Topochemical models for anti-HIV activity of 1-alkoxy-5-alkyl-6-(arylthio)uracils

Relationship between topochemical indices and anti-HIV-1 (HTLV-III) inhibitory activity of 1-alkoxy-5-alkyl-6-(arylthio)uracils has been studied. Superadjacency, an adjacency-cum-distance-based, topochemical index and Wiener’s, a distance-based, topochemical index were calculated for a set of 36 1-alkoxy-5-alkyl-6-(arylthio)uracils. Resulting data were analyzed and suitable models were developed after identification of the active ranges. Subsequently, a biological activity was assigned to each of the compounds using these models and compared with the reported anti-HIV-1 activity. High accuracy of prediction was observed using these models. Statistical analysis revealed significance of the proposed models as well as a lack of correlation between the topochemical indices employed for the chosen data set.     

Synthesis and anti-HIV-1 activity of a series of 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils and -2-thiouracils

A series of 1-(alkoxymethyl)-5-alkyl-6-(phenylselenenyl)uracils and -2-thiouracils modified at the 3- and/or 5-position of the C-6 phenylselenenyl ring with methyl or fluoro substituent has been synthesized and tested for their ability to inhibit HIV-1 replication. Lithiation of the acyclic uracil and 2-thiouracil derivatives 11-14 and 27-32 with lithium diisopropylamide or lithium bis(trimethylsilyl)amide followed by reaction with an appropriate diaryl diselenide afforded 6-arylselenenyl compounds 18-26 after removal of the tert-butyldimethylsilyl protecting group and 35-47 . Compounds 48-54 were prepared from compounds 38-44 by oxidative hydrolysis of the thione function. Of these compounds, 50 inhibited HIV -1 replication in human T₄ lymphoblastoid cells at a 50% effective concentration (EC₅₀) of 0.0047 μM with a selectivity index of >42600.     

Unique chlorine effect in regioselective one-pot synthesis of 1-alkyl-/allyl-3-(o-chlorobenzyl) uracils: anti-HIV activity of selected uracil derivatives

2,4-Bis(trimethylsilyloxy)pyrimidines 1/2 on reaction with o-chlorobenzyl chlorides in 1,2-dichloroethane in the presence of I₂ undergo single step 1,3-dibenzylation to provide 1,3-bis(o-chlorobenzyl)pyrimidine-2,4-diones. The reactions of 1 with allyl/alkyl bromide followed by subsequent addition of o-chlorobenzyl chloride provide a simple one-pot synthesis of 1,3-unsymmetrical pyrimidine-2,4-diones. Amongst these, 1,3-bis(o-chlorobenzyl)uracil (6a) shows anti-HIV-1 activity.     

Synthesis of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles as potential selective serotonin reuptake inhibitors

Two 2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2a,b have been synthesized by the reaction of isoindoline with 4-chloropyridines. In addition, a number of 1-alkyl-2,3-dihydro-2-(4-pyridinyl)-1H-isoindoles 2c-h were obtained from 2-(4-pyridinyl)phthalimide (5). The addition of alkyl Grignard reagents to 5 gave 1-alkylhydroxyisoindolones 6a-f which, in two cases 6a,b , were dehydrated and subjected to three separate reductions to give targets 2c,d . In three cases, the intermediate hydroxyisoindolones 6c-e were reduced in one step to the target compounds 2c-g with lithium aluminum hydride-aluminum chloride. When 6f , the product of the addition of phenyl Grignard to 5 , was subjected to these conditions, a hydroxyisoindoline 7 was obtained which was further reduced to 2h with triethylsilane-trifluoroacetic acid. The lithium aluminum hydride-aluminum chloride conditions were successfully applied to the synthesis of a 1-benzyl-4-piperidine derivative 21.     

Synthesis and stereochemistry of 1-alkyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl) aziridines

Two diastereoisomeric 1-alkyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl) aziridines with an E configuration of the aziridine ring were obtained by the reaction of 2-methyl-2-cinnamoyoxiranes with iodine-methylamine and iodine-ethylamine complexes. The relative configuration of the chiral centers of the synthesized compounds was established by means of spectral data. The predominant formation of diastereomers with the RRR (SSS) relative configuration is explained by the effect of steric factors in the diastereomeric chelated amino enols that precede the formation of the epoxy keto aziridines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 880–883, July, 1980.     

