RT Inhibitors Research Articles

Coping with the HIV epidemic 1982–2007: 25‐year outcomes of the Hershey Haemophilia Cohort

Coping with the HIV epidemic 1982–2007: 25‐year outcomes of the Hershey Haemophilia Cohort

Novel N 1-substituted 1,3-dihydro-2 H-benzimidazol-2-ones as potent non-nucleoside reverse transcriptase inhibitors

Several N 1-substituted 1,3-dihydro-2 H-benzimidazol-2-ones were synthesized and evaluated as anti-HIV agents. Some of them proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentration as potent non-nucleoside HIV-1 RT inhibitors (NNRTIs) with low cytotoxicity. SAR studies highlighted that the nature of the substituents at N 1 and on the benzene ring of benzimidazolone moiety significantly influenced the anti-HIV activity of this class of potent antiretroviral agents.

Predicting anti-HIV activity of 1,3,4-thiazolidinone derivatives: 3D-QSAR approach

HIV-1 (human immunodeficiency virus type-1) is the pathogenic retrovirus and causative agent of AIDS. HIV-1 RT is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as NNRTIs and NRTIs. NNRTIs bind to a region that is not associated with the active site of the enzyme. Within the NNRTIs category, there is a set of inhibitors commonly referred to as thiazolidinone derivatives. The present 3D-QSAR study attempts to explore the structural requirements of thiazolidinone derivatives for anti-HIV activity. Based on the structures and biodata of previous thiazolidinone analogs, 3D-QSAR studies have been performed with a training set consisting of 96 molecules, which resulted in two reliable computational models, CoMFA and CoMSIA with r 2 values of 0.931 and 0.972, standard error of estimation (SEE) of 0.173 and 0.089, and q 2 values of 0.663 and 0.784, respectively, with the number of partial least-squares (PLS) components being six. It is shown that the steric and electrostatic properties predicted by CoMFA contours and the hydrogen bond acceptor, hydrogen bond donor, and hydrophobic properties predicted by CoMSIA contours are related to anti-HIV activity. The predictive ability of the resultant model was evaluated using a test set comprising of 17 molecules and the predicted r 2 values of CoMFA and CoMSIA models were 0.861 and 0.958, respectively. These models are more significant guide to trace the features that really matter especially with respect to the design of novel compounds.

Profile of drug resistance mutations among HIV-1-infected Tunisian subjects failing antiretroviral therapy

Three years after the introduction of antiretroviral therapy (ART) in Tunisia (North Africa), we aimed to determine the prevalence of drug resistance mutations in Tunisian HIV-1-infected patients failing ART. Plasma samples of 80 patients were tested for genotypic resistance using two distinct line probe assays, LiPA HIV-1 reverse transcriptase RT and LiPA HIV-1 protease assay. Of the 80 patients, 82.5% showed resistance to at least one antiretroviral molecule. In the RT gene, resistance to nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) were recognized in 66.25 and 37.5%, respectively, with M184V, T215Y and K103N being the codons most frequently involved. Resistance to protease inhibitors (PIs) was found in 46.25% of cases. Despite the presence of different mutations, the viral variants were still susceptible to other RTIs and PIs that are currently not available in Tunisia. Thus, alternative therapeutic options exist but are not yet accessible.

A Multidisciplinary Approach for the Identification of Novel HIV‐1 Non‐Nucleoside Reverse Transcriptase Inhibitors: S‐DABOCs and DAVPs

Among the FDA approved drugs for the treatment of AIDS, non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of first-line anti-HIV-1 therapy because of the less-severe adverse effects associated with NNRTIs administration in comparison to therapies based on other anti-HIV-1 agents. In this contest, 3,4-dihydro-2-alkoxy-6-benzyl-4-oxypyrimidines (DABOs) have been the object of many studies aimed at identifying novel analogues endowed with potent inhibitory activity towards HIV-1 wild type and especially drug-resistant mutants. Accordingly, based on the encouraging results obtained from the biological screening of our internal collection of S-DABO derivatives, we started with the systematic functionalization of the pyrimidine scaffold to identify the minimal required structural features for RT inhibition. Herein, we describe how the combination of synthetic, biological, and molecular modeling studies led to the identification of two novel subclasses of S-DABO analogues: S-DABO cytosine analogues (S-DABOCs) and 4-dimethyamino-6-vinylpyrimidines (DAVPs).

