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The anti-HIV-1 effects of 204 crude drugs of common use in Japan were evaluated in vitro. As a result, 45 samples inhibited HIV-1-induced cytopathogenicity in MT-4 cells. In particular, the hot water extracts of Lithospermum erythrorhizon (root) and Prunella vulgaris (spike) showed the strongest anti-HIV-1 activities. Their IC100 values were both 16 micrograms/ml. In general, the hot water extracts of the crude drug suppressed the replication of HIV-1 growth more strongly than the cold water extracts.

Nucleocidin 1 has been synthesised from the adenosine derivative 4via the intermediacy of the dihalogeno compound 9. The latter compound showed slight but significant activity against HIVinfected cells while the isomer 10 and the monohalogeno compound 60 were inactive. Synthetic approaches towards other 4′-fluorinated nucleoside derivatives are also described. The epimeric 4′fluorinated nucleosides 26 and 27 displayed similar activity against HIV-infected cells to that observed for the dihalogenated compound 9.

[reaction: see text] L-2'-Fluoro-4'-thio-2',3'-unsaturated cytidine 11 was synthesized from (R)-2-fluorobutenolide 2, which was prepared from 2,3-O-isopropylidene-L-glyceraldehyde 1. The synthesized compound 11 shows potent antiviral activity against HIV-1.

The first copper-mediated oxidative cyanation of arylboronate esters [freshly prepared by borylation of the arenes (I)] or of arylboronic acids such as (IV) or (VI) is reported to proceed with great functional group tolerance.

In recent years, HIV-1 integrase (IN) has become an attractive target for designing antiretroviral agents. The first IN inhibitor approved for clinical use, raltegravir, has validated the pharmacological viability of IN inhibitors and signals the advent of a new generation of antiretroviral drugs. The development of raltegravir and other successful lead IN inhibitors has also influenced the IN inhibitor design strategy. This has led to the identification of several potent inhibitors in these last two years. Further, an increased understanding of IN structural biology has opened up novel approaches to inhibiting IN, such as targeting its multimerization or interaction with cellular cofactors. This review covers recent developments in the field of IN inhibitor design from 2007 to 2008. © 2010 Wiley Periodicals, Inc. Med Res Rev, 30, No. 6, 890–954, 2010

A total of 36 compounds including the new prenylated flavonoids (I) and (II) are isolated from the stem bark of Poncirus trifoliata.

Among a series of title compounds, the derivative (I) is shown to represent a promising agent against HIV-1 and is the subject of further studies.

The alkylation of 5-alkyl-6-(2,6-dihalobenzyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-ones with MeI, AllSCH2Cl, and MeSCH2Cl in the K2CO3–DMF, NaOMe–MeOH, and KOH–EtOH systems was investigated. A hypothetical mechanism for the reaction is examined, and an explanation is proposed for the composition of the reaction products. The presence of high anti-HIV-1 activity was established in the obtained derivatives of 2-{[(allylsulfanyl)methyl]sulfanyl}pyrimidin-4(3H)-one.

Optimized conditions are developed to significantly improve the selective synthesis of the chroman derivatives via a simple alkylation/cyclization.

Among the compounds synthesized, derivative (VI) is found to be a potent inhibitor in vitro for the replication of HIV-1.

The new nortriterpenoid, 20-hydroxymicrandilactone D (I), and the novel lignan glycoside, lancilignanside A (II) are isolated from the leaves and stems of Schisandra lancifolia along with three known nortriterpenoids and nine known phenolics.

Three new dibenzocyclooctadienes (I), named schilancifolignans A-C, are isolated together with several known lignans from leaves and stems of the title plant.

