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We have recently described a novel hemagglutinin (HA) conformational change inhibitor of human influenza virus, Stachyflin (Yoshimoto et al, Arch. Virol., 144, 1-14, 1999). Stachyflin-resistant variants of human influenza A/WSN/33 (H1N1) virus were isolated in vitro and the nucleotide sequences of their HA genes were determined. The relation of amino acid substitutions and Stachyflin resistance was analyzed with in vitro membrane fusion between HA-expressing cells and octadecylrhodamine (R18)-labelled chick erythrocytes (RBC). The amino acid substitutions, lysine to arginine at position 51 or lysine to glutamic acid at position 121 of the HA2 subunit of the HA protein was enough to confer a Stachyflin-resistant phenotype of HA protein. The molecular mechanism of anti-HA conformational change activity of Stachyflin is discussed.

S-1153 (AG1549) is perhaps the most promising non-nucleoside inhibitor of HIV-1 reverse transcriptase currently under development as a potential anti-AIDS drug, because it has a favorable profile of resilience to many drug resistance mutations. We have determined the crystal structure of S-1153 in a complex with HIV-1 reverse transcriptase. The complex possesses some novel features, including an extensive network of hydrogen bonds involving the main chain of residues 101, 103, and 236 of the p66 reverse transcriptase subunit. Such interactions are unlikely to be disrupted by side chain mutations. The reverse transcriptase/S-1153 complex suggests different ways in which resilience to mutations in the non-nucleoside inhibitors of reverse transcriptase binding site can be achieved.

Purpose. Stachyflin and its derivatives which are active against the influenza virus in vitro, were studied to improve their reduced in vivo activity after oral administration by chemical modification and some vehicles.

The ambident anion character of thiamin ylide was demonstrated by alkylation reactions of the «isolated thiamin ylide» under neutral or basic conditions. Alkylation with alkyl halides yielded S-alkyl derivatives of the yellow form of thiamin (pyrimidopyrimidine derivatives) instead of 2-alkylthiamin. These and previous results provide chemical evidence that thiamin ylide and thiaminium neothiaminthiolate undergo a facile interconversion in EtOH

Capravirine (CPV; formerly AG1549 and S-1153) is a novel, nonnucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) that has demonstrated potent in vitro antiviral activity against several HIV-1 laboratory strains and clinical isolates with EC 50 values ranging from 0.7 to 10.3 nM. In this study, we evaluated the resistance and cross-resistance profiles of CPV through selection of resistant HIV-1 variants from in vitro serial passage of HIV-1 NL4-3 and HIV-1 IIIB and by performing susceptibility assays on HIV-1 variants constructed to contain CPV-specific amino acid substitutions in reverse transcriptase (RT). Results demonstrate that HIV-1 variants selected at increasing CPV concentrations contained multiple substitutions in diverse patterns including L100I, Y181C, G190E and/or L234I in various combinations with K101R/E, K103T, V106A/I, V108I, E138K, T139K, A158T, V179D/I/G, Y188D, V189I, G190A, F227C, W229R, L234F, M230I/L and P236H/T. Interestingly, HIV-1 variants constructed to contain the T215Y zidovudine (AZT)-resistance associated substitution with CPV-resistance associated substitutions V106A, Y181C, F227C, F227L, L234I or V106A/F227L demonstrated 2.4–5.4-fold increased susceptibility to CPV. Results also demonstrate that the CPV-resistance associated substitutions Y181C, F227C, F227L and L234I reverse the phenotypic resistance to AZT conferred by the T215Y substitution.

A series of 2-alkoxyimino- N -(2-isoxazolin-3-ylmethyl)acetamides and related compounds were synthesized and their antiviral activities against human influenza A virus were assessed. Studies of the structure–activity relationships revealed the strongest antiviral activity when position-5 of the isoxazoline ring was substituted with a tert -butyl group. When the alkoxyimino moiety was substituted with a methyl, ethyl, isopropyl or allyl group, good antiviral activity was obtained. Among the geometrical isomers at the oxime moiety, the E -isomers were more active than the Z -isomers. Among the compounds examined, ( E )-2-allyloxyimino-2-cyano- N -(5- tert -butyl-2-isoxazolin-3-ylmethyl)acetamide ( 1j ) was the most active inhibitor with an EC 50 of 3 μg/mL in vitro.

