Potent anti-HIV Activity Research Articles

Elvitegravir: A Review of Its Use in Adults with HIV-1 Infection

The HIV integrase inhibitor elvitegravir is now available as a single-agent tablet (Vitekta(®)) in the EU, where it is indicated for once-daily oral use, in combination with a ritonavir-boosted protease inhibitor (PI) and other antiretrovirals, for the treatment of HIV-1 infection in adults without known mutations associated with resistance to elvitegravir. The drug has potent anti-HIV activity and a well characterized resistance profile, although cross resistance with raltegravir is observed. When used in combination with ritonavir-boosted PI-based antiretroviral therapy (ART) in treatment-experienced adults in a randomized, double-blind, phase III trial, once-daily elvitegravir was associated with virological suppression noninferior to that seen with twice-daily raltegravir after 48weeks' treatment, and such benefits were largely maintained at 96weeks. Moreover, in an open-label extension of this study, in which all patients received an elvitegravir regimen, virological suppression continued to be observed in most patients at 144weeks. Elvitegravir is generally well tolerated, with diarrhoea and nausea being the most common tolerability issues. Thus, single-agent elvitegravir extends the treatment options available for use in the ritonavir-boosted PI-based ART regimens of adults infected with HIV-1 and has the convenience of once-daily administration.

Coupling Evolutionary Information with Functional Dynamics to Reengineer the Oligosaccharide Specificity of Cvn with Bp-Dock

Cyanovirin-N (CVN) is a cyanobacterial lectin with potent anti-HIV activity, mediated by binding to Man(1,2)Man with high affinity and specificity. These sugar-binding sites are located in two quasi-symmetric domains (A and B) of the CVN protein. We explore both the evolutionary and functional dynamics of CVN and reengineer CVN mutants with different binding affinity for the oligo-mannosides, through integrated computational and experimental strategies. We perform statistical analysis on CVN homologs to find correlated mutations between amino acids1 and in parallel; we also analyze the positions whose correlated fluctuations are critical for function through a dynamic flexibility index (dfi) metric.2 Integrating the evolutionary information with the dynamically coupled positions that are critical for function, we model various CVN mutants and obtain these variants in complex with di-mannose sugar with a fast and flexible docking method called BP-Dock.3 We later characterize these mutants experimentally with NMR or ITC. Overall, this study helps us to explore the sugar binding properties of CVN mutants obtained from evolutionary and functional analysis and thus provide better insights about the mechanism of glycan recognition.

Inhibitors of the ‘point of no return’ in human immunodeficiency virus infectivity – discovery of novel antihuman immunodeficiency virus integrase compounds with dual mechanism of action

Although the global therapeutic response to human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) has seen tangible progress, this viral pandemic continues to ravage many worldwide communities nevertheless. At least 34 million people in the world are infected with HIV and a few million additional HIV infections occur each year. Moreover, co-infection of HIV and tuberculosis (TB), and particularly multidrug-resistant (MDR)-TB, has taken the pandemic to a substantially elevated level of seriousness with significant increases in mortality. Although progress has been made in the field of anti-HIV active integrase inhibitors and their use in combination therapeutics against HIV/AIDS, some very significant challenges still remain to be surmounted with next-generation integrase inhibitors for HIV/AIDS. These include appropriate profiles with respect to phase I and II metabolism, minimizing adverse drug – drug interactions, cross-resistance issues and, very importantly, HIV co-infections involving drug-resistant infections. In our laboratory we have discovered a novel class of HIV integrase inhibitors, exemplified by 4-[5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]-4-hydroxy-2-oxo-N-(2-oxopyrrolidin-1-yl)but-3-enamide (compound 2), which exhibits potent anti-HIV activity against a large and diverse set of HIV isolates. This drug displays low cytotoxicity and its resistance and related drug susceptibility data are also positive. Its profile with respect to phase I and II metabolic isozymes/isoforms of cytochrome P450 and uridine 5 ′ -diphospho-glucuronosyltransferase are very favourable, which is of significant advantage in drug – drug interaction issues. Preclinical studies in animals revealed a positive pharmacokinetic profile and no adverse treatment-related findings. The ability to synthesize pure compounds of this family in very high yields, and therefore the potential for worldwide availability, is another positive aspect of this drug discovery. Finally, the most significant part of this drug discovery is the remarkable dual mechanism of action of these conceptually new small molecules against both HIV and MDR-TB.

