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Title compound (IX*) is prepared from racemic lactol (I) using small-molecule-mediated dynamic kinetic resolution and a selective pyranose-to-furanose ring contraction as the key steps.

Background Purine nucleoside analogs (PNAs) constitute an important group of cytotoxic drugs for the treatment of neoplastic and autoimmune diseases. In the present study, classification models have been developed for the prediction of the anti-HIV activity of purine nucleoside analogs. Results The topochemical version of superaugmented pendentic index-4 has been proposed and successfully utilized for the development of models. A total of 60 2D and 3D molecular descriptors (MDs) of diverse nature were selected for building the classification models using decision tree (DT), random forest (RF), support vector machine (SVM), and moving average analysis (MAA). The values of most of these descriptors for each of the analogs in the dataset were computed using the Dragon software (version 5.3). An in-house computer program was also employed to calculate additional MDs which were not included in the Dragon software. DT, RF, and SVM correctly classified the analogs into actives and inactives with an accuracy of 89 %, 83 %, and 78 %, respectively. MAA-based models predicted the anti-HIV activity of purine nucleoside analogs with a non-error rate up to 98 %. Therapeutic active spans of the suggested MAA-based models not only showed more potency but also exhibited enhanced safety as revealed by comparatively high values of selectivity index (SI). The statistical importance of the developed models was appraised via intercorrelation analysis, specificity, sensitivity, non-error rate, and Matthews correlation coefficient. Conclusions High predictability of the proposed models clearly indicates an immense potential for developing lead molecules for potent but safe anti-HIV purine nucleoside analogs.

isolation, structure elucidation, biogenetic pathway and HIV-1 replication inhibitory activity

New thienopyrimidine derivatives (IIa) and (IIb) exhibit significant inhibitory activities against HIV-1 replication.

Six new lignans (I), (II), (III), and (IV) are isolated along with five known ones from the leaves and stems of Schisandra chinensis.

Novel quinazoline non-nucleosides analogues of Emivirine were described. Compounds 1a-c were silylated and reacted with the appropriate chloroethers (2a-c) in the presence of CsI to give the corresponding non-nucleosides 3a-h and 4a-h. Silylation of 1a-c and treatment with bis(allyloxy)methanes (5a,b) afforded the corresponding 1-(allyloxymethyl)quinazolines 6a-f. 1-(Propargyloxymethyl)-quinazolines 8a,b were obtained by treatment of the silylated 1a,b with bis(propargyloxy)methane (7) in the presence of TMS triflate.

One‐step synthesis of biologically active (±)‐confluentin is described from commercially available orcinol with trans,trans‐farnesal in the presence of ethylenediamine diacetate as a catalyst. Further conversion of synthetic confluentin to highly potent anti‐HIV agent, (±)‐daurichromenic acid, is accomplished by formylation and oxidation in two steps.

A novel highly discriminating adjacency-cum-distance based topological descriptor, termed as augmented eccentric connectivity index, has been conceptualized and it's discriminating power investigated with regard to anti-HIV activity of 2-pyridinone derivatives. The discriminating power of the augmented eccentric connectivity index was found to be far superior when compared to that of the distance based Wiener‘s index and adjacency based molecular connectivity index. This index did not exhibit any degeneracy amongst all possible structures with three, four and five vertices. The values of augmented eccentric connectivity index, Wiener's index and first-order molecular connectivity index of each of the 72 3-aminopyridin-2(1H)-one analogues comprising the dataset were computed using in-house computer program. The resulting data was analyzed and suitable models were developed after identification of the active ranges. Subsequently, a biological activity was assigned to each of the compounds involved in the dataset using these models which was then compared with the reported anti-HIV activity. High degree of prediction ranging from 81% to 89% was observed using models based upon these topological descriptors. Exceptionally high discriminating power amalgamated with decreased degeneracy of the proposed index, offers a vast potential for structure-activity/property studies.