HIV integrase, the enzyme that inserts the viral DNA into the host chromosome, has no mammalian counterpart, making it an attractive target for antiviral drug design. As one of the three enzymes produced by HIV, it can be expected that inhibitors of this enzyme will complement the therapeutic use of HIV protease and reverse transcriptase inhibitors. We have determined the structure of a complex of the HIV-1 integrase core domain with a novel inhibitor, 5ClTEP, 1-(5-chloroindol-3-yl)-3-hydroxy-3-(2 H -tetrazol-5-yl)-propenone, to 2.1-Å resolution. The inhibitor binds centrally in the active site of the integrase and makes a number of close contacts with the protein. Only minor changes in the protein accompany inhibitor binding. This inhibitor complex will provide a platform for structure-based design of an additional class of inhibitors for antiviral therapy.

S-1153 is a new imidazole compound that inhibits human immunodeficiency virus (HIV) type 1 (HIV-1) replication by acting as a nonnucleoside reverse transcriptase inhibitor (NNRTI). This compound inhibits replication of HIV-1 strains that are resistant to nucleoside and nonnucleoside reverse transcriptase inhibitors. S-1153 has a 50% effective concentration in the range of 0.3 to 7 ng/ml for strains with single amino acid substitutions that cause NNRTI resistance, including the Y181C mutant, and also has potent activity against clinical isolates. The emergence of S-1153-resistant variants is slower than that for nevirapine, and S-1153-resistant variants contained at least two amino acid substitutions, including F227L or L234I. S-1153-resistant variants are still sensitive to the nucleoside reverse transcriptase inhibitors zidovudine (AZT) and lamivudine. In a mouse and MT-4 (human T-cell line) in vivo HIV replication model, S-1153 and AZT administered orally showed a marked synergy for the inhibition of HIV-1 replication. S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur. S-1153 may be an appropriate candidate for two- to three-drug combination therapy for HIV infection.

In vivo efficacy of anti-HIV compounds is affected by various factors such as bioavailability, metabolism, clearance, and toxicity. Here we report a simple and rapid method that might be useful for preliminary evaluation of in vivo efficacy of anti-HIV compounds. MT-4 cells carrying proviral HTLV-1 were infected with HIV-1 in vitro and injected into the peritoneal cavity of SCID mice or BALB/c mice. Inoculated cells survive for 1-2 days, and support one to two cycles of viral replication which can be monitored by RT activity or p24 content in the supernatants of peritoneal wash fluids. Test compounds were administered either orally or subcutaneously. AZT, DDC and DDI, the nucleoside-type RT inhibitors currently in clinical use, all showed potent anti-HIV-1 activities in this mouse/MT-4 assay. HEPT (E-EBUdM), a non-nucleoside RT inhibitor, also showed potent anti-HIV-1 activity in vivo, whereas TIBO (R82913), another non-nucleoside RT inhibitor, was less active. In protease inhibitors KNI-272 and Ro 31-8959 showed good in vivo activities, while KNI-144, a compound closely related to KNI-272, showed poor in vivo activity. This mouse/MT-4 assay, although having a number of shortcomings as an animal model for HIV-1 infection, may be of some practical utility for preliminary evaluation of in vivo efficacy of potential anti-HIV compounds.

The ambident anion character of thiamin ylide was demonstrated by alkylation reactions of the «isolated thiamin ylide» under neutral or basic conditions. Alkylation with alkyl halides yielded S-alkyl derivatives of the yellow form of thiamin (pyrimidopyrimidine derivatives) instead of 2-alkylthiamin. These and previous results provide chemical evidence that thiamin ylide and thiaminium neothiaminthiolate undergo a facile interconversion in EtOH

A series of the title compounds was prepared via condensation of the 3-(aminomethyl)triazolylbenzophenone (5) with N-protected amino acids, followed by deprotection, amination of the 3-[(chloroacetamido)methyl]triazolylbenzophenone (6a,b), or reduction of the relevant azide derivative (6c). Some of the title compounds were also derived directly from the quinazolines 3 or 4 by acid-induced rearrangement, followed by deprotection. These new amino acid amide derivatives of the triazolylbenzophenones (2) were evaluated for central nervous system (CNS) activity. Members of this class of compounds exhibited a high level of CNS activities. For example, 2',5-dichloro-2-[3-[(glycylamino)methyl]-5-methyl-4H-1,2,4-triazol-4-yl] benzophenone (2c) was as active as triazolam, with an ED50 of 0.58 mg/kg (mice, po), against antifighting activity in the foot shock-induced fighting test. Other triazolylbenzophenone derivatives (2a-f) showed similar pharmacological activities.