Structure–activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers. Part II: P2/P3 region and discovery of cobicistat (GS-9350)

The HIV protease inhibitor (PI) ritonavir (RTV) has been widely used as a pharmacoenhancer for other PIs, which are substrates of cytochrome P450 3A (CYP3A). However the potent anti-HIV activity of ritonavir may limit its use as a pharmacoenhancer with other classes of anti-HIV agents. Ritonavir is also associated with limitations such as poor physicochemical properties. To address these issues a series of compounds with replacements at the P2 and/or P3 region was designed and evaluated as novel CYP3A inhibitors. Through these efforts, a potent and selective inhibitor of CYP3A, GS-9350 (cobicistat) with improved physiochemical properties was discovered.

Differential Expression of SDF-1 Isoforms in Bladder Cancer

SDF-1 is a ligand of the chemokine receptors CXCR4 and 7. The 6 known SDF-1 isoforms are generated by alternative mRNA splicing. While SDF-1 expression has been detected in various malignancies, only few groups have reported differential expression of SDF-1 isoforms and its clinical significance. We evaluated the expression of 3 SDF-1 isoforms (α, β and γ) in bladder cancer. Using quantitative polymerase chain reaction we measured SDF-1α, β and γ mRNA levels in 25 normal and 44 bladder cancer tissues, and in 210 urine specimens (28 normal, 74 benign, 57 bladder cancer, 35 bladder cancer history, 8 other cancer history and 8 other cancer) from consecutive patients. Levels were correlated with clinical outcome. Of the SDF-1 isoforms only SDF-1β mRNA was significantly over expressed 2.5-fold to sixfold in bladder cancer compared to normal bladder tissues. SDF-1α was expressed in bladder tissues but SDF-1γ was undetectable. On multivariate analysis SDF-1β was an independent predictor of metastasis and disease specific mortality (p=0.017 and 0.043, respectively). In exfoliated urothelial cells only SDF-1β mRNA levels were differentially expressed with 91.2% sensitivity and 73.8% specificity for detecting bladder cancer. In patients with a bladder cancer history increased SDF-1β levels indicated a 4.3-fold increased risk of recurrence within 6 months (p=0.0001). SDF-1 isoforms are differentially expressed in bladder tissues and exfoliated urothelial cells. SDF-1β mRNA levels in bladder cancer tissues predict a poor prognosis. Furthermore, SDF-1β mRNA levels in exfoliated cells detect bladder cancer with high sensitivity and they are a potential predictor of future recurrence.

Toward the natural didemnaketal A: total synthesis of the isomer of didemnaketal A

The total synthesis of isomer of didemnaketal A was achieved in 26 steps. The position of esters is switched at C7 and C8 with respect to their proposed position in natural didemnaketal A, which shows potent anti-HIV activity but so far has not been synthesized in the laboratory. Structural analysis of synthetic isomer of didemnaketal A indicates that the esters at C7 and C8 are correctly assigned, suggesting that the problems for the structural reassignment of natural didemnaketal A lie elsewhere.

Cell-permeable stapled peptides based on HIV-1 integrase inhibitors derived from HIV-1 gene products.

HIV-1 integrase (IN) is an enzyme which is indispensable for the stable infection of host cells because it catalyzes the insertion of viral DNA into the genome and thus is an attractive target for the development of anti-HIV agents. Earlier, we found Vpr-derived peptides with inhibitory activity against HIV-1 IN. These Vpr-derived peptides are originally located in an α-helical region of the parent Vpr protein. Addition of an octa-arginyl group to the inhibitory peptides caused significant inhibition against HIV replication associated with an increase in cell permeability but also relatively high cytotoxicity. In the current study, stapled peptides, a new class of stabilized α-helical peptidomimetics were adopted to enhance the cell permeability of the above lead peptides. A series of stapled peptides, which have a hydrocarbon link formed by a ruthenium-catalyzed ring-closing metathesis reaction between successive turns of α-helix, were designed, synthesized, and evaluated for biological activity. In cell-based assays some of the stapled peptides showed potent anti-HIV activity comparable with that of the original octa-arginine-containing peptide (2) but with lower cytotoxicity. Fluorescent imaging experiments revealed that these stapled peptides are significantly cell permeable, and CD analysis showed they form α-helical structures, whereas the unstapled congeners form β-sheet structures. The application of this stapling strategy to Vpr-derived IN inhibitory peptides led to a remarkable increase in their potency in cells and a significant reduction of their cytotoxicity.