Synthesis of 1-(dihydroxypropyl)-5-substituted uracils

Novel 1-(dihydroxypropyl)-5-substituted uracils were synthesized in the reaction of 1-(4-nitrophenyl)-5-substituted uracil derivatives with appropriate aminopropanediols under mild conditions. In the case of 3-amino-1,2-propanediol both racemic and enantiomerically enriched products were obtained. These compounds may be considered as new building blocks for oligonucleotide synthesis.     

Synthesis and anti-TMV activity of novel N-(3-alkyl-1H-pyrazol-4-yl)-3-alkyl-4-substituted-1H-pyrazole-5-carboxamides

In order to investigate the biological activity of novel bis-pyrazole compounds,a series of N-（3-alkyl-5-（N-methylcarbamyl）- 1H-pyrazol-4-yl）-3-alkyl-4-substituted-1H-pyrazole-5-carboxamides were designed and synthesized with ethyl 3-alkyl-1H-pyrazole -5-carboxylate 1 as starting materials.N-Methyl-3-alkyl-4-amino-1H-pyrazole-5-carboxamides 6 were obtained from 1 via 5 steps.3-Alkyl-4-substitued-1H-pyrazole-5-carboxyl chlorides 4a,4b,11a,11b,11c or 12 were also obtained from 1 via several steps.Target compounds 7a-7g were obtained after the reaction of 6 with the above 1H-pyrazole-5-carboxyl chlorides.Preliminary bioassay showed some compounds possessing good inactivation effect against TMV（tobacco mosaic virus）.Compound 7a showed higher activity superior to ningnanmycin at a concentration of 5.0×10^-4 g/mL and equal activity at 1.0×10^-4 g/mL;7b and 7c showed equal activity to virazole both at concentrations of 5.0×10^-4 g/mL and 1.0×10^-4 g/mL.     

A new route to the improved synthesis of 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils

A new route to C-6-selenenyl analogs of compound 1a from 5-alkyl-6-chlorouracils 6a-b has been described. A mild and highly efficient synthesis of 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils 8a-e has been accomplished from 6a-b in good yields using a two step procedure. Silylation of 5-alkyl-6-chlorouracils 6a-b using N,O-bis(trimethylsilyl)acetamide followed by regioselective alkylation of the silylated intermediate with ethyl or benzyl chloromethyl ether in dichloromethane afforded the desired 1-(alkoxymethyl)-5-alkyl-6-chlorouracils 7a-d in 88–94% yields. Compounds 7a-d readily underwent addition-elimination reaction with an appropriate arylselenol in the presence of ethanolic sodium hyroxide to produce the corresponding 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils 8a-e in excellent yields (94–99%).     

Synthesis and anti-HIV-1 activity of 1,5-dialkyl-6-(arylselenenyl)uracils and -2-thiouracils

The 1,5-dialkyl-6-(arylselenenyl)uracils 10a-h and -2-thiouracils 10i-p have been synthesized as potential anti-HIV-1 agents. Cyclization of N-alkyl-N'-[3,3-di(methylthio)-2-alkylacryloyl]ureas 6a-d and -thioureas 6e-h in acetic acid either containing a catalytic amount of methanesulfonic acid at 80°or containing 1 equivalent of methanesulfonic acid at room temperature afforded 1,5-dialkyl-6-(methylthio)uracils 7a-d in 84–96% yields and 1,5-dialkyl-5,6-dihydro-6,6-di(methylthio)-2-thiouracils 11a-d in 88–99% yields, respectively. Oxidation of 7a-d and 11a-d with either 3-chloroperoxybenzoic acid in benzene or aqueous sodium periodate solution in methanol gave 1,5-dialkyl-6-(methylsulfonyl)uracils 8a-d in 88–98% yields and 1,5-dialkyl-6-(methylsulfinyl)-2-thiouracils 12a-d in 57–73% yields, respectively, which were subsequently treated with arylselenol 9a-b in ethanolic sodium hydroxide solution to afford 10a-p in 6099% yields. Of these compounds, 6-[(3,5-dimethylphenyl)selenenyl]-5-isopropyl-1-(3-phenylpropyl)uracil ( 10h ) inhibited HIV-1 replication in MT-4 cells at a 50% effective concentration (EC₅₀) of 0.0006 μM with a selective index of 44833, which is 7.7-fold more potent than AZT.     