Acquired immunodeficiency syndrome patients face great socio-economic difficulties in obtaining treatment. There is an urgent need for new, safe, and cheap anti-HIV agents. Traditional medicinal plants are a valuable source of novel anti-HIV agents and may offer alternatives to expensive medicines in future. Various medicinal plants or plant-derived natural products have shown strong anti-HIV activity and are under various stages of clinical development in different parts of the world. The present study was directed towards assessment of anti-HIV activity of various extracts prepared from Indian medicinal plants. The plants were chosen on the basis of similarity of chemical constituents with reported anti-HIV compounds or on the basis of their traditional usage as immunomodulators. Different extracts were prepared by Soxhlet extraction and liquid–liquid partitioning. Ninety-two extracts were prepared from 23 plants. Anti-HIV activity was measured in a human CD4+ T-cell line, CEM-GFP cells infected with HIV-1NL4.3. Nine extracts of 8 different plants significantly reduced viral production in CEM-GFP cells infected with HIV-1NL4.3. Aegle marmelos, Argemone mexicana, Asparagus racemosus, Coleus forskohlii, and Rubia cordifolia demonstrated promising anti-HIV potential and were investigated for their active principles.

The highly N-methylated linear polypeptides koshikamide C-E and the cyclic analogues F-H are isolated from Theonella swinhoei and Theonella cupola.

Brasilamides B (Ib), C (IIa), and D (IIb) show modest inhibitory effects on HIV-1 replication in C8166 cells.

Lipophilic prodrugs of acyclic cyclobutylated C-nucleosides, isocytosine (VI) and 9-deazaadenine (XI), are prepared by applying the bis(SATE) approach.

Title compound (IIa) is synthesized in 4 steps from acid (Ia) and converted to its chloride (IIb).

A series of 2',3'-dideoxy-4'-thionucleoside analogues of purines and pyrimidines, including 4'-thioddI (17), 4'-thioddC (27), and 4'-thioAZT (34), were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus (HIV). A stereospecific synthesis of the 2,3-dideoxy-4-thioribofuranosyl carbohydrate precursor 11 starting with L-glutamic acid is described. 2',3'-Dideoxy-4'-thiocytidine (27) displayed significant, but modest activity in vitro against human immunodeficiency virus.

Acid catalyzed etherification of 5-hydroxymethyluracil (3) afforded the corresponding 5-alkoxymethyluracils (4a-h). Treatment of the sodium salt of compounds (4a-g) with 4-bromobutyl acetate afforded 1,3-bis-(4-acetyloxybutyl)- (5a-g) and 1,4-acetyloxybutyluracil derivetives -6a-g). Alkylation of 4h with 5-chloropentyl benzoate gave 1,3-bis-(5-benzoyloxypentyl)- (8) and 1-(5-benzoyloxypentyl)-5-b-butyloxymethyluracil (9). Ammonolysis of 6a-g and 9 at room temperature gave the corresponding hydroxyalkyl derivatives (7a-g and 10)

The synthesis of 9-[(2R,5R)-2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]-2,6-diaminopurine ( 2 ) is described. This compound exhibited good inhibitory activity against HIV replication in MT-4 cells.

To investigate the design of prodrugs of antiviral nucleosides for targeting to the central nervous system, the bis(4-acyloxybenzyl) esters of the 5′-monophosphate of AZT 5(R = Me, Et, Pri or But) have been prepared. The reaction of the appropriate bis(4-acyloxybenzyl)N,N-diisopropylphosphoramidite 10(R = Me, Et, Pri or But) with AZT in the presence of 1H-tetrazole, followed by oxidation of the PIII intermediate with 3-chlcroperoxybenzoic acid gave the required triesters 5 in good yield. The lithium salts of the mono (4-acyloxybenzyl) esters of the 5′-phosphate of AZT 7(R = Me, Et, Pri or But) were prepared by treatment of the triesters 5 with lithium iodide. In the presence of porcine liver carboxyesterase the triesters 5 and diesters 7 decomposed readily to the 5′-monophosphate of AZT 9. The anti-HIV activities of the triesters 5 and diesters 7 were, with one exception, comparable to that of AZT, but the greater cytotoxicity of certain compounds in particular types of cell significantly reduced their selectivity indices.

