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A series of acyclonucleosides substituted 1-(4,5-dihydroxypentyl) (13-8) and 2-(4,5-dihydroxypentyloxy)quinoxalines (19-24) were synthesized by the sharpless asymmetric dihydroxylation of the derivatives 1-6 and 7-12, respectively. Treatment of the quinoxaline base 26 with (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl-p-toluenesulfonate (27) in the presence of NaH/DMF furnished 28. Acid hydrolysis of 28 gave 1-(2,3-dihydroxypropyl)-6,7-dimethyl-quinoxaline-2-one (29). Alternatively, 29 was prepared by sharpless dihydroxylation of 30. All the compounds were evaluated for their in vitro anti-HIV-1 and HIV-2 in MT-4 cell and found inactive, except 29, which showed inhibition of HIV-1 with EC50 value of 0.15 +/- 0.1 microg/ml and a therapeutic index (SI) of 73.

A series of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (7-15) and the thiadiazine analogues 16-18 have been synthesized under microwave irradiation (MWI). All synthesized compounds are evaluated for their antiviral activity against the replication of HIV-1 and HIV-2 activity in MT-4. However, compounds 12 and 18 showed EC(50) = 2.11 and 1.97 mug/mL. The results suggest that these compounds can be considered as a new lead in the development of antiviral agents. Compounds 4-18 were tested in vitro against a panel of tumor cell lines. All compounds are inactive against all the tumor sub-lines, except 10 which exhibited activity against CD4(+) human acute T-lymphoblastic leukaemia of CC(50) = 64 muM.

The new regioisomer 7-methyl-pyrazolo[4,5-e][1,2,4]thiadiazine nucleus (5) was synthesized, and its novel mono-N2- or N4-substituted pyrazolo[4,5-e][1,2,4]thiadiazines (6, 7) were regioselectively prepared by deprotonation of N2 or/and N4 atoms with different molar ratio of NaH and alkyl halides. Anti-HIV-1 screening tests showed some compounds to be potent as HIV-1 non-nucleoside reverse transcriptase inhibitors (HIV-1 NNRTIs).

A series of acyclonucleosides 6,7-disubstituted 1-(pent-4-enyl)quinoxalin-2-one derivatives and the O-analogs were synthesized by a one-step condensation of the corresponding quinoxaline bases with 5-bromo-1-pentene.The acyclonucleosides prepared were assayed against HIV-1 and HIV-2 in MT-4 cells. 6,7-Dimethyl-2-(pent-4-enyloxy)quinoxaline showed inhibition of HIV-1 with EC50 value of 0.22 ± 0.08 µg/ml and a therapeutic index of 13. This means that it was cytotoxic to MT-4 cells at CC50 of 2.6 ± 0.1 µg/ml.

Antiviral activity of 1,3-disubstituted uracil derivatives was evaluated against HIV-1 and HCMV. It appears that the nitrogen of the 1-cyanomethyl group is important for anti-HIV-1 activity, suggesting interaction with the amino acid residues of HIV-1 reverse transcriptase. 1-Arylmethyl derivatives also exhibited good anti-HIV-1 activity; and that of the 2- and 4-picolyl derivatives was particularly excellent.

In the process of developing a series of novel, fluorinated biaryl ether NNRTIs, we fortuitously discovered derivative 20, which possesses excellent potency against both wild-type and clinically relevant mutations of the reverse transcriptase enzyme.

Working hypotheses to solve the critical problems of the existing highly active anti-retroviral therapy were proposed. The study based on the hypotheses proved the validity of the hypotheses and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, with highly potent activity against all HIV-1, very favorable toxic profiles, and stability in plasma. The nucleoside will prevent or delay the emergence of drug-resistant HIV-1 variants and be an ideal therapeutic agent for both HIV-1 and HBV infections.

