Evaluation Of anti-HIV Activity Research Articles

Total Synthesis and Anti-HIV Activity Evaluation of Desmosdumotin D and Analogues

The natural product Desmosdumotin D (hereafter referred to as Des-D), isolated from the plant Desmos dumosus, showed potent anti-HIV activity. However, the subsequent pharmacological activity and clinical studies are limited due to the low content of Des-D in the plant. Therefore, the total synthesis path of Des-D was optimized in this paper, and the total yield was increased from 4.4% to 11.9%. Additionally, twelve analogues were obtained following the synthesis route of Des-D. The anti-HIV activity evaluation results in vitro showed that Des-D had the highest activity, with an IC50 value of 13.6 μM, and compounds 17 and 11 had the lowest anti-HIV activity, with IC50 values of 101.3 μM and 161.0 μM, respectively. Through the molecular docking of compounds Des-D and 17 with HIV-IN, the results show that phenolic hydroxyl groups and two benzene rings interact with HIV-IN and are possible pharmacodynamic groups.

New 2-alkylthio-1-benzylimidazole-5-carboxylic acid derivatives targeting gp41: design, synthesis and in vitro anti-HIV activity evaluation.

Background Although current available medications have increased the quality of life in HIV-infected patients, there are still some shortcomings in HIV treatment arising from viral resistance, drug side effects and high cost of medication. Therefore, there is an urgent need for some suitable HIV inhibitors with different mechanisms of action. Gp41, located on the HIV cell surface, plays an important role in the fusion of viral and host cell membranes. With the same structure in different HIV strains, gp41 seems to be a promising target for developing novel HIV fusion inhibitors. Objective Based on the essential structural elements of gp41 inhibitors, two series of compounds were prepared and their inhibitory effect on HIV cell growth was investigated. Compared to the known small-molecule gp41 inhibitors, 2-Alkylthio-1-benzylimidazole-5-carboxylic acid (series I) and (E)-4-{[5-(((1-benzyl-1H-1,2,3-triazol-4-yl)methoxyimino)methyl)-2-(alkylthio)-1H-imidazol-1-yl]methyl}benzoic acid derivatives (series II) had more flexible skeleton with extra moieties interacting with the gp41 key residues. Method In silico drug design approaches including molecular docking and molecular dynamics simulations were employed to design these novel compounds prior to preparation. The designed compounds exhibited proper chemical interactions and stable complexes with gp41. Then, the selected candidates were efficiently synthesized, and their anti-HIV-1 and anti-HIV-2 activities, as well as their cellular cytotoxicity in MT-4 cells were determined. Results None of the compounds belonging to the series I were active against HIV-1 and HIV-2 replication in cell cultures, and most of the compounds in series II exhibited significant cytotoxicity against MT-4 cells in low micro molar concentrations. Conclusion The smaller molecular structures of the compounds in series I might be responsible for their poor anti-HIV effects. The high toxicity of the series II compounds on the host cell makes it impossible to assess their anti-HIV activities.

Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir.

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several classes of derivatives were synthesized. The synthesized compounds were characterized by 1H NMR, IR, UV, and mass spectrometry. In addition, several of the synthesized compounds were evaluated as racemic mixtures for anti-HIV activity in vitro in a single round infection assay using TZM-bl cells at 100 ng/mL. TFV (1) was used as a positive control and inhibited HIV infection by 35%. Among all the evaluated compounds, the disubstituted heptanolyl ester alanine phosphonamidate with naphthol oleate (69), pentanolyl ester alanine phosphonamidate with phenol oleate (62), and butanolyl ester alanine phosphonamidate with naphthol oleate (87) ester conjugates of TFV were more potent than parent drug TFV with 79.0%, 76.5%, 71.5% inhibition, respectively, at 100 ng/mL. Furthermore, two fatty acyl amide conjugates of tenofovir alafenamide (TAF) were synthesized and evaluated for comparative studies with TAF and TFV conjugates. Tetradecanoyl TAF conjugate 95 inhibited HIV infection by 99.6% at 100 ng/mL and showed comparable activity to TAF (97–99% inhibition) at 10–100 ng/mL but was more potent than TAF when compared at molar concentration.

Design, synthesis, antimicrobial activity and anti-HIV activity evaluation of novel hybrid quinazoline–triazine derivatives

A series of novel hybrid quinazoline–triazine derivatives was designed and synthesized from cyanuric chloride and anthranilic acid through sequential reactions, which contain different pharmacophores like quinazoline and substituted diaryl triazine (DATA) linked with ethylene diamine. All the newly synthesized compounds were characterized by infrared, 1H-NMR, 13C-NMR, MS and elemental analysis. Further, we evaluated the in vitro anti-HIV activity of the newly synthesized compounds against HIV-1 (IIIB) and HIV-2 (ROD) viral strains and as well as in vitro antimicrobial activity against four bacteria (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, Klebsiella pneumoniae) and two fungi (Aspergillus clavatus, Candida albicans) using the paper agar streak dilution method. The bioassay results indicate that four compounds namely 7d, 7n, 7r and 7s could be considered as possible potential agents.