Diterpenoids from Euphorbiaceae with Potent Anti-CHIKV and Anti-HIV Activities: Are these Antiviral Properties Correlated?

In the course of our ongoing program focusing on the characterization of anti-CHIKV (Chikungunya virus) compounds from higher plants, we found that several diterpenoids possessing daphnane, tigliane or jatrophane carbon skeletons, isolated from various Euphorbiaceae species were potent and selective inhibitors of the CHIKV replication. Since some daphnane-type and tigliane-type diterpenoids, such TPA and Prostratin, are well known to possess anti-HIV activities, we evaluated the antiviral activity of compounds isolated, as well as commercially available phorbol esters on HIV-1 and HIV-2 viruses. The results of this biological survey, still under investigation, indicate that potent anti-CHIKV diterpenoids possess also anti-HIV activities. Chikungunya virus (CHIKV) is an alpha virus (Togaviridae) that is transmitted to humans mainly by Aedes aegypti and A. albopictus mosquitoes, while HIV virus is a lentivirus (Retroviridae). Although there is no apparent relationship between these viruses, the mechanism of action by which diterpenoids would act could involve similar targets for the two viruses. We will report in this communication the main structural characteristics of the diterpenoids isolated and their antiviral activities on CHIKV, SINV (Sindbis virus), SFV (Semliki forest virus) and HIV viruses.

Design, Synthesis, and Evaluation of WC5 Analogues as Inhibitors of Human Cytomegalovirus Immediate‐Early 2 Protein, a Promising Target for Anti‐HCMV Treatment

Although human cytomegalovirus (HCMV) infection is mostly asymptomatic for immunocompetent individuals, it remains a serious threat for those who are immunocompromised, in whom it is associated with various clinical manifestations. The therapeutic utility of the few available anti-HCMV drugs is limited by several drawbacks, including cross-resistance due to their common mechanism of action, i.e., inhibition of viral DNA polymerase. Therefore, compounds that target other essential viral events could overcome this problem. One example of this is the 6-aminoquinolone WC5, which acts by directly blocking the transactivation of essential viral Early genes by the Immediate-Early 2 (IE2) protein. In this study, the quinolone scaffold of the lead compound WC5 was investigated in depth, defining more suitable substituents for each of the scaffold positions explored and identifying novel, potent and nontoxic compounds. Some compounds showed potent anti-HCMV activity by interfering with IE2-dependent viral E gene expression. Among them, naphthyridone 1 was also endowed with potent anti-HIV activity in latently infected cells. Their antiviral profile along with their innovative mechanism of action make these anti-HCMV quinolones a very promising class of compounds to be exploited for more effective antiviral therapeutic treatment.

Abstract supplement: HIV Drug Therapy in the Americas Congress 13–15 June 2013, São Paulo, Brazil

Abstract supplement: HIV Drug Therapy in the Americas Congress 13–15 June 2013, São Paulo, Brazil

Exploration of the in vitro Antiviral Activity of a Series of New Pyrimidine Analogues on the Replication of HIV and HCV