2,4-Bis(trimethylsilyloxy)pyrimidines 1 / 2 on reaction with o -chlorobenzyl chlorides in 1,2-dichloroethane in the presence of I 2 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.

Twelve novel primary (4a-c, 5a-c) and secondary (4d-f, 5d-f) benzenesulfonamides bearing 2,5-disubstituted-1,3,4-oxadiazole moiety have successfully been prepared by direct chlorosulfonation of phenyl substitutent present on the 2-position of 5-mercapto-1,3,4-oxadiazoles 2a-c and their methylhio derivatives 3a-c using chlorosulfonic acid under anhydrous conditions. Structures of the synthesized compounds were established by their physical and spectral data. Some of the synthesized compounds have been screened in vitro for their antimicrobial and anti-HIV activity; the results were in accordance with SAR.

Cyclotides are a large family of mini-proteins that have the distinguishing features of a head-to-tail cyclised backbone and a cystine knot formed by six conserved cysteine residues. They are present in plants from the Rubiaceae, Violaceae and Cucurbitaceae families. The unique structural features of the cyclotides make them extremely resistant to chemical, thermal and proteolytic degradation. In this article we review recent studies from our laboratory that dissect the role of the individual structural elements in defining the stability of cyclotides. The resistance of cyclotides to chemical and proteolytic degradation is in large part due to the cystine knot, whereas the thermal stability is a composite of several features including the cystine knot, the cyclic backbone and the hydrogen bonding network. A range of biological activities of cyclotides is critically dependent on the presence of the cyclic backbone.

Four new isoquinoline derivatives bearing guanidinium group or amino group-terminated side chain were synthesized to target the HIV-1 TAR element. Their abilities to bind TAR RNA and inhibit Tat–TAR RNA interaction were determined by CE analysis, a Tat-dependent HIV-1 LTR-driven CAT assay and SIV-induced syncytium evaluation.

The synthesis of new acyclic nucleosides is described. These syntheses were accomplished by various methods: glycosylation, selective or total deprotection, oxidation/reduction, chlorination or azidation of hydroxyl groups. The compounds were characterized with NMR, mass and IR spectroscopy. Antiviral properties of these compounds were evaluated on HIV-1 infected cell lines.

A series of 6-naphthylmethyl substituted HEPT analogues bearing a β-carbonyl and a terminal phenyl ring or ester groups on the N-1 side chain of uracil were synthesized, and the in vitro anti-HIV activity was evaluated. Most of these HEPTs were considerably less potent and selective or inactive, only a few compounds showed moderate or high activity against HIV-1. The results demonstrated that the anti-HIV-1 activity of 6-naphthylmethyl substituted HEPT analogues was diminished or eliminated when the β-oxygen of N-1 side chain was replaced by a carbonyl group.

Isolation and characterization of novel cyclotides from Viola hederaceae - Solution structure and anti-HIV activity of vhl-1, a leaf-specific expressed cyclotide

Relationship between topochemical indices and anti-HIV activity of 4-Benzyl pyridinone derivatives has been investigated. The values of molecular connectivity topochemical index (an adjacency based topochemical descriptor) Wiener's topochemical index (a distance based topochemical descriptor) and superadjacency topochemical index (an adjacency cum distance based topochemical descriptor) were calculated for each of the 32 compounds comprising the data set using an in-house computer program. The resultant data was analyzed and suitable models were developed after identification of the active ranges. Subsequently, a biological activity was assigned using these models to each of the compounds involved in the dataset which was then compared with the reported anti-HIV activity. Exceptionally high accuracy of prediction was observed using these models. These models offer vast potential for providing lead structures for the development of potent anti-HIV agents.

The beta-D-enantiomer of FDOC (2',3'-dideoxy-5-fluoro-oxacytidine) exhibits potent anti-HIV-1 activity. It was obtained in optically pure form by employing a tandem kinetic resolution/chiral salt crystallization protocol. In addition, conditions were developed that allowed the unwanted butyrate ester of the L-enantiomer of FDOC to be racemized. This material could then be recycled in future resolutions.