From RT Inhibitor to RT/IN Dual Inhibitor: An Rational Design

From RT Inhibitor to RT/IN Dual Inhibitor: An Rational Design

Comparative molecular similarity indices analysis for predicting anti-HIV activity of phenyl ethyl thiourea (PET) derivatives

Human immunodeficiency virus type-1 (HIV-1) is a pathogenic retrovirus and the causative agent of acquired immunodeficiency syndrome (AIDS). HIV-1 RT is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as nonnucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs. NNRTIs bind in a region not associated with the active site of the enzyme. Within the NNRTIs category, there is a set of inhibitors commonly referred to as phenyl or pyridyl ethyl thiourea (PET) derivatives. The present three-dimensional (3D) quantitative structure–activity relationship (QSAR) study attempts to explore the structural requirements of (phenyl ethyl thiourea) PET derivatives for anti-HIV activity. Based on the structures and biodata of previous PET analogs, comparative molecular similarity indices analysis (CoMSIA) is performed to explain the structural requirements for the anti-HIV activity of PET derivatives. The CoMSIA studies resulted in reliable computational models. The obtained CoMSIA model has high predictive ability, q 2 = 0.584, r 2 = 0.882 and standard error of estimation (SEE) = 0.352, explaining the majority of the variance in the data with four partial least square (PLS) components. The predictive ability of the developed models (3D QSAR) was also confirmed by using a test (external validation) set comprised of 11 molecules with a predicted r 2 value of 0.871. It is shown that the steric, electrostatic, hydrophobic, and hydrogen-bond acceptor and donor properties predicted by CoMSIA contours can be related to anti-HIV activity. This model is a significant guide to trace the features that really matter especially with respect to the design of novel compounds. Comparative molecular similarity indices analysis for predicting anti-HIV activity of phenyl ethyl thiourea (PET) derivatives The parameters indicated in the substitution position of compound are responsible for anti-HIV activity.

Subtype Assignment and Phylogenetic Analysis of HIV Type 1 Strains in Patients from Swaziland

Aim of this study was to assess HIV-1 subtype distribution and prevalence of transmitted mutations related to antiretroviral drugs in Swaziland. According to the WHO guidelines, 47 plasma samples from naive patients stored at HIV/AIDS National Reference Laboratory in Mbabane between 2002 and 2003, before the introduction of antiretroviral therapy in the country, were studied. HIV-1 RNA was extracted from the plasma samples, RT and protease regions of pol gene were amplified and sequenced. The mutations associated to drug resistance were defined as major or minor on the basis of the recommendations of the International AIDS Society-USA panel. A mutation associated to non nucleoside inhibitors (Y181I) was found in one case showing a prevalence of transmitted drug resistance <5% in Swaziland. No major mutations conferring resistance to protease and nucleoside RT inhibitors were found. Clade assignment was performed by phylogenetic analysis of pol gene. The general time-reversible model of substitution was used to study the phylogenetic relationships between sequences obtained from Swazi patients and sequences from neighbor countries. All patients were found to carry a C subtype. No phylogenetic relationships were detected within Swazi sequences, indicating the absence of epidemiological relationships among patients in study. Although local variants of subtype C have been recently recognized, phylogenetic analysis did not reveal the presence of significant cluster of Swaziland sequences within African variants. This finding may be explained by multiple introduction of C strains.

Synthesis and Antiviral Evaluation of 6‐(Trifluoromethylbenzyl) and 6‐(Fluorobenzyl) Analogues of HIV Drugs Emivirine and GCA‐186

The present study describes the synthesis and antiviral evaluation of a series of novel 6-(3-trifluoromethylbenzyl) and 6-(fluorobenzyl) analogues of the HIV drugs emivirine and GCA-186. The objective was to investigate whether the fluoro or trifluoromethyl substituents could lead to an improved antiviral activity against HIV-1 wild type and mutants resistant to non-nucleoside RT inhibitors. The biological test results showed that the most of theses compounds showed good activity against wild type HIV-1. Among them, compound 1-(ethoxymethyl)-6-(3-fluorobenzyl)-5-isopropyluracil (9i) showed the largest inhibitory potency (EC(50) = 0.02 microM), resulting equally potent than emivirine against wild type HIV-1. Furthermore, compound 9i showed marginal better activity against resistant mutants than emivirine. The key steps in the synthesis of the target compounds were either reaction of an appropriate beta-keto ester with thiourea or a cross-coupling reaction of 6-chloro-2,4-dimethoxypyrimidines with benzylic Grignard reagents.

Synthesis and Biological Evaluation of N‐Acetyl‐β‐aryl‐1,2‐didehydroethylamines as New HIV‐1 RT Inhibitors in vitro.

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Docking studies on the effect of β-ring expansion in binding of TIBO derivatives to HIV-1 reverse transcriptase

Designing of new inhibitors to human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) is one of the important research area in AIDS therapies. Non-nucleoside inhibitors of reverse transcriptase (NNIRT) are attractive drug candidates for their unique binding site to the reverse HIV-1 RT and less adverse side effects. The effect of expansion of diazepine ring from seven to eight in some tetrahydroimidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-thione (TIBO) derivatives as NNIRT has been investigated by docking procedure. Sixteen conventional TIBO derivatives with known HIV-1 RT inhibitor activity were selected and their β-ring was expanded to eight. The three-dimensional (3D) geometry of the molecules was optimized by AM1 semiempirical method and then interacted with the HIV-1 RT enzyme using Autodock program. Twelve out of sixteen of the new molecules were docked into the enzyme. The resulted free energies of docking indicated that the newly proposed molecules bond to the enzyme with comparable tendency in relative to their corresponding conventional homologous. It was found that three new compounds bind to the receptor stronger than that of their corresponding 7-membered ring derivatives and can be considered as new candidate for synthesis.

Reaction time inhibition from subliminal cues: Is it related to inhibition of return?

Task-irrelevant visual cues with near zero visibility proved apt to retard reaction time for the detection of supraliminal visual targets presented at the cued location. The time course of the effect was similar to that of the so-called inhibition-of return (IOR), which is assumed to be due to the withdrawal of attention from the inhibited location. However the present subliminal cues consistently failed to induce an RT facilitation prior to the RT inhibition, contrary to what would be expected if the cue were able to attract attention to the cued location. Since the RT inhibition from subliminal cues could not be attributed to the withdrawal of attention from the cued location, it can be argued that such cues acted both outside of consciousness and without the influence of attention. Therefore, the RT inhibitory effect seems best accounted for by an automatic, unconscious and attention-independent self-inhibition of response tendencies instructed by irrelevant information, akin to that postulated by (Eimer, M., & Schlaghecken, F. (1998). Effects of masked stimuli on motor activation: behavioural and electrophysiological evidence. Journal of Experimental Psychology Human Perception and Performance, 24, 1737–1747.) to explain the negative compatibility effect.

Design, Synthesis and Pharmacological Evaluation of HIV-1 Reverse Transcriptase Inhibition of New Indolin-2-Ones

The design, synthesis and anti HIV-1 replication inhibition of 3-(cyclopropylethynyl)-3-hydroxy-indolin-2-ones, analogues of efavirenz (Sustivatrade mark), are described. Different substituted isatins were used to generate final products that contain pharmacophoric features for RT inhibition, such as the oxoindole and cyclopropylethynyl groups. The suitability of the indolin-2-one ring in the planned compounds in replacement to the benzoxazinone ring of efavirenz was proven, since compound 15 presented a greater activity than efavirenz against HIV-1 replication and was not significantly cytotoxic.

Resistance to anti-retroviral therapy in Chilean patients with HIV-1 from 2002 to 2005

Resistance limits the effectiveness of anti-retroviral therapy. In Chile, there is free access to highly active anti-retroviral therapy since 2001, but there is no information about the frequency of mutations associated to drug resistance. To determine the most common mutations associated to anti-retroviral drug resistance in Chile. Retrospective study of 710 genotype analysis coming from 568 patients aged 22 to 70 years (85% males) with virological failure. The analysis was performed using a commercially available sequencing kit (Trugene HIV-1 genotypic assay from Bayer S.A). Mean CD4(+) cell count and viral load were 154 cells/microl and 228784 RNA copies/ml, respectively. The frequency of resistance to nucleoside RT inhibitors (NRTI), non nucleoside RT inhibitors (NNRTI) and protease inhibitors (PI) was 71 %, 62% and 22%, respectively. The most common mutations found were T215Y (46%), L10F (44%), Ml84V (3896), K103N (35%) and M41L (32%). Fifty five percent of mutations corresponded to the TAM (thymidine analogue mutations) group. Multiresistance was 47% to NNRTI, 7% to NRTI, 4% to PI and 0.7% to all groups. During the four years of the study, there was a significant increase in NNRTI resistance. These data provides important information about the epidemiology of drug resistance mutations and should help to design new HAART strategies.

Resistencia a la terapia antirretroviral en pacientes infectados con el virus VIH-1 en Chile 2002-2005

Resistance limits the effectiveness of anti-retroviral therapy. In Chile, there is free access to highly active anti-retroviral therapy since 2001, but there is no information about the frequency of mutations associated to drug resistance.To determine the most common mutations associated to anti-retroviral drug resistance in Chile.Retrospective study of 710 genotype analysis coming from 568 patients aged 22 to 70 years (85% males) with virological failure. The analysis was performed using a commercially available sequencing kit (Trugene HIV-1 genotypic assay from Bayer S.A).Mean CD4(+) cell count and viral load were 154 cells/microl and 228784 RNA copies/ml, respectively. The frequency of resistance to nucleoside RT inhibitors (NRTI), non nucleoside RT inhibitors (NNRTI) and protease inhibitors (PI) was 71 %, 62% and 22%, respectively. The most common mutations found were T215Y (46%), L10F (44%), Ml84V (3896), K103N (35%) and M41L (32%). Fifty five percent of mutations corresponded to the TAM (thymidine analogue mutations) group. Multiresistance was 47% to NNRTI, 7% to NRTI, 4% to PI and 0.7% to all groups. During the four years of the study, there was a significant increase in NNRTI resistance.These data provides important information about the epidemiology of drug resistance mutations and should help to design new HAART strategies.

Suppression of Viremia and Evolution of Human Immunodeficiency Virus Type 1 Drug Resistance in a Macaque Model for Antiretroviral Therapy

Antiretroviral therapy (ART) in human immunodeficiency virus type 1 (HIV-1)-infected patients does not clear the infection and can select for drug resistance over time. Not only is drug-resistant HIV-1 a concern for infected individuals on continual therapy, but it is an emerging problem in resource-limited settings where, in efforts to stem mother-to-child-transmission of HIV-1, transient nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy given during labor can select for NNRTI resistance in both mother and child. Questions of HIV-1 persistence and drug resistance are highly amenable to exploration within animals models, where therapy manipulation is less constrained. We examined a pigtail macaque infection model responsive to anti-HIV-1 therapy to study the development of resistance. Pigtail macaques were infected with a pathogenic simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT-SHIV) to examine the impact of prior exposure to a NNRTI on subsequent ART comprised of a NNRTI and two nucleoside RT inhibitors. K103N resistance-conferring mutations in RT rapidly accumulated in 2/3 infected animals after NNRTI monotherapy and contributed to virologic failure during ART in 1/3 animals. By contrast, ART effectively suppressed RT-SHIV in 5/6 animals. These data indicate that suboptimal therapy facilitates HIV-1 drug resistance and suggest that this model can be used to investigate persisting viral reservoirs.

The design and synthesis of N-1-alkylated-5-aminoaryalkylsubstituted-6-methyluracils as potential non-nucleoside HIV-1 RT inhibitors

Novel compounds 1a– u, which can be considered as hybrid analogues of MKC-442 and pyridinon, have been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (HIV-1 RT). Starting from 6-methyuracil 2, 1-alkylated-5-bromomethyl-6-methyluracils 8 was prepared in four steps by hydroxylmethylation, etherification, N-1 alkylation, and bromination. Finally, compounds 1a– u were achieved in the displacement of 5-bromomethyl group by nucleophiles with amino compounds. Some of compounds 1a– u showed potent inhibitory activity against HIV-1 RT. The most active compounds showed activity in the low micromolecular range with IC 50 values (IC 50 0.82–5.09 μM) comparable to that of nevirapine (IC 50 10.60 μM). The biological testing results are in accordance with the docking.

Calculation of binding affinities of HIV-1 RT and β-secretase inhibitors using the linear interaction energy method with explicit and continuum solvation approaches

The linear interaction energy (LIE) approach has been applied to estimate the binding free energies of representative sets of HIV-1 RT and beta-Secretase inhibitors, using both molecular dynamics (MD) and tethered energy minimization sampling protocols with the OPLS-AA potential, using a range of solvation methodologies. Generalized Born (GB), 'shell' and periodic boundary condition (PBC) solvation were used, the latter with reaction field (RF) electrostatics. Poisson-Boltzmann (PB) and GB continuum electrostatics schemes were applied to the simulation trajectories for each solvation type to estimate the electrostatic ligand-water interaction energy in both the free and bound states. Reasonable agreement of the LIE predictions was obtained with respect to experimental binding free energy estimates for both systems: for instance, 'PB' fits on MD trajectories carried out with PBC solvation and RF electrostatics led to models with standard errors of 1.11 and 1.03 kcal mol(-1) and coefficients of determination, r (2) of 0.76 and 0.75 for the HIV-1 RT and beta-Secretase sets. However, it was also found that results from MD sampling using PBC solvation provided only slightly better fits than from simulations using shell or Born solvation or tethered energy minimization sampling.

Genotypic Analysis of the Protease and Reverse Transcriptase of HIV Type 1 Isolates from Recently Infected Injecting Drug Users in Western China

The partial pol gene was analyzed to determine circulating HIV-1 subtypes and the prevalence of drug resistance among recently infected injecting drug users in the west of China. Phylogenetic and bootscanning analyses showed that all 25 sequences belonged to CRF07_BC. No major drug resistance mutations were found, while the CRF07_BC sequences harbored a few highly prevalent polymorphic positions in both the protease and reverse transcriptase regions. It is notable that D60E, L63P and I93L substitutions, which were more common in HIV-1 isolates from PI-treated than untreated patients, were present in most of the isolates. Compared with subtype B, the CRF07_BC strains had a decreased genetic barrier for the V106M mutation, which is selected by efavirenz and leads to high-level resistance to all present nonnucleoside RT inhibitors. Further studies are needed to determine the impact of genetic features of CRF07-BC on antitretroviral susceptibility and evolution of drug resistance mutations.

Synthesis of 1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyluracils as Potent Nonnucleoside HIV‐1 RT Inhibitors

1‐(Alkyl)‐5‐dimethylamino‐6‐phenethyl uracils (1) and (2) are analogs of MKC‐442, which is a very potent inhibitor of HIV‐1 reverse transcriptase. The target compound 1 was synthesized by the first approach, from the corresponding 1,3‐dibenzyl‐5‐(dimethylamino)‐6‐phenethylpyrimidine‐2,4(1H,3H)‐dione (7), which was synthesized in four steps from 6‐methyluracil (3) by nitration, benzylation, reduction, and methylation of the amino group. Compound 7 was then debenzylated to give the complete deprotected compound 8 with very low yield. To improve the yield, another pathway was developed for introducing the ethoxymethyl group at N‐1 of the uracil ring first. The result of adjusting reaction sequences increased the overall yield dramatically. All synthesized compounds were tested for their inhibition of HIV‐1 reverse