Flazin isolated from the fruiting bodies of Suillus granulatus was found to possess weak anti-HIV activity (EC(50)=2.36 microM, TI=12.1). To establish a SAR study, 46 flazin analogues were synthesized, and their anti-HIV activities were evaluated in vitro. Among them, flazinamide (9a) showed the most potent activity with an EC(50) value of 0.38 microM and a TI value of 312.0. The results suggested that appropriate substituents at positions 3, 1', and 5' of flazin might play a crucial role in determining their anti-HIV activities, and that flazinamide can be considered as a promising, readily available anti-HIV agent.

Different analogues of TMC120 derived from pyridazin-3(2H)-one rings were synthesized by coupling of 3,6-dichloropyridazine with arylacetonitriles, phenols and/or aniline derivative followed by hydrolysis and alkylation with different benzyl bromide derivatives.

Synthesis of 2′ -β-hydroxymethyl nucleosides 3–6 was accomplished, using stereoselective hydroxymethylation as a key step. Adenine nucleoside 3 showed potent anti-HCV activity, implying that 2′ -β-hydroxymethyl group has the appropriate electronic properties interfering with HCV polymerase.

Two closely structurally related coumarins, 4-hydroxy-8-isopropyl-5-methylcoumarin and 4-hydroxy-6-chloro-7-methylcoumarin were acylated at C-3 and further converted to the respective chalcones and two series of eighteen new compounds, which were evaluated for possible antiviral activity.

Heterocyclic thioureas having multiple substitutions were prepared in two steps with overall yields of 60–80%. Condensation of a substituted heterocyclic amine with thiocarbonyldiimidazole, followed by treatment with a disubstituted phenylethylamine in dimethyl formamide (DMF), yielded the desired heterocyclic thioureas as crystalline solids.

With the emergence of HIV strains resistant or cross-resistant to nearly all antiretroviral regimen, novel therapy approaches have to be considered. As a part of our current work on viral mutagenic compounds, we prepared 1-(2′ -deoxy-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (2′ -deoxy-ribavirin) and its 5′ -triphosphate derivative. The nucleoside mutagenic activity was evaluated on HIV-1 NL4-3 in CEMx174 cell culture. After 2.5 months, no reduction on HIV-1 viability was observed. On the other hand, in vitro experiments with purified HIV-1 RT demonstrated that the triphosphate analog can be incorporated opposite to several natural nucleosides.

This paper discusses the racemic and stereoselective synthetic route for novel 4'α -methyl and 6'α -methyl analogues of abacavir. The quaternary carbon at the 4'-position of carbocyclic nucleoside was installed successfully via a Claisen rearrangement. The stereocontrolled construction of a methyl group in the 6'α - position was directed through the Felkin-Anh rule. A Bis-vinyl compound 9 was cyclized successfully using Grubbs' catalyst II to provide a carbocycle nucleus for the target compound. The synthesized compound 15 showed moderate anti-HIV activity (EC50 = 10.67 μM, MT-4 cell lines).

A series of novel 2,4-disubstituted 7-methyl-1,1,3-trioxo-2,4-dihydro-pyrazolo[4,5-e] [1,2,4]thiadiazines (PTDs) was synthesized, structurally confirmed by spectral analysis, and evaluated for their anti-HIV activities by inhibition of HIV-induced cytopathogenicity in MT-4 cell culture. The results showed that some compounds exhibited inhibitory activity specifically against HIV-2 replication. The most active HIV-2 inhibitor was compound 7i (R1 = benzyl, R2 = 4-t-butyl-benzyl) with an EC50 value of 18.7 microM and SI=15, which may provide a useful lead for further molecular optimization.