A modification of Wiener's index, termed as Wiener's topochemical index (Wc), has been conceptualized. This topochemical index is not only sensitive to the presence of heteroatoms but also exhibits far less degeneracy when compared to Wiener's index. The relationship of the Wiener's topochemical index and Wiener's index with the anti-HIV activity of phenethylthiazolethiourea (PETT) compounds was investigated. The values of both the indices for each of the 62 analogs comprising the dataset were computed and suitable models were developed after identification of the active ranges. Subsequently, each analog was assigned a biological activity using these models, which was then compared with the reported anti-HIV activity. Accuracy of prediction was found to be ∼90% using models based upon Wiener's index as well as Wiener's topochemical index.

The introduction of a beta-carbonyl group to the C-2 side chain of S-DABO led to the finding of a series of novel potent anti-HIV agent. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations. Furthermore, the novel S-DABOs differ from the classical NNRTIs in that some compounds are active against both HIV-1 and HIV-2. They might interfere with another target or at least act on RT in a different way as compared to typical NNRTIs.

Antiviral cyclam macrocycles block viral entry into cells by binding to the CXCR4 co-receptor. Cyclams bind transition metal ions strongly and can potentially form a range of trans (I–V) and cis configurations which may be recognised differently by co-receptor proteins. A survey of the CSD (crystallographic structural database) shows that the trans -III configuration is the most common in the solid state for complexes of cyclam itself. Other configurations can be induced by N-substitution or ternary complexation and by interaction with solvents in solution. We report X-ray structures for the square-planar trans -III complexes [Pd(cyclam)]Cl 2 · 2MeOH and the C–C linked dimer [Pd 2 (2,2 ′ -bi-(1,4,8,11-tetraazacyclotetradecane))](ClO 4 ) 4 , in which the planes of the two cyclam rings are close to perpendicular (100.1°), and for tetra- N -benzyl-cyclam and its 5-coordinate Ni(II) complex [Ni(Bz 4 -cyclam)Cl]Cl which has the unusual trans -I configuration.

A set of 14 biflavonoid compounds with anti-human immunodeficiency virus (anti-HIV) activity is studied by using quantum chemical and chemometric methodologies with the aim to calculate some molecular properties and correlate them with the biological activity. The AM1 semi-empirical method was used to calculate the molecular properties of the 14 biflavonoid compounds and the chemometric methods stepwise discriminant analysis (SDA), K-nearest neighbours (KNN) and soft independent modelling of class analogy (SIMCA) were used to obtain the relationship between the calculated properties and the biological activity under study. Afterwards we used the results obtained with SDA, KNN and SIMCA to predict the anti-HIV activity of a new set of biflavonoid molecules.

Two new natural cycloartanes, tubiferolide methyl ester ( 1 ) and tubiferaoctanolide ( 2 ), together with the known coronalolide ( 3 ) and coronalolide methyl ester ( 4 ) have been isolated from leaves and twigs of Gardenia tubifera. In addition, a new flavone 5,3′,5′-trihydroxy-7,4′-dimethoxyflavone ( 5 ), five known flavones 6–10 and hexacosyl 4′-hydroxy-trans-cinnamate ( 11 ) were also obtained from the same source. The structures were assigned on the basis of spectroscopic methods. Compounds 3 , 7 , 9 , and 10 showed significant cytotoxic activities only in P-388 cell line. Compound 1 was cytotoxic against P-388, KB, Col-2 and Lu-1, while 4 was active in P-388 and BCA-1. Compounds 3 and 4 displayed significant anti-HIV activities in the HIV-1RT assay; compound 7 showed moderate activity in this assay. Compounds 5–10 were also found to be active in the ΔTat/RevMC 99 syncytium assay.