1,3-Dithiolium and 1,3-oxathiolium salts are positively charged 6φ electronically conjugated cations containing two hetero atoms in a five-membered ring. They exhibit a high reactivity toward nucleophiles. This study has shown that 1,3-dithiolium cations form an interesting class of compounds because of their non-benzenoid aromaticity and that 1,3-oxathiolium cations are highly versatile synthetic intermediates which can provide a number of novel heterocyclic compounds and their precursors depending on the nature of the nucleophiles and the reaction conditions.

A novel method of synthesizing 2-disubstituted-amino-4-arylthiazol-5-ylalkanoic acids (3) was studied. Dehydration of S-(α-benzoyl-β-ethoxycarbonyl) ethyl 1-piperidinethiocarbonate (5a) in the presence of aqueous perchloric acid-acetic anhydride yielded 4-ethoxycarbonyl-methyl-5-phenyl-2-piperidino-1, 3-oxathiolium perchlorate (1a). Nucleophilic reaction of ammonia with 1a afforded 5-ethoxycarbonylmethyl-4-phenyl-2-piperidinothiazole (2a). Acid-catalyzed hydrolysis of 2a gave 3a as a hydrochloride. The acids (3) were also synthesized by the classical Hantzsch method. These alkanoic acids were evaluated as antiinflammatory agents on carrageenin-induced abscess in rat.

The action of two equivalents of NaOEt on thiamin hydrochloride in EtOH gives a neutral compound. Spectroscopic data and its chemical behavior indicated that the compound is thiamin ylide 1. The chemical behaviors of 1 are entirely consistent with those of in situ generated thiamin ylide.

The reaction of 2-dialkylamino-5-phenyl-1,3-oxathiolium cation 1 with sulphur ylides 2 was investigated. The behavior of 1 was solvent-dependent. In CH 2 Cl 2 , carbamate ester 3 was obtained: in CH 3 CN, the intermediate sulphonium salt 5 , which on hydrolysis gave 3 , was isolated. On the other hand, reaction in MeOH gave the diphenacyl derivative 6 . The reaction mechanism is discussed.

Synthese a partir de la reaction des anions des cyano-3 et phenylthio-3 phtalides avec des accepteurs de Michael

The synthesis of (5-acylaminomethyl-3-carbamoyl-1H-1,2,4-triazol-1-yl)benzophenone derivatives 4a-i, 14a-d, 15a-d, 16a-c, is described. Acylation of the key intermediate, 1-benzoylphenylazo-1-aminoacetamide 7, followed by cyclization in the presence of acid afforded 1H-1,2,4-triazole derivatives. These compounds were evaluated for their central nervous system (CNS) activity. Some of these compounds exhibited high activities in anti-pentylene tetrazole and rotarod test in mice when orally administered.

Peptidoaminobenzophenones (1), terminal N-substituted peptidoaminobenzophenones (14), and acylglycylaminobenzophenones (16) were prepared as a novel series of ring-opened derivatives of 1,4-benzodiazepine. Z-Gly- and Z-Ala-N-methylaminobenzophenones (4) were treated with HBr-HOAc to give Gly- and Ala-N-methylaminobenzophenone hydrobromides (8). Reaction of 8 with chloroacetyl chloride in dimethylformamide (DMF) or hexamethylphosphoramide (HMPA) gave chloracetamide (13), which was allowed to react with various amines to afford a number of terminal N-substituted derivatives (14). Reaction of 8 with various acyl halides in HMPA or DMF gave a number of acylglycyl-N-methylaminobenzophenones (16). Peptidoaminobenzophenones (1) were also prepared by several convenient methods. Many of these compounds exhibited high CNS activity in animals when given orally. In antianxiety activity the potency of some compounds is equal to or higher than that of diazepam.

