Good anti-HIV Activity Research Articles

Photo-induced scandium-catalyzed biomimetic skeleton conversion of lathyrane to naturally rare eupholathone Euphorbia diterpenes.

The naturally scarce eupholathone-type euphornin E (1) was efficiently prepared from abundant lathyrane-type Euphorbia factor L1via a visible-light-induced Sc(OTf)3-catalyzed tandem process. Eupholathones 2 and 3 were also smoothly obtained by changing the reaction solvent. This route provides a convenient method for easily constructing scarce eupholathone- from lathyrane-type Euphorbia diterpenes, and confirms the biogenetic relationship between them from a chemical standpoint. Notably, compound 1 exhibited good anti-HIV activity.

Nanomedicine perspective in HIV therapy: biosynthesized gold nanoparticles exhibiting enhanced anti-HIV property

BackgroundGlobally, HIV/AIDS is a major public health issue. Currently, available antiretroviral therapy (ART) has a number of impediments. The need for long-term usage of antiretroviral drugs is associated with the problem of drug resistance, high cost, and other side effects. Hence, there is a constant urge for the development of novel drugs to combat the disease. The synthesis of nanoparticles is of great interest because of their reported application in diverse fields. In contrast to chemical synthesis, green synthesis is inexpensive and enviro-safe.ResultsCalophyllum inophyllum (CI) is a plant that is known to possess anti-HIV activity. Hence, this plant was exploited for the synthesis of gold nanoparticles (AuNPs) in the present study. Two parts of the plant, namely, the fruit and leaves (CIF and CIL) were used for the synthesis of nanocompounds. The two nanocompounds were tested on HIV-1 isolates at different concentrations and the EC50 values were determined. While CIF-AuNP demonstrated very good anti-HIV activity with an EC50 value of 0.09097 ng/ml, CIL-AuNPs did not show significant anti-HIV activity.ConclusionsThe present study is a novel attempt to produce nanocompounds that incorporate the medicinal properties of certain plants that are known to have anti-HIV activity within nanoparticles, such that the compound possesses the attributes of a nanomaterial alongside the phytoactivity. Our results provide evidence to suggest that the CIF-AuNP can be further explored for in vivo activity. In vitro cytotoxicity of the AuNPs was checked in VERO cell lines using the MTT assay. Cytotoxicity was observed to be minimal at all the tested concentrations.

Development and evaluation of mucoadhesive bigel containing tenofovir and maraviroc for HIV prophylaxis

BackgroundSexual transmission of HIV is the most common means of acquiring the disease. Topical microbicides have been investigated to prevent transmission. This study will use a specific entry inhibitor, maraviroc, and a nucleotide reverse transcriptase inhibitor (NRTI), tenofovir, a dual combination which will provide a synergist effect that can enhance the efficacy of HIV microbicides via a mucoadhesive dual compartment bigel. Bigel formulation via hydrogel organogel linkages were developed and evaluated for their physicochemical characteristics, safety, and anti-HIV efficacy. In vitro diffusion studies were performed with Franz diffusion cells having effective diffusion surface area of 1.76cm2 and receiver chamber volume of 15mL.ResultThe bigel formulations showed a viscosity ranging from 14179 to 14560 cPs and had a good spreadability and acidic pH in the range of 4.0 ± 0.34 to 5.2 ± 0.18. The bigel formulations showed good anti-HIV activity at a concentration of 0.1 μg/mL. The in vitro release study of maraviroc from the bigel formulations showed a release rate ranging from 2.675 to 3.838 μg/cm2/min½ while the release rate for tenofovir ranged from 3.475 to 3.825 μg/cm2/min½. The bigel formulations were non-toxic to the human vagina as there was < 1 log10 change in Lactobacilli crispatus viability.ConclusionThis study successfully developed a dual compartment bigel containing maraviroc and tenofovir. BG C was found to be stable and safe towards vaginal and rectal epithelium, and it actively prevented HIV transmission. This bigel has the potential for long-term pre-exposure prophylaxis prevention of HIV transmission.