In continuation of our search for new anti-HIV and anti-HCV agents, the suggestion, synthesis and structure elucidation of a new series of 2,6-diamino-4-alkylthio- or (2-benzylhydrazinyl)-5-p-chlorophenylazopyrimidines), 2,6-diamino-4-(2-benzylhydrazinyl)-5-(aryl-[1,1'-biphenyl]-4-yl)pyrimidines, 2,6-diamino-4-(aryl)-5-(aryl[1,1'-biphenyl]-4-yl) pyrimidines), 6-(aryl)-1,3-dimethyl-5-nitro pyrimidine-2,4-dione and 6-amino-4-methoxy-N,N-dimethyl-6-arylpyrimidines were described. The anti-HIV-1 (strain IIIB) and HIV-2 (strain ROD) activity of the newly synthesized pyrimidine analogues was evaluated in vitro in human MT-4 cells using the MT-4/MTT assay. Similarly, the same compounds were evaluated in vitro for their selective antiviral activity against HCV in the Huh 5-2 replicon system (type 1b, Con1 strain). None of the tested compounds exhibited inhibition of HIV-1 and HIV-2 replication in cell culture. Even though many compounds yielded a 50% effective concentration in the HCV replicon system with selectivity indexes up to 6.9, none of the compounds matched the selection criteria of a selective inhibitor of virus replication in this assay (that is, >70% inhibition at concentrations that do not elicit an anti-metabolic effect on the host cells). Structural modification of these compounds might optimize their anti-HCV activity by introducing diverse and potent functional groups at the pyrimidine backbone, like nitrile residue. Because of the nature of the molecules, these new derivatives will also be evaluated for their potential anti-HIV activity.

Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations

While some examples are known of integrase inhibitors that exhibit potent anti-HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis- and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained through their binding interactions within the active site of the HIV-1 integrase intasome. The more active enantiomer 3 (EC50 25nM) was relatively stable in human liver microsomes. Kinetic data revealed that its impact on key cytochrome P450 isozymes, as either an inhibitor or an activator, was minor, suggesting a favorable CYP profile.

Anti-HIV and NO production inhibition activities of epi-aleuritolic acid derivatives

Fifteen epi-aleuritolic acid derivatives were synthesized and evaluated for anti-HIV activity in 293 T cells and NO production inhibition activity. Of the derivatives, 1, 2, 3, 4, 11, and 13 showed relatively potent anti-HIV activity with EC50 values ranging from 5.80 to 13.30 μM. The most potent compound, 3α-2′,2′-dimethylsuccinic acyl epi-aleuritolic acid (11), displayed significant anti-HIV activity with an EC50 value of 5.80 μM. Compounds 1, 3, 4, and 11 showed NO inhibition activity, with IC50 values ranging from 3.40 to 7.10 μM and compound 1 inhibited NO production with an IC50 value of 3.40 μM.

Isolation, Structure Determination, and Anti-HIV Evaluation of Tigliane-Type Diterpenes and Biflavonoid from Stellera chamaejasme

Five novel tigliane-type diterpenes, stelleracins A-E (3-7), a novel flavanone dimer, chamaeflavone A (8), and six known compounds were isolated from the roots of Stellera chamaejasme. Their structures were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for anti-HIV activity in MT4 cells. New compounds 3-5 showed potent anti-HIV activity (EC90 0.00056-0.0068 μM) and relatively low or no cytotoxicity (IC50 4.4-17.2 μM). These new compounds represent promising new leads for development into anti-AIDS clinical trial candidates.

CD4 mimics as HIV entry inhibitors: Lead optimization studies of the aromatic substituents

Several CD4 mimics have been reported as HIV-1 entry inhibitors that can intervene in the interaction between a viral envelope glycoprotein gp120 and a cell surface protein CD4. Our previous SAR studies led to a finding of a highly potent analogue 3 with bulky hydrophobic groups on a piperidine moiety. In the present study, the aromatic ring of 3 was modified systematically in an attempt to improve its antiviral activity and CD4 mimicry which induces the conformational changes in gp120 that can render the envelope more sensitive to neutralizing antibodies. Biological assays of the synthetic compounds revealed that the introduction of a fluorine group as a meta-substituent of the aromatic ring caused an increase of anti-HIV activity and an enhancement of a CD4 mimicry, and led to a novel compound 13a that showed twice as potent anti-HIV activity compared to 3 and a substantial increase in a CD4 mimicry even at lower concentrations.

Chemical Constituents from an Endophyte, Cercosporella sp.