A new method for the synthesis of bipyridinyl S‐glycosides 11 and 12 has provided the title compounds in a higher yield. Application of a one‐pot glycosylation methodology resulted in an efficient, high‐yield synthesis of biazine S‐glycosides 17–20 An X‐ray diffraction analysis of 11 disclosed the conformation of this glycoside as the S‐glycoside and not the corresponding N‐form.

Syntheses of phosphoramidate protides of several 2′,3′-dideoxy-3′-fluoroadenosine derivatives by treatment of the nucleoside with phosphorochloridates in the presence of pyridine and t-BuMgCl is described. Several of these protides showed significantly improved antiviral potency over the parent nucleoside against HIV and HBV. Especially marked was the improvement in potency of phosphoramidate protides of 2′,3′-dideoxy-3′-fluoroadenosine against both HIV and HBV.

The synthesis of peptidomimetic inhibitors of HIV-1 protease based on 6-deoxy-6-amino-β- d -glucopyranoside and 6-deoxy-6-amino-β- d -mannopyranoside scaffolds has been achieved. The inhibitors had IC 50 values in the micromolar range. The results provide a platform for the development of more potent carbohydrate based inhibitors of HIV-1 and other aspartic proteases.

Several 1,3-thiazolidin-4-ones bearing a 2,6-dihalophenyl group at C-2 and a variously substituted phenyl ring at N-3 have been synthesized and tested as anti-HIV agents. The results of the in vitro tests showed that some of them proved to be effective inhibitors of HIV-1 replication.

We developed a novel approach to introduce a carbohydrate moiety into the structure of thiourea compounds targeting the NNI binding pocket of the HIV-1 reverse transcriptase. The described method involves the synthesis of an amino-substituted carbohydrate moiety which is then condensed with various thiocarbonylimidazole derivatives of substituted aromatic amines.

Sulfated astragalus polysaccharide (sulfated astragalan, SA) was prepared by chemical modification of astragalus polysaccharide abstracted from an astragalus menbranceus used as a Mongolia herbal medicine. Anti-HIV activity of SA was assayed in vitro and the results indicated that the SA showing high anti-HIV activity and lower cytotoxity. Sulfation of astragalan was carried out by using sulfur trioxide-pyridine complex in a mixture of dimethylsulfoxide (DMSO) to give sulfated astragalan with degree of substitution (DS) of 1.14–1.20 and a number average molecular weight (Mn) of 1.27–1.46 × 104. Copyright © 2003 John Wiley & Sons, Ltd.

Bioassay-guided fractionation of the aerial parts of Dasymaschalon echinatum led to the isolation of five known aristolactams; aristolactam AII (1), aristolactam BII (2), piperolactam A (3), piperolactam C (4), and goniopedaline (5), together with two aphorphine alkaloids; duguevalline (6) and noraristolodione (7) and two amide derivatives; asperphenamate (8), and N -benzoyl-L-phenylalaninol (9). Alkaloids 2 and 7 were isolated for the first time from the Dasymaschalon genus. The anti-HIV 1 reverse transcriptase (RT) activity of all isolated compounds was determined. Except for aristolactam BII (2), this is the first report of the anti-HIV 1-RT activity of compounds 1 and 3-9. Compounds 1, 3, 5, 6 and 8 showed weak anti-HIV 1-RT inhibitory activity with IC50ranging from 112.74 to 225.55μM.

A series of eleven heterodimers containing both a nucleoside analogue (d4U, d4T) and a non-nucleoside type inhibitor (Trovirdine analogue) were synthesized and evaluated for their ability to inhibit HIV replication. Unfortunately, the (N-3)d4U-Trovirdine conjugates (9a-e) and (N-3)d4T-Trovirdine conjugates (10a-f) were found to be inactive suggesting that the two individual inhibitor compounds do not bind simultaneously in their respective sites.