This report describes new triterpene conjugates of α-D-glucosamine, i.e. modified glycyrrhizic acid (GA) analogs containing 18,19-dehydroglycyrrhetic acid 3-O-hemisuccinate and maleate and 11-deoxyglycyrrhetic acid 3-O-hemiphthalate fragments synthesized using N,N′-dicyclohexylcarbodiimide-N-hydroxybenzotriazole. 3-O-[3-(N-2-deoxy-α-D-glucopyranos-2-yl)-carbamoyl]-phthaloyl-11-deoxyglycyrrhetic acid was found to have marked anti-HIV activity (the CD50 (50% cytotoxic concentration) was 150 µg/ml, the ID50 (50% effective concentration) was 1.5 µg/ml, and the index of selectivity (IS, IC50/ID50) was 100) andwas more active than GA in terms of IS (IS = 9.6).

This article describes an efficient route for synthesizing novel cyclopropyl homologous PMEA analogues. The condensation of the bromide 8 with nucleosidic bases (A, U, T, C, 5-FU, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid analogues 14 approximately 18 and 21. These compounds were evaluated for their potential antiviral properties against various viruses. Guanine derivative 21 showed significant antiviral activity.

The reaction of 2,3,4-tri-O-acetyl-β-D-xylopyranosyl isothiocyanate (1) and 2-amino-4-arylthiazoles (2) gave xylosylthioureas 3. These thiourea derivatives reacted with alkyl/aryl amine in the presence of HgCl2 to give a new series of N-alkyl/aryl-N″-(4-arylthiazol-2-yl)-N″-xylosyl guanidines 4. Some of the synthesized guanidines were screened for their biological activity. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:688–694, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20379

Several 2-(4-chloro-2-mercapto-5-R-benzenesulfonyl)-3,4-dihydroxy-1,1-dioxo-2H-1,2,4,6-thiatriazines (9-12) have been synthesized as potential anti-HIV (9-10) or anticancer (11-12) agents. The in vitro anti-HIV or antitumor activities were tested at the US National Cancer Institute (Bethesda, MD), and the structure-activity relationships are discussed. Compound 9 (R = Me) showed good anti-HIV activity with 50% effective concentration (EC 50 ) value of 73.2 μM and moderate cytotoxic effect (IC 50 = 220.0 μM). The compounds 11 and 12 exhibited high or reasonable activity against most (98%) of the human tumor cell lines tested. Compound 12 (R = 4-ClC 6 H 4 NHCO) is the prominent of the compounds due to its good activity against 54 human tumor cell lines (GI 50 = 0.67-38.9 μM), and remarkable selectivity toward renal cancer RXF 393 cell line (GI 50 = 0.67 μM).

A QSAR study on a series of pyrimidinyl and triazinyl amines was performed to explore the physico-chemical parameters responsible for their anti-HIV activity and cytotoxicity. Physico-chemical parameters were calculated using WIN CAChe 6.1. Stepwise multiple linear regression analysis was carried out to derive QSAR models which were further evaluated for statistical significance and predictive power by internal and external validation. The selected best QSAR models showed correlation coefficient R of 0.914 and 0.901, and cross-validated squared correlation coefficient Q 2 of 0.685 and 0.691 for anti-HIV activity and cytotoxicity, respectively. The developed significant QSAR model indicates that hydrophobicity of the whole molecule plays an important role in the anti-HIV activity and cytotoxicity of pyrimidinyl and triazinyl amine derivatives. When hydrophobicity is increased, anti-HIV activity of the present series of compounds is decreased leading to high cytotoxicity.

Myricetin is a common plant-derived flavonoid and is well recognised for its nutraceuticals value. It is one of the key ingredients of various foods and beverages. The compound exhibits a wide range of activities that include strong anti-oxidant, anticancer, antidiabetic and anti-inflammatory activities. It displays several activities that are related to the central nervous system and numerous studies have suggested that the compound may be beneficial to protect against diseases such as Parkinson's and Alzheimer's. The use of myricetin as a preserving agent to extend the shelf life of foods containing oils and fats is attributed to the compound's ability to protect lipids against oxidation. A detailed search of existing literature revealed that there is currently no comprehensive review available on this important molecule. Hence, the present work includes the history, synthesis, pharmaceutical applications and toxicity studies of myricetin. This report also highlights structure-activity relationships and mechanisms of action for various biological activities.