Synthesis of 4-alkyl-4H-benzo[e]- and 4H-pyrido[2,3-e]-1,2,4-triazin-3-one 1-oxides for potential anticancer activity

Alkylation of the sodium salt of 4H-benzo[e]-1,2,4-triazin-3-one 1-oxide and its 7-methyl homolog with benzyl bromide and chloromethoxyethyl acetate gave the 4-substituted products. Alkylation with aceto-bromoglucose formed the 3-ether. Alkylation of 4H-pyrido[2,3-e]-1,2,4-triazin-3-one 1-oxide gave the 4-substi-tuted products with both benzyl bromide and acetobromoglucose. Deacetylation of both the tetra-O-acetyl-glucosyl and acetoxyethoxymethyl derivatives was accompolished was accompolished. Antileukemia tests for several of the 4-alkyl derivatives showed no activity.     

Synthesis,structure, and growth-promoting activity of 1-alkyl-4-(3-naphthyloxyprop-1-ynyl)piperidin-4-ols

Alkylation of 1- and 2-naphthols with propargyl bromide in acetone in the presence of potassium carbonate led to prop-2-ynyloxynaphthalenes, which upon reaction with 1-alkyl-piperidin-4-ones under the Favorsky conditions afforded the corresponding tertiary alcohols. 1-Methyl-4-[3-(2-naphthyloxy)prop-1-ynyl]piperidin-4-ol hydrochloride was found to possess a high growth-promoting activity in the concentration of 0.001% upon the pre-sowing treatment of beetroot seeds and potatoes and increase their productivity by ～20%.     

Synthesis and anticonvulsant activity of 3-alkyl-3,4-dihydro-2(1H)-quinazolinones

Previously we reported the potent anticonvulsant activity of 3-dimethylamino-3,4-dihydro-2(1H)-quinazolinone. In this report, a series of 3-alkyl-3,4-dihydro-2(1H)-quinazolinones was synthesized in three steps from isatoic anhydrides or an anthranilic acid. Structure/activity investigations revealed optimal activity for the 3-isopropyl and 3-cyciohexyl analogs. These compounds were effective against seizures induced by maximal electroshock.     

Synthesis of functionalized 5-(3-R-1-adamantyl)uracils and related compounds

Efficient synthetic approaches to functionalized 5-(3-R-1-adamantyl)uracils and related compounds (R=OH, COOH, NH₂, etc.) are described. The selective hydroxylation of the adamantane tertiary C-H bonds in 5-(1-adamantyl)uracils with H₂SO₄ in trifluoroacetic anhydride is used as the key step. Subsequent electrophilic reactions of 5-(3-hydroxy-1-adamantyl)uracils with N- and C-nucleophiles in CF₃COOH, H₂SO₄ or H₂SO₄/AcOH media yielded derivatives with amide, amino, aryl, carboxy and thiourea groups in the adamantane core. The preliminary evaluation of the antiviral activity revealed that some of the synthesized species display moderate antiviral activity against HSV-1 (SI∼20) in Vero cells.     

Synthesis of 2-alkyl-3-(2-benzoxazolon-3-yl)indoles

It was shown that 3-(2-oxoalkyl)-2-benzoxazolones with phenylhydrazine in the presence of polyphosphoric acid form the corresponding 2-alkyl-3-(2-benzoxazolon-3-yl)-indoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1086–1087, August, 1984.     

Synthesis and some transformations of 2-alkyl-2-(prop-1-ynoxymethyl)-1, 3-dioxolanes

Conclusions 2-Alkyl-2-(prop-1-ynoxymethyl)-1, 3-dioxolanes have been synthesized and the conditions found under which prototropic isomerization of them is stopped at the stage of allene formation.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1626–1628, July, 1968.     

Reaction of 1-alkyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl)aziridines with boron trifluoride etherate in methanol

The reaction of boron trifluoride etherate in methanol with trans-1-methyl(ethyl)-or cis-1-cyclohexyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl)aziridines leads to the formation of the corresponding boron fluoride complexes on the nitrogen atom of the aziridine ring. Reaction with trans-1-cyclohexyl-2-phenyl-3-(2-methyl-2,3-epoxypropionyl)aziridines occurs with stereospecific opening of the aziridine ring to give diastereomeric 2-methyl-5-methoxy-5-phenyl-4-cyclohexylamino-1,2-epoxypen-tan-3-ones, as well as products from the opening of the epoxide and aziridine rings — tetrahydrofuranones and tetrahydropyranones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 596–600, May, 1986.     

Synthesis of 9-(2,3-dihydroxy-1-propoxymethyl)guanine - a new potential antiviral agent

Coupling of tris(trimethylsilyl)guanine (4) with 1,2-di-$\text{O}$-acetyl-3-$\text{O}$chloromethyl glycerol (3), followed by removal of the protecting groups afforded 9-(2,3-dihydroxy-1-propoxy)guanine (1). Compound 1 exhibited potent antiviral activity.