5α-Cycloart-24-ene-3,23-dione ( 1 ), 5α-cycloart-24-ene-3,16,23-trione ( 2 ) and methyl 3,4- seco -cycloart-4(28),24-diene-29-hydroxy-23-oxo-3-oate ( 3 ), together with five known flavones 5,7,4′-trihydroxy-3,8-dimethoxyflavone ( 4 ), 5,7,4′-trihydroxy-3,8,3′-tri-methoxyflavone ( 5 ), 5,7,4′-trihydroxy-3,6,8-trimethoxyflavone ( 6 ), 5,4′-dihydroxy-3,6,7,8-tetramethoxyflavone ( 7 ) and 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone ( 8 ) have been isolated from the leaves and twigs of Gardenia obtusifolia . The structures were assigned on the basis of spectroscopic methods. Compounds 3 – 8 and some of the modified compounds showed significant cytotoxic activities in several mammalian cell lines, especially 8 and its diacetate 21 which exhibited potent cytotoxicities (compound 8 : P-388 0.05 μg/mL, KB 0.09 μg/mL, BCA-1 0.63 μg/mL, Lu-1 0.09 μg/mL, ASK 0.70 μg/mL; its diacetate: P-388 0.27 μg/mL, KB 0.06 μg/mL, BCA-1 0.53 μg/mL, Lu-1 0.49 μg/mL). It was also found that 5 , 8 and 21 showed antimitotic acitivity in the ASK assay. Compounds 2 , 4 , 6 , 7 and some of the modified compounds displayed interesting anti-HIV activity in the syncytium assay, but were inactive or exhibited weak activity in the HIV-1 RT assay; while compound 3 was found to be active in the HIV-1 RT assay (99.9 % inhibition at 200 μg/mL), but cytotoxic in the syncytium assay.

A novel highly discriminating adjacency-cum-distance-based topological descriptor, termed the adjacent eccentric distance sum index, has been conceptualized and its discriminating power investigated with regard to the anti-HIV activity of 4,5,6,7-tetrahydro-imidazo-[4,5,1- jk] [1,4] benzodiazepin-2 (1 H)-one (TIBO) derivatives. The discriminating power of the adjacent eccentric distance sum index was compared with that of the eccentric connectivity index - another adjacency-cum-distance-based topological descriptor. The values of the eccentric connectivity index and the adjacent eccentric distance sum index of each of 121 analogues comprising the data set were computed and active ranges were identified. Subsequently, a biological activity was assigned to each analogue involved in the data set and this was then compared with the reported anti-HIV activity. Excellent correlations were observed between anti-HIV activity and both the topological descriptors. Although the overall accuracy of prediction was found to be approximately 84% in case of the eccentric connectivity index and approximately 86% in case of adjacent eccentric distance sum index, the predictability using the adjacent eccentric distance sum index in the active range itself was92%. The proposed index offers a vast potential for structure-activity/property studies.

Three naphthalene glycosides (1-3), four flavonoids (4-7), and two galloyl glycosides (8-9) were isolated from the stem-bark of Juglans mandshurica (Juglandaceae). Their structures were determined by chemical and spectral means, including to 2D-NMR (COSY, HMQC, and HMBC) experiments. Amongst the isolated compounds, taxifolin (4) showed the most potent HIV-induced cytopethic activity against MT-4 cells with complete inhibitory concentration (IC100) value of 25 microg/ml and maximum cytotoxic concentration (CC100) value of above 100 microg/ml. However, naphthalene glycosides (1-3), flavonoids (5-7), and galloyl tannins (8-9) were inactive against anti-HIV-1 activity.

Quantitative structure-activity relationship (QSAR) models are useful in providing a biochemical understanding of the biological activity of natural and synthetic chemicals based solely on molecular structure. One- to three-parameter multiregression equations were generated for three different groups of flavonoids to model experimental flavonoid-induced cytotoxicity and inhibition of human immunodeficiency virus I replication in lymphocyte-infected cells, using quantum chemical and geometrical parameters derived from optimized molecular structures. Both biological properties were basically dependent on electronic parameters describing charge distribution on the two fused rings of the flavonoid molecule. Atomic charges in C3 and the carbonyl carbon as well as the dipolar moment were important electronic descriptors to define the studied biological properties of flavonoids.