Cercosporella sp., an endophyte, was isolated from Schisandra chinensis Baill., a medicinal plant. Extracts of Cercosporella sp. are nontoxic to human lymphocytic MT-4 cells and exhibited potent anti-HIV activity in an in vitro MTT assay [1]. The selectivity index (SI) value was 5.6. The fungi were cultured in wheat bran culture medium (containing dextrose, monopotassium phosphate, magnesium sulfate) on a rocking bed without light. The cultured fungus was filtered to separate mycelium from fermentation liquor. Mycelia were rinsed to eliminate fermentation liquor before desiccation, and dry mycelia, about 832 g, were extracted twice with 95% ethanol for 1 h by reflux. The solvents were removed under reduced pressure to give a crude extract (120 g). The aqueous suspension of the extract was partitioned successively with light petroleum, EtOAc, and n-BuOH, resulting in light petroleum (56 g), ethyl acetate (13 g), and n-BuOH (12 g) extracts. The ethyl acetate-soluble fraction was concentrated and subjected to 200–300 mesh silica gel column chromatography eluting with a gradient of CHCl3–MeOH (from 0:1 to 1:1 ) to yield thirteen fractions. The subfractions were then purified by successive column chromatography on 300–400 mesh silica gel using light petroleum–EtOAc and CHCl3–MeOH as elution systems, monitored by TLC, which led to the isolation of compounds 1–6. The structures were elucidated by 1H NMR, 13C NMR, HSQC, HMBC, and MS analysis. All these data were in good agreement with the literature data. All compounds were isolated from Cercosporella sp. for the first time. Compounds 1 and 4 exhibited potent anti-HIV activity, and the SI values were respectively 3.22 and 2.53 in the in vitro MTT assay. 5,6,7-Trihydroxyflavone (1) [2], 19 mg; yellow needles; C15H10O5, mp 223–226 C. Mass spectrum (EI, 70 eV), m/z: 270 (M+, 100%), 242 (M – CO), 168, 140, 112, 102, 77, 69. 5,7-Dihydroxy-6-methoxyflavone (2) [3], 28 mg; saffron yellow needles; C16H12O5, mp 231–232 C. PMR spectrum (500 MHz, CD3OD, , ppm, J/Hz): 8.02 (2H, dd, J = 9.0, 2.0, H-2 , H-6 ), 7.57 (3H, m, H-3 , H-4 , H-5 ), 6.76 (1H, s, H-8), 6.28 (1H, s, H-3), 3.93 (3H, s, 6-OCH3). 13C NMR spectrum data (125 MHz, CD3OD, , ppm): 184.0 (C-4), 165.4 (C-7), 159.0 (C-9), 158.3 (C-2), 151.3 (C-5), 133.1 (C-4 ), 132.5 (C-6), 130.3 (C-1 ), 129.3 (C-3 , C-5 ), 127.4 (C-2 , C-6 ), 105.9 (C-10), 105.4 (C-3), 100.4 (C-8), 62.0 (6-OCH3). Mass spectrum (EI, 70 eV), m/z: 284 (M+), 269 (M – 15, 100%), 241, 167, 139, 103, 77, 69. Physcion (3) [4], 38 mg; red needles; C16H12O5, mp 203–205 C. PMR spectrum (600 MHz, CD3OD, , ppm, J/Hz): 12.31 (1H, s, OH), 12.11 (1H, s, OH), 7.63 (1H, dd, J = 1.5, 0.5, H-14), 7.37 (1H, d, J = 2.5, H-10), 7.08 (1H, dd, J = 2.5, 1.0, H-9), 6.69 (1H, d, J = 2.5, H-13), 3.94 (3H, s, H-16), 2.45 (3H, s, H-15). 13C NMR spectrum data (150 MHz, CD3OD, , ppm): 190.8 (C-1), 182.0 (C-2), 162.5 (C-3), 166.6 (C-4), 148.4 (C-5), 165.2 (C-6), 133.2 (C-7), 113.7 (C-8), 124.5 (C-9), 110.3 (C-10), 135.3 (C-11), 108.2 (C-12), 106.8 (C-13), 121.3 (C-14), 22.1 (C-15), 56.1 (C-16). Indole-3-carboxylic Acid (4) [5], 10 mg; flavo-green crystal; C9H7O2N, mp 232–234 C. Mass spectrum (EI, 70 eV), m/z: 161 (M+, 100%), 144 (M – OH), 132 (M – CHO), 116 (M – COOH). 4-Hydroxyphenylacetic Acid (5) [5], 5 mg; colorless needles; C8H8O3, mp 148–150 C. 2-(4 -Hydroxyphenyl)ethanol (6) [5], 60 mg; colorless needles; C8H10O2, mp 89–92 C. Mass spectrum (EI, 70 eV), m/z: 138 (M+), 120 (M – H2O), 107 (M – CH2OH, 100%).