Carrageenan-Based Gel Retains Limited Anti-HIV-1 Activity 8–24 Hours After Vaginal Application by HIV-Infected Thai Women Enrolled in a Phase I Safety Trial

Carrageenan-Based Gel Retains Limited Anti-HIV-1 Activity 8–24 Hours After Vaginal Application by HIV-Infected Thai Women Enrolled in a Phase I Safety Trial

Synthesis and Inhibiting Activity of Some 4-Hydroxycoumarin Derivatives on HIV-1 Protease

Six novel 4-hydroxycoumarin derivatives were rationally synthesized, verified, and characterized by molecular docking using crystal HIV-1 protease. Molecular docking studies predicted antiprotease activity of (7) and (10). The most significant functional groups, responsible for the interaction with HIV-1 protease by hydrogen bonds formation are pyran oxygen, atom, lactone carbonyl oxygen and one of the hydroxyl groups. The newly synthesized compounds were biologically tested in MT-4 cells for inhibiting HIV-1 replication, exploring the protection of cells from the cytopathic effect of HIV measured by cell survival in MTT test. One derivative −7 showed 76–78% inhibition of virus infectivity with IC50 = 0.01 nM, much less than the maximal nontoxic concentration (1 mM). Antiprotease activity of 7 in two different concentrations was detected to be 25%. Nevertheless, the results of study of (7) encourage using it as a pharmacophore for further synthesis and evaluation of anti-HIV activity.

Synthesis and anti-HIV activity evaluation of new phenyl ethyl thiourea (PET) derivatives

This manuscript describes the synthesis of a new series of phenyl ethyl thiourea (PET) derivatives, with the aim to extend the SAR studies of the well known PET molecules endowed with anti-HIV activity. Preliminary results indicated that the synthesized compounds possess low anti-HIV activity.

Novel 1,2,3-thiadiazole derivatives as HIV-1 NNRTIs with improved potency: Synthesis and preliminary SAR studies

A novel synthetic route and anti-HIV activity evaluation of a new series of 2-(4-(2,4-dibromophenyl)-1,2,3-thiadiazol-5-ylthio)acetamide (TTA) derivatives are described. Bioactivity assay indicated that most of the title compounds showed good activities against HIV-1. In particular, compound 7c displayed the most potent anti-HIV-1 activity (EC 50 = 36.4 nM), inhibiting HIV-1 replication in MT-4 cells more effectively than NVP (by sevenfold) and DLV (by eightfold). The preliminary structure–activity relationships (SAR) of the newly synthesized congeners are discussed, and molecular modeling of compound 7c in complex with HIV-1 RT is described, allowing rationalization of some SAR conclusions.

Synthesis and anti-HIV activity evaluation of 2-(4-(naphthalen-2-yl)-1,2,3-thiadiazol-5-ylthio)- N-acetamides as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

A series of 2-(4-(naphthalen-2-yl)-1,2,3-thiadiazol-5-ylthio)acetamide (TTA) derivatives were synthesized and evaluated as potent inhibitors of HIV-1. Among the newly disclosed TTAs, compounds 7f, 7g and 7c were the most potent inhibitors of HIV-1 replication of the series (EC 50 = 0.17 ± 0.02, 0.36 ± 0.19 and 0.39 ± 0.05 μM, respectively), coupled with a reasonable selectivity index (SI > 1452, >845, and >774, respectively). They possess improved or similar HIV-1 inhibitory activity compared with NVP (EC 50 = 0.208 μM) and DLV (EC 50 = 0.320 μM). The preliminary structure–activity relationships among the newly synthesized congeners are discussed briefly and rationalized by docking studies.

Synthesis and anti-HIV activity evaluation of 1-[(alkenyl or alkynyl or alkyloxy)methyl]-5-alkyl-6-(1-naphthoyl)-2,4-pyrimidinediones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

The synthesis and anti-HIV activity evaluation of a new series of 2,4-pyrimidinediones bearing a 6-(1-naphthoyl) group are described. In general, it was found that most of the title compounds showed good activities against human immunodeficiency virus type-1 (HIV-1). In particular, compound 26 displayed the most potent anti-HIV-1 activity (IC 50 = 0.11 ± 0.05 μM), inhibiting HIV-1 replication in MT-4 cells more effectively than HEPT (by 45-fold) and DDI (by 50-fold).