Nucleocidin 1 has been synthesised from the adenosine derivative 4via the intermediacy of the dihalogeno compound 9. The latter compound showed slight but significant activity against HIVinfected cells while the isomer 10 and the monohalogeno compound 60 were inactive. Synthetic approaches towards other 4′-fluorinated nucleoside derivatives are also described. The epimeric 4′fluorinated nucleosides 26 and 27 displayed similar activity against HIV-infected cells to that observed for the dihalogenated compound 9.

A series of 5-substituted uracil and cytosine dioxolanyl nucleosides were synthesized as potential anti-HIV agents. Compounds 3a and 3c were found to be extremely in acutely infected human lymphocytes.

Methyl 3-azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-erythro-furanosi de (3) was coupled with silylated 5-hydroxymethyluracil (1a) and its C1-C6 alkyl ethers 1b-g to give the corresponding protected nucleosides 4a-g which were deprotected with Bu4NF to afford 3-azido nucleosides 5a-g and 6a-g. The alpha-anomers 6f,g show moderate activity against HIV. No significant activity against HSV-1 was found for the compounds 5 and 6.

8-Aza-analogues of the potent antiviral nucleotide analogues 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and 9-[2-(phosphonomethoxy)-ethyl]guanine (PMEG) were prepared and evaluated for activity against human immunodeficiency viruses. When compared to the parent compounds, 8-aza-PMEA (1) and -PMEG (2) were less cytotoxic for MT-4 cells, but also less potent against HIV-1 and HIV-2. A new synthesis of PMEG starting from guanine is also reported.

Methyl 2,3-dideoxy-3-fluoro-5-0-(4-phenylbenzoyl)-β-D-erythro-pentofuranoside was condensed with trimethylsilylated 5-substituted uracils to give nucleosides using trimethylsilyl trifluoromethanesulfonate as catalyst. In the case of 5-nitrouracil an acyclic nucleoside believed to be an intermediate for the corresponding nucleoside was isolated. The 5-substituents were selected from neural network calculations on compounds with potential activity against HIV-1. All compounds from the condensation reactions were deacylated by treatment with sodium methoxide in methanol

4-Acyloxybenzyl bis(nucleosid-5′-yl) phosphates 7a-c and 9a-c were prepared as potential prodrugs of the anti-HIV nucleosides 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxyinosine (ddI) or their 5′-monophosphates. The anti-HIV activities of these triesters were determined in two T-cell lines. In a C8166 cell line they displayed activities comparable to and in some cases superior to AZT, but they also exhibited an increase in cytotoxicity. In a thymidine kinase deficient JM T-cell line the activity was reduced but was still superior to AZT. In the presence of porcine liver carboxyesterase (PLCE), triester 7b biodegrades to the diester 10 which, with phosphodiesterase, gives initially AZT monophosphate 3 and AZT.

The bis( S -acetyl-2-thioethyl) phosphotriester derivative of 2′,3′-didehydro-2′,3′-dideoxythymidine has been synthesized and evaluated for its inhibitory effects on the replication of HIV-1 in several cell culture systems. This pronucleotide showed potent anti-HIV activity and proved to be significantly superior to the parent nucleoside with regard to the antiviral efficiency.

A series of 6-alkoxy and 6-alkylamino carbovir derivatives were synthesized in order to evaluate prodrug approaches to increased bioavailability of the anti-HIV agent, carbovir. All of the compounds were active against HIV with the N-alkyl derivatives less active than the corresponding O-alkyl derivatives. The adenosine deaminase inhibitor, EHNA, had no effect on the anti-HIV activity of 6-propoxycarbovir, while the adenylic acid deaminase inhibitor, 2′-deoxycoformycin, significantly decreased antiviral activity. These observations suggest that the 6-alkoxycarbovirs are metabolized directly to the monophosphates and are subsequently converted to carbovir monophosphate via adenylic acid deaminase

A synthetic pathway to 5,6-dihydrovaltrate (I) is described using an asymmetric Diels—Alder reaction between diethyl fumarate and cyclopentadiene as key step (catalyst and product configuration are not specified, yield quant., 95% e.e.).