Two-chain and gemini catanionic analogs of galactosylceramide were easily prepared in quantitative yields, affording high anti-HIV activities with low cytotoxicities on human cells (e.g. for gemini 4b an EC50 of 0.5 µM with a CC50 of >100 µM were obtained).

Seven new highly oxygenated nortriterpenoids, rubriflorins D-J (1-7), were isolated from the leaves and stems of Schisandra rubriflora, and their structures were elucidated on the basis of extensive analysis of spectroscopic data. These new compounds feat

Three new, highly functionalized ingol diterpenes, ingol 7,8,12-triacetate 3-phenylacetate ( 1 ), ingol 7,8,12-triacetate 3-(4-methoxyphenyl)acetate ( 2 ) and 8-methoxyingol 7,12-diacetate 3-phenylacetate ( 3 ), together with the novel spirotriterpene, 3 S ,4 S ,5 R ,7 S ,9 R ,14 R -3,7-dihydroxy-4,14-dimethyl-7[8 → 9]- Abeo -cholestan-8-one ( 4 ), have been isolated from Euphorbia officinarum latex. Structures were established on the basis of their spectroscopic data, including two-dimensional NMR analysis and NOE experiments. The biological effects of 1 – 3 on cell cycle and HIV-1 gene transcription were analysed in the Jurkat T cell line. Compound 3 induced cell-cycle arrest and HIV-1-LTR promoter activation and could represent a novel lead compound for the development of therapies against HIV-1 latency.

A number of new benzofuran derivatives, ethyl 3-[(alkylamino)methyl]-6-methoxy-1-benzofuran-2-carboxylates (5a-i), were obtained via the reaction between ethyl 3-(bromomethyl)-6-methoxy-l-benzofuran-2-carboxylate (3) and amines or amino acid ethyl esters. In addition, 1,4-bis[(ethyl 6-methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]piperazine (9), N,N'-diethyl-N,N'-bis[(6-methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]but-2-ene-1,4-diamine (10) and 1,2-bis[(ethyl 6-methoxy-1-benzofuran-3-yl-2-carboxylate)methyl]-11,2-dimethylhydrazine (11) were also obtained from the reaction of 3 with diamines. Their in vitro anti-HIV-1 (strain III B ) and HIV-2 (strain ROD) activities of the synthesized compounds in human T-lymphocyte were tested; ethyl 3-bromomethyl-6-methoxycoumarlate displayed an ability to inhibit HIV-1 and HIV-2 replication in cell culture at non-toxic concentrations.

2-Amino-1-[4-(1-benzyl-2-ethyl-4-nitro-1 H-imidazol-5-yl)piperazin-1-yl]ethanone [6] was prepared from 1-(1-benzyl-2-ethyl-4-nitro-1 H-imidazol-5-yl) piperazine [3]. A series of new 2-oxoethyl-arylamide [9,10] and 2-oxoethyl-arylsulphonamide [11–14] derivatives were synthesized from [6] with the aim of developing new non-nucleoside reverse transcriptase inhibitors. Alternatively, the amine [17] was synthesized from [3] via the phthalimide derivative [16]. The arylsulphonamide derivatives [18–23] and the arylamide analogues [24–26] were synthesized from [17]. The compounds were evaluated for their anti-HIV-1 and anti-HIV-2 activity in MT-4 cells.

The total synthesis of anibamine, the first and only natural product known as a chemokine receptor CCR5 antagonist, is reported herein. Anibamine was synthesized from acetylacetone and cyanoacetamide in 10 steps.

A new lupane acid, 2 beta-carboxyl, 3 beta-hydroxyl-norlupA (1)-20 (29)-en-28-oic acid (1), together with five known lupane acid derivatives (2-6), were isolated from the stings of Gleditsia sinensis Lam.. Their structures were elucidated on the basis of 1D and 2D NMR techniques. All these known compounds were isolated from this genus for the first time. The new compound 1 showed strong anti-HIV activity.