Spiro-Lactams as Novel Antimicrobial Agents.

Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out. The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. The designed structural modulation of biologically active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between β- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the activity against both HIV and Plasmodium.

Synthesis and Biochemical Evaluation of Novel Coumarin Derivatives as Anticancer and Anti-HIV Inhibitors Targeting CDK2

The present investigation dealt with finding new compounds that can act on both cancer and HIV-1 reverse transcriptase targeting CDK2. We constructed a library of new coumarin derivatives and developed a fingerprint pharmacophore model by using known CDK2 inhibitors (in clinical trial phase) and HIV-1 reverse transcriptase crystal structure (3DLG). The proposed library was mapped to the generated pharmacophore models and according to their fit-values; they were selected for docking into CDK2 enzyme. Compounds with high binding energy were selected for chemical preparation. Developing or adapting methods for the preparation of the selected compounds was applied and structures of the target compounds have been established by spectral analysis data. Five compounds 7b, 9d, 7c, 7d and 8c have shown very good anti-HIV activity in MT-4 cells. Similarly, five compounds 7b, 9d, 8b, 7c and 7d have exhibited very significant CDK2 inhibition activity. Compounds 7b and 7d were found to have dual anti-HIV and anticancer activities.

Molecular Modeling, Synthesis, and Anti-HIV Activity ofNovel Isoindolinedione Analogues as Potent Non-nucleoside Reverse Transcriptase Inhibitors.

Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti-HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti-HIV activity and the molecules having sulfonamide linkages were the most potent HIV-RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood-brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti-HIV drugs. In vitro screening was performed using HIV-1 strain IIIB in MT-4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV-1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under invitro conditions. Some of these molecules have shown good anti-HIV activity at 3-4nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV-1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti-HIV activity at 3-4nm concentrations.

A facile method for synthesizing water-soluble and superior sustained release anti-HIV prodrug SCs-d4T.

To efficiently deliver stavudine (d4T) for AIDS therapy, chitosan-stavudine conjugate (Cs-d4T) was synthesized. However, its poor water-solubility limited its clinical application. In this study, a sulphonated chitosan-stavudine conjugate (SCs-d4T) was synthesized with a mild SO3·Py complex sulphonation strategy. Chemical characteristics and morphology of Cs-d4T and SCs-d4T were performed by NMR, XRD, FTIR, ICP-AES and SEM. SCs-d4T demonstrated satisfactory solubility (106-bold of Cs-d4T solubility), good anti-HIV activity (6-fold of d4T anti-HIV activity), and well sustained release ability. The major release product O-isopropyl-5'-H-phosphonate of d4T (d4T-P-H) showed higher anti-HIV activity than d4T. For further evaluating the influence of linker and sulphonation strategy on anti-HIV activity, chitosan grafted with d4T by succinyl linker (Cs-sd4T) and SCs-d4T sulphonated by oleum were also prepared. The result showed that the O-isopropyl monophosphate linker of Cs-d4T and SO3·Py complex sulphonation strategy revealed higher anti-HIV activity than succinyl linker of Cs-sd4T and oleum sulphonation strategy, respectively.

Fluorine Substituted 1,2,4-Triazinones as Potential Anti-HIV-1 and CDK2 Inhibitors

Fluorine substituted 1,2,4-triazinones have been synthesized via alkylation, amination, and/or oxidation of 6-(2-amino-5-fluorophenyl)-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one1and 4-fluoro-N-(4-fluoro-2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)phenyl)benzamide5as possible anti-HIV-1 and CDK2 inhibitors. Alkylation on positions 2 and 4 in 1,2,4-triazinone gave compounds6–8. Further modification was performed by selective alkylation and amination on position 3 to form compounds9–15. However oxidation of5yielded compounds16–18. Structures of the target compounds have been established by spectral analysis data. Five compounds (5, 11, 14, 16, and17) have shown very good anti-HIV activity in MT-4 cells. Similarly, five compounds (1, 3, and14–16) have exhibited very significant CDK2 inhibition activity. Compounds14and16were found to have dual anti-HIV and anticancer activities.