Considering the promising anti HIV activity displayed by some diPNA-arginine conjugates, a library has been generated to determine the target(s) and mode(s) of action of these presumed multi targets drugs and to optimize the antiviral properties of lead compounds. This library has been prepared using a combinatorial liquid-phase strategy, involving easily available N- protected PNA dimeric backbones as building blocks.

The prediction of biologically active compounds plays a very important role for high-throughput screening approaches in drug discovery. Most computational models, in this area, concentrate on measuring structural similarities between chemical elements. There are various methods to predict anti-HIV activity, such as artificial neural network and support vector machine, but generally using shallow machine learning with low accuracies and less samples. In this work, one of deep learning methods, stacked auto-encoder (SAE), is proposed to predict anti-HIV activity of a broad group of compounds for the first time. Through contrasting experiments of artificial neural network, support vector machine, and SAE under the same condition, the accuracy after descriptors screening is higher than using raw descriptors, and SAE performs better than the other two methods to achieve the perfect forecast of anti-HIV activity. It has a great significance on promoting anti-HIV drug design, which therefore can reduce research and development costs and improve the efficiency of anti-HIV drug discovery.

Screening of a small library of natural product extracts derived from endophytic fungi of the Sonoran desert plants in a cell-based anti-HIV assay involving T-cells infected with the HIV-1 virus identified the EtOAc extract of a fermentation broth of Alternaria tenuissima QUE1Se inhabiting the stem tissue of Quercus emoryi as a promising candidate for further investigation. Bioactivity-guided fractionation of this extract led to the isolation and identification of two new metabolites, altertoxins V (1) and VI (2) together with the known compounds, altertoxins I (3), II (4), and III (5). The structures of 1 and 2 were determined by detailed spectroscopic analysis and those of 3–5 were established by comparison with reported data. When tested in our cell-based assay at concentrations insignificantly toxic to T-cells, altertoxins V (1), I (3), II (4), and III (5) completely inhibited replication of the HIV-1 virus at concentrations of 0.50, 2.20, 0.30, and 1.50 μM respectively. Our findings suggest that the epoxyperylene structural scaffold in altertoxins may be manipulated to produce potent anti-HIV therapeutics. 2014 Elsevier Ltd. All rights reserved.

Novel cyclic sulfonamide-based inhibitors of HIV-1 protease are designed, synthesis and evaluated for their activity.

Background It has been shown that genital lesions and altered innate mucosal immunity caused by HSV-2 are important cofactors to increase the rate of HIV transmission and infection. Therefore, a product that inhibits HIV and HSV would have potential benefits in the prophylaxis against these sexually transmitted viruses. The labyrinthopeptin A1 (LabyA1) is a prototype peptide of a novel class of carbacyclic lantibiotics. Here, we extensively evaluated LabyA1 for its broad-spectrum activity against HIV and HSV.

Fucoidans are sulfated polysaccharides derived from marine brown algae. In the current work the anti-HIV activity of three fucoidans, extracted from three brown seaweeds Sargassum mcclurei, Sargassum polycystum and Turbinara ornata and collected from Nha Trang bay, Vietnam was investigated. Fucoidans extracted from the three species displayed similar antiviral activities with a mean IC50 ranging from 0.33 to 0.7 μg/ml while displaying no cell toxicity. Our results showed that the anti-HIV activity of fucoidans is not primarily linked to the sulfate content and the appropriate position of sulfate groups in the fucoidan backbones was also not associated with the antiviral activity. Fucoidans inhibited HIV-1 infection when they were pre-incubated with the virus but not with the cells, and not after infection, blocking the early steps of HIV entry into target cells. These data contribute to a better understanding of the influence of fucoidans structural characteristics on their biological activity.