We have developed an efficient route for the synthesis of a novel bicyclic nucleoside using a key intermediate 13, which was prepared from 1,2:5,6-di-O-isopropylidene-α-d-glucose. 1,2-Nucleophilic addition of aldehyde 8 with allyltrimethylsilane and intramolecular Williamson reaction were successfully achieved to synthesize an intermediate with a 3,7-anhydrooctofuranosyl skeleton.

A series of 4-nitroimidazole derivatives bearing substituted piperazines (5, 8, 9, 12, 14, 16, 17, and 19 - 21) were synthesized with the aim to develop new non-nucleoside reverse transcriptase inhibitors (NNRTIs). The newly synthesized compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. All compounds are inactive, except compound 21 which showed inhibition of HIV-1 with EC50 0.20 μg/mL, and therapeutic indexes (SI) of 12.

The synthesis of 4-chloro-2-mercapto-N-(l,5-dimethyl- or 1-alkyl-1,4,5,6-tetrahydrol,2,4-triazin-3-yl)benzenesulfonamides 15-28 is described. Suggested mechanism of the investigated reaction is discussed. The compounds 15-17 and 19 were tested for their in vitro anti-HIV potency at the National Cancer Institute and only 4-chloro-2-mercapto-N-(1-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)benzenesulfonamide (15) showed reasonable activity (TI 50 = 6.21).

Norcarbovir (1) and norabacavir (2), the desmethylene derivatives of anti-HIV agents carbovir and abacavir, were efficiently synthesized from a common intermediate 4. Their antitumor and antiviral activities were evaluated and the results indicate norabacavir showed comparable anti-HIV activity to that of abacavir.

We report the synthesis of 2′,3′-didehydro-2′,3′-dideoxyuridine (d4U) and 2′,3′-dideoxyuridine (ddU) phosphoramidate ‘ProTide’ derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates.

Novel nucleoside analogues of structure 3-5 were synthesized starting from (±)-cis-2-amino-3-cyclopentenylmethanol (1). The chlorine derivative 3 inhibited both HIV-1 and HIV-2 replication in MT-4 cells with IC50 values of 10.67 μM and of 13.79 μM, respectively. © 2006 Pharmaceutical Society of Japan.

A new series of N,S-substituted 4-chloro-2-mercapto-5-methylbenzenesulfonamide derivatives 12-15, 17, 18 and 20-24 have been synthesized as potential anti-HIV agents. All compounds were screened at the National Cancer Institute (Bethesda, USA) for their in vitro anti-HIV-1 activity, and relationships between structure and anti-HIV activity are discussed. The prominent compounds with remarkable activity were [5-chloro-4-methyl-2-(1H-pyrrol-l-ylsulfonyl)phenylthio]acetamide 22 (EC 50 = 5.9 μM) and 4-bromophenyl 5-chloro-4-methyl-2-(1H-pyrrol-1-ylsulfonyl)phenylthiomethyl ketone 4-phenylsemicarbazone 24 (EC 50 = 5.1 μM).

A series of novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues bearing a 6-(1-naphthoyl) group of non-nucleoside human immunodeficiency virus (HIV) reverse transcriptase inhibitors were synthesized and evaluated for their activity against HIV-1 and HIV-2. It was found that most of these compounds showed good activity against HIV-1. Among them, compound 5-isopropyl-6-(1-naphthoyl)-1-[(2E)-3-phenylallyl]-2,4-pyrimidinedione (23) displayed the greatest inhibitory potency (IC(50)=0.14 muM), which is about 35-fold more active than HEPT and DDI. To rationalize the relationships between structure and activity of these novel compounds, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was also generated. The results provided a tool for guiding the further design of more potent antiviral agents and for predicting the affinity of related compounds.