Synthesis, drug release and anti-HIV activity of a series of PEGylated zidovudine conjugates

A series of methoxy poly(ethylene glycol)-succinyl-5′-O-zidovudine conjugates (mPEG-succinyl-AZT) with different molecular weight (Mw: 750Da, 2, 5 or 10kDa) of mPEG were synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy, 1H nuclear magnetic resonance (1H NMR) spectroscopy, and matrix-assisted laser desorption/ionization time of flight mass (MALDI TOF MS) spectrometry analysis. All conjugates showed good stability in vitro release experiments, and good anti-HIV activity and low cytotoxicity in MT-4 cells, in which, mPEG750-succinyl-AZT exhibited good inhibition to wild-type viruses (strains IIIB and ROD) with EC50 values of 0.11 and 0.090μmol/L, respectively, and it showed no cytotoxicity up to 110μmol/L. Oral pharmacokinetic study in rats showed the half-life time (T1/2) of all conjugates are prolonged compared to free AZT. Especially, mPEG750-succinyl-AZT displayed a ∼2.3-fold prolonged half-life and approximately 224% increased bioavailability of AZT.

ChemInform Abstract: Asymmetric Synthesis of 1,3-Dioxolane-Pyrimidine Nucleosides and Their Anti-HIV Activity.

In order to study the structure-activity relationships of dioxolane nucleosides as potential anti-HIV agents, various enantiomerically pure dioxolane-pyrimidine nucleosides have been synthesized and evaluated against HIV-1 in human peripheral blood mononuclear cells. The enantiomerically pure key intermediate 8 has been synthesized in nine steps from 1,6-anhydro-D-mannose (1), which was condensed with 5-substituted pyrimidines to obtain various dioxolane-pyrimidine nucleosides. Upon evaluation of these compounds, cytosine derivative 19 was found to exhibit the most potent anti-HIV agent although it is the most toxic. The order of anti-HIV potency was as follows: cytosine (beta-isomer) greater than thymine greater than cytosine (alpha-isomer) greater than 5-chlorouracil greater than 5-bromouracil greater than 5-fluorouracil derivatives. Uracil, 5-methylcytosine, and 5-iodouracil derivatives were found to be inactive. Interestingly, alpha-isomer 20 showed good anti-HIV activity without cytotoxicity. As expected, other alpha-isomers did not exhibit any significant antiviral activity. (-)-Dioxolane-T was 5-fold less effective against AZT-resistant virus than AZT-sensitive virus.

Synthesis and In‐vitro Activity of 4′‐Modified Analogues of ddA as Potent Anti‐HIV Agents

This paper reports the synthesis of novel 4'-hydrophobic pocket deoxythreosyl C-nucleosides. The key threose-like intermediates 9 and 14 were constructed from acyclic ketone derivatives, respectively. The antiviral activities of the synthesized compounds against the HIV-1, HSV-1, HSV-2, and HCMV viruses were evaluated. The 9-deaza-adenine derivatives 10 and 20 showed good anti-HIV activity without exhibiting significant cytotoxicity.

Preparation and anti-HIV activities of retrojusticidin B analogs and azalignans

Ten lignans ( 2– 11) and a series of azalignans including 1-aryl-pyrronaphthalenes 20– 24 and 3- N-alkylaminomethyl-1-arylnaphthalenes 25– 28, structurally related to two HIV reverse transcriptase inhibitors, retrojusticidin B and phyllamyricin A, were prepared from phyllanthin ( 1) for evaluation of anti-HIV activities. Anti-HIV activity of these compounds on a R5 pseudotype virus, ConB/pNL43E-L+, in the U87-CD4-CCR5 cells has been measured. Compounds 5, 22, 23, and 28 showed good anti-HIV activity with IC 50 value of 0.25, 1.07, 0.01, 0.32 μg/mL, respectively.