Probabilistic Neural Network Model for the In Silico Evaluation of Anti-HIV Activity and Mechanism of Action

A theoretical model has been developed that discriminates between active and nonactive drugs against HIV-1 with four different mechanisms of action for the active drugs. The model was built up using a probabilistic neural network (PNN) algorithm and a database of 2720 compounds. The model showed an overall accuracy of 97.34% in the training series, 85.12% in the selection series, and 84.78% in an external prediction series. The model not only correctly classified a very heterogeneous series of organic compounds but also discriminated between very similar active/nonactive chemicals that belong to the same family of compounds. More specifically, the model recognized 96.02% of nonactive compounds, 94.24% of active compounds that inhibited reverse transcriptase, 97.24% of protease inhibitors, 97.14% of virus uncoating inhibitors, and 90.32% of integrase inhibitors. The results indicate that this approach may represent a powerful tool for modeling large databases in QSAR with applications in medicinal chemistry.

Synthesis and evaluation of anti-HIV activity of isatin β-thiosemicarbazone derivatives

On the basis of pharmacophoric modelling studies of existing NNRTIs, a series of isatin β-thiosemicarbazone derivatives was synthesized and evaluated for their anti-HIV activity in HTLV-III B strain in the CEM cell line. Three compounds showed significant anti-HIV activity, whereupon compound 6 was found to be the most active compound with an EC 50 value of 2.62 μM and a selectivity index of 17.41, while not being cytotoxic to the cell line at a CC 50 value of 44.90 μM. Other tested compounds exhibited marked activity below their toxicity threshold.

Synthesis and evaluation of anti-HIV activity of 3-azido-4-(hydroxymethyl)tetrahydrofuran derivatives containing 2-(thymin-1-yl)methyl, 2-(cytosin-1-yl)methyl or 2-(adenin-9-yl)methyl substituents – a new series of AZT analogues

The three monocyclic AZT analogues 6, 7 and 8 {3-azido-4-(hydroxymethyl)tetrahydrofuran derivatives containing 2-[(thymin-1-yl)methyl], 2-[(cytosin-1-yl)methyl] and 2-[(adenin-9-yl)methyl] substituents} are synthesized via methyl 3-azido-3-deoxy-2-O,4-C-methylene-D-ribofuranoside 13 as key intermediate. All nucleoside analogues proved to be devoid of anti-HIV activity in MT-4 cells.

Synthesis and Anti-HIV Activity of Alkyl Steroidal 3′-Azido-3′-deoxythymidin-5′-yl Phosphotriesters as Prodrugs of AZT

Abstract Alkyl steroidal AZT 5′-monophosphate triesters are designed as lipophilic prodrugs of AZT to improve its therapeutic efficiency. We have synthesized four phosphotriesters of AZT, in one-pot, using phosphoramidite-phosphite triester methodology. This method afforded the desired prodrugs in high yields under mild conditions. The in vitro evaluation of anti-HIV activity of these prodrugs is also reported.

Anti-AIDS agents, 11. Betulinic acid and platanic acid as anti-HIV principles from Syzigium claviflorum, and the anti-HIV activity of structurally related triterpenoids.

Betulinic acid [1] and platanic acid [2], isolated from the leaves of Syzigium claviforum, were found to be inhibitors of HIV replication in H9 lymphocyte cells. Evaluation of anti-HIV activity with eight derivatives of 1 revealed that dihydrobetulinic acid [3] was also a potent inhibitor of HIV replication. The C-3 hydroxy group and C-17 carboxylic acid group, as well as the C-19 substituents, contribute to enhanced anti-HIV activity. The inhibitory activity of these compounds against protein kinase C (PKC) was also examined, since a correlation between anti-HIV and anti-PKC activities has been suggested. However, there was no apparent correlation between anti-HIV activity and the inhibition of PKC among these compounds.

5-Amino Derivatives of 2',3'-Dedeoxynucleosides for Evaluation of Anti-HIV Activity

Reaction of protected 2,3-dideoxy-D-ribose (2) with silylated 5-amino derivatives of uracil using trimethylsilyl trifluoromethanesulfonate as catalyst afforded the 2',3'-dideoxynucleosides (3a-d) which were deprotected with methanolic ammonia and separated by chromatography to give α-anomers (4a-d) and β-anomers (5a-d). Compounds (3a-c) were converted to 4-(1,2.4-triazol-1-yl) derivatives (6a-c). Ammonia in dioxane converted the 4-(1,2,4-triazole-1-yl)pyrimidin-2(1H)-one moiety into cytosin-1-yl. In case of 6b, 4-methoxypyrimidin-2-one 2,3-dideoxyriboside was accomplished via transformation of the 4-triazolyl moiety with methanol on silica. Methanolic ammonia was used for deprotection of the sugar moiety to afford 7-10