The influence of the contribution of the dipolar form to the resonance hybrid structure on the chemical stability of 1, 3-dithiol- and oxathiol-2-ylidene derivatives was investigated by means of infrared, ultraviolet, nuclear magnetic resonance, and dipole moment measurement. It is concluded that though the contribution of the polar form to the resonance hybrid is small, it is nevertheless important for double bond isomerization through nonbenzenoid aromatic stabilization of its positive charge. Protonation of the double bond in acid medium does not necessarily occur, since some of the title compounds are not Hammett bases.

A series of noval peptidoaminobenzophenones has been prepared via several routes and was evaluated for CNS activity. The structure--activity relationships in the series are discussed. In general, dipeptido-N-methylaminobenzophenones showed higher activities than the corresponding NH derivatives. Some compounds had very high activities in antipentylenetetrazole and antifighting tests in mice when orally administered. Very weak toxicity was also found in these compounds. Water solubility of the peptidoaminobenzophenones and their salts were tested. Possible in these compounds. Water solubility of the peptidoaminobenzophenones and their salts were tested. Possible in vivo conversion of peptidoaminobenzophenone by enzymatic cleavage of the terminal amino acid, followed by chemical cyclization to 1,4-benzodiazepine, is also discussed. Such novel open-ring derivatives of 1,4-benzodiazepine may serve as useful CNS agents.

The ultraviolet absorption and phosphorescence emission spectra of various methyl and phenyl substituted 4-pyrones, 4-thiopyrones and 4-pyridones have been measured. The lowest energy absorption of the unhindered 4-pyrones and 4-thiopyrones is the carbonyl n, π* transition, whereas 4-pyridones do not show the n, π* transition. The hypsochromic shifts and hypochromic effects observed for the hindered 4-pyrones, 4-thiopyrones and 4-pyridones are attributed to the steric effect of substituents. These compounds show little or no fluorescence at room temperature or at 77 K, while the lowest triplet states are mainly of π, π* orbital character. An intramolecular heavy-atom effect appears to play an important role in the phosphorescence spectra of 4-thiopyrones. The results of SCF LCAO MO calculations with configuration interaction are reported for each of these three classes of compounds.

Peptidoaminobenzophenones (1), terminal N-substituted peptidoaminobenzophenones (14), and acylglycylaminobenzophenones (16) were prepared as a novel series of ring-opened derivatives of 1,4-benzodiazepine. Z-Gly- and Z-Ala-N-methylaminobenzophenones (4) were treated with HBr-HOAc to give Gly- and Ala-N-methylaminobenzophenone hydrobromides (8). Reaction of 8 with chloroacetyl chloride in dimethylformamide (DMF) or hexamethylphosphoramide (HMPA) gave chloracetamide (13), which was allowed to react with various amines to afford a number of terminal N-substituted derivatives (14). Reaction of 8 with various acyl halides in HMPA or DMF gave a number of acylglycyl-N-methylaminobenzophenones (16). Peptidoaminobenzophenones (1) were also prepared by several convenient methods. Many of these compounds exhibited high CNS activity in animals when given orally. In antianxiety activity the potency of some compounds is equal to or higher than that of diazepam.

The ultraviolet absorption and phosphorescence emission spectra of various methyl and phenyl substituted 4-pyrones, 4-thiopyrones and 4-pyridones have been measured. The lowest energy absorption of the unhindered 4-pyrones and 4-thiopyrones is the carbonyl n, π* transition, whereas 4-pyridones do not show the n, π* transition. The hypsochromic shifts and hypochromic effects observed for the hindered 4-pyrones, 4-thiopyrones and 4-pyridones are attributed to the steric effect of substituents. These compounds show little or no fluorescence at room temperature or at 77 K, while the lowest triplet states are mainly of π, π* orbital character. An intramolecular heavy-atom effect appears to play an important role in the phosphorescence spectra of 4-thiopyrones. The results of SCF LCAO MO calculations with configuration interaction are reported for each of these three classes of compounds.