b) compounds. Treatment with diluted acid followed by potassium cyanide treatment and acid hydrolysis afforded 6-substituted 3-(purin-9-yl)- and 3-(2-aminopurin-9-yl)-2-hydroxypropanoic acids (8–10). Reaction of compounds 3 with malonic acid in aqueous solution gave exclusively the product of isomerisation, 6-substituted 4-(purin-9-yl)-3-butenoic acids (15).     

A new synthesis of certain 7-(beta-D-ribofuranosyl) and 7-(2-deoxy-beta-D-ribofuranosyl) derivatives of 3-deazaguanine via the sodium salt glycosylation procedure.

A facile synthesis of 7-beta-D-ribofuranosyl-3-deazaguanine (1) and certain 8-substituted derivatives of 1 via the sodium salt glycosylation method has been developed. Glycosylation of the sodium salt of methyl 2-chloro(or methylthio)-4(5)-cyanomethylimidazole-5(4)-carboxylate (5 and 13b) with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide (6) gave exclusively methyl 2-chloro(or methylthio)-4-cyanomethyl-1-(2,3, 5-tri-O-benzoyl-beta-D-ribofuranosyl)imidazole-5-carboxylate (7 and 14a), respectively. Ammonolysis of 7 and 14a provided 6-amino-2-chloro(or methylthio)-3-beta-D-ribofuranosylimidazo-[4,5-c]pyridin-4(5H)-one (11 and 17), which on subsequent dehalogenation (or dethiation) gave 1. Similarly, reaction of the sodium salt of 5 and 13b with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofuranose (8), and ammonolysis of the glycosylated imidazole precursors (9 and 16) gave 6-amino-2-chloro(or methylthio)-3-(2-deoxy-beta-D-erythro-pentofuranosyl) imidazo[4,5-c]-pyridin-4(5H)-one (10a and 15), respectively. Dehalogenation of 10a or dethiation of 15 gave 2'-deoxy-7-beta-D-ribofuranosyl-3-deazaguanine (10b). This procedure provided a direct method of obtaining 10b without the contaminating 9-glycosyl isomer 4.     

3-Methoxy-4-(2-nitrovinyl)phenyl glycosides as potential chromogenic substrates for the assay of glycosidases

Selective glycosidation of 2,4-dihydroxybenzaldehyde with either 2,3,4, 6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide, 2-acetamido-3,4,6-tri-O-acetyl-alpha-D-glucopyranosyl chloride, or 2,3,4,6-tetra-O-acetyl-alpha-D-galactopyranosyl bromide afforded the corresponding 4-O-glycosyl derivatives. Subsequent O-methylation, O-deacetylation, and condensation with nitromethane afforded the appropriate beta-glycoside of 3-methoxy-4-(2-nitrovinyl)phenol. The phenol is highly coloured at alkaline pH so that these glycosides may be suitable as chromogenic substrates for the assay of glycosidases.     

Microbial transformation of 17alpha-ethynyl- and 17alpha-ethylsteroids, and tyrosinase inhibitory activity of transformed products

The microbial transformation of the 17alpha-ethynyl-17beta-hydroxyandrost-4-en-3-one (1) (ethisterone) and 17alpha-ethyl-17beta-hydroxyandrost-4-en-3-one (2) by the fungi Cephalosporium aphidicola and Cunninghamella elegans were investigated. Incubation of compound 1 with C. aphidicola afforded oxidized derivative, 17alpha-ethynyl-17beta-hydroxyandrosta-1,4-dien-3-one (3), while with C. elegans afforded a new hydroxy derivative, 17alpha-ethynyl-11alpha,17beta-dihydroxyandrost-4-en-3-one (4). On the other hand, the incubation of compound 2 with the fungus C. aphidicola afforded 17alpha-ethyl-17beta-hydroxyandrosta-1,4-dien-3-one (5). Two new hydroxylated derivatives, 17alpha-ethyl-11alpha,17beta-dihydroxyandrost-4-en-3-one (6) and 17alpha-ethyl-6alpha,17beta-dihydroxy-5alpha-androstan-3-one (7) were obtained from the incubation of compound 2 with C. elegans. Compounds 1-6 exhibited tyrosinase inhibitory activity, with compound 6 being the most potent member (IC(50)=1.72 microM).