Interaction between phospholipids and new Gemini catanionic surfactants having anti-HIV activity

Abstract Monolayers at the air/water interface are used as 2D models of biological membrane to study the interaction of a new Gemini catanionic surfactant, Gem16,12, with the phospholipid DPPC. Gem16,12 is a synthetic analog of galactosylceramide (a cell receptor for HIV-1) and shows both good anti-HIV activity and low toxicity. Adsorption kinetics measurements are performed at Gemini concentrations below the critical aggregation concentration (CAC) and show a decrease of surface tension with increasing concentration. If the surface is covered with a DPPC monolayer at molecular areas with still zero surface pressure the adsorption of Gem16,12 is faster and leads to a higher surface pressure compared with the pure air/water interface. Film balance, fluorescence microscopy and grazing incidence X-ray diffraction (GIXD) experiments were performed after reaching the equilibrium surface tension. The experiments show an incorporation of Gem16,12 molecules into the fluid phase as well as into the condensed domains of a DPPC monolayer. GIXD experiments confirmed these results showing a smaller tilt angle in a DPPC monolayer on a Gemini subphase compared to DPPC on pure water. Compressing such a mixed monolayer leads first to the squeezing out of Gem16,12 molecules from the fluid part of the monolayer and above 30 mN/m to the squeezing out from the condensed part.

Structure of HIV-1 protease with KNI-272: a transition state mimetic inhibitor containing allophenylnorstatine.

Inhibitors of human immunodeficiency virus type 1 protease (HIV PR) are the subject of wide interest for the development of therapeutic drugs against AIDS [1–4]. The crystal structures of numerous HIV PR/inhibitor complexes have been solved to aid the process of inhibitor design and to rationalize the structure-activity relationships (SAR) for various classes of inhibitors [5–7]. Incorporation of allophenylnorstatine (APNS) [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] into peptidomimetics can lead to highly potent inhibitors of HIV PR [8]. However, no structure of APNS containing inhibitor complexes has been reported. Recently, KNI-272, a conformationally-constrained inhibitor containing APNS (Figure la), has been shown to possess good anti-HIV activity [9]. As a step towards understanding the high affinity of this novel class of inhibitors, we determined the three dimensional structure of KNI-272 bound to HIV PR.

Anticoagulant Activity of Sulfated Schizophyllan

Sulfated schizophylians with lower anticoagulant activity and higher anti-HIV activity were prepared. Those with sulfur contents above 6% showed anticoagulant activity irrespective of molecular weight. The activity was correlated with sulfur content. The triple helical structure of sulfated schizophylians did not affect their anticoagulant activity. A sulfated schizophyllan with a sulfur content of 5.0% showed low anticoagulant activity and good anti-HIV activity. These results indicate that the latter sulfated schizophyllan (sulfur content, 5%) would be useful as an anti-HIV agent for treatment of HIV-infected hemophiliacs.

LIGHT‐MEDIATED ACTIVITIES OF THIARUBRINES AGAINST HUMAN IMMUNODEFICIENCY VIRUS

Two thiarubrines (dithiacyclohexadienes), which were isolated recently from species of Asteraceae, were investigated for light-mediated antiviral activity against human immunodeficiency virus (HIV-1). Both compounds (thiarubrines A and D) showed good anti-HIV activity, in micromolar concentrations, which was dependent upon UVA radiation. They showed no anti-viral activity in the dark, and only weak visible light-mediated activity, despite the significant absorbance of these compounds in the 480 nm region. The resulting inactivated virus was unable to replicate in cell cultures, as indicated by loss of cytopathogenicity, the absence of cells expressing HIV-1 antigens and lack of production of HIV-1 p24 protein. Although this antiviral activity was not as efficient as that shown by the photoactive plant thiophene, alpha-terthienyl, both thiarubrines demonstrated increased activity when the serum component of the virus stock was reduced. This suggested that a component of bovine serum interfered to some extent with the anti-HIV activity.