Insight into the Binding Mode between HIV-1 Integrase and Pyrimidone Analogue Inhibitors with MD Simulation and 3D-QSAR

HIV-1 integrase (HIVIN) plays a key role in the replication of the HIV-1 virus and represents an attractive target for anti-HIV drug design. Experimental observation suggests that pyrimidone analogues have potent anti-HIV activity. Then, we modeled an HIVIN catalytic core domain based on the crystal structure of the prototype foamy virus (PFV) integrase. Molecular docking and molecular dynamics simulations were used to investigate the interaction mechanism between pyrimidone analogues and the HIVIN catalytic core domain. MD results suggest that the most active molecule (6K) has more stable hydrogen bonds and hydrophobic contacts than the FDA approved anti-HIV drug Raltegravir. Furthermore, the analogues and Raltegravir might have similar binding modes with HIVIN. Finally, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to construct three dimensional quantitative structure-activity (3D-QSAR) models. Eleven test set compounds which are not included in the training set were used to evaluate these models. The results suggest that these models are robust and have good prediction abilities.

Sulfation and biological activities of konjac glucomannan

The sulfation of konjac glucomannan and its anti-HIV and blood anticoagulant activities were investigated. Konjac glucomannan is a polysaccharide occurring naturally in konjac plant tubers and has high molecular weights. Solubility in water is very low, and the aqueous solutions at low concentrations have high viscosity. Before sulfation, hydrolysis by diluted sulfuric acid was carried out to decrease the molecular weights of M¯n=19.2×104−0.2×104. Sulfation with piperidine-N-sulfonic acid or SO3-pyridine complex gave sulfated konjac glucomannans with molecular weights of M¯n=1.0×104−0.4×104 and degrees of sulfation (DS) of 1.3–1.4. It was found that the sulfated konjac glucomannans had potent anti-HIV activity at a 50% effective concentration, (EC50) of 1.2–1.3μg/ml, which was almost as high as that of an AIDS drug, ddC, whose EC50=3.2μg/ml, and moderate blood anticoagulant activity, AA=0.8–22.7units/mg, compared to those of standard sulfated polysaccharides, curdlan (10units/mg) and dextran (22.7units/mg) sulfates. Structural analysis of sulfated konjac glucomannans with negatively charged sulfated groups was performed by high resolution NMR, and the interaction between poly-l-lysine with positively charged amino groups as a model compound of proteins and peptides was measured by surface plasmon resonance measurement, suggesting that the sulfated konjac glucomannans had a high binding stability on immobilized poly-l-lysine. The binding of sulfated konjac glucomannan was concentration-dependent, and the biological activity of the sulfated konjac glucomannans may be due to electrostatic interaction between the sulfate and amino groups.

From the chemistry of epoxy-sugar nucleosides to the discovery of anti-HIV agent 4'-ethynylstavudine-Festinavir.

Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxysugar nucleosides serve as versatile precursor for the stereo-defined synthesis of these nucleoside derivatives on the basis of its ring opening with organoaluminum or organosilicon reagents. In this review article, novel methods for the synthesis of nucleoside analogues branched at the 1' and 4'-position will be described. During this study, we could discover an anti-HIV agent, 4'-ethynylstavudine (Festinavir). Festinavir showed more potent anti-HIV activity than the parent compound stavudine (d4T). Other significant properties of Festinavir are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors. Detailed profile of the antiviral activities, biology and pharmacology of Festinavir are also described.

Synthesis, biological screening and ADME prediction of benzylindole derivatives as novel anti-HIV-1, anti-fungal and anti-bacterial agents

Present study is focused on design, synthesis, and biological evaluation of substituted benzylindole derivatives as anti-HIV, anti-fungal, and anti-bacterial agents. Out of the reported compounds, compound B1 and B2 showed potent Anti-HIV activity, whereas compound B1–B4 showed good anti-fungal and anti-bacterial activity. ADME properties of benzylindol analogs were analyzed using Qikprop 2.5 tool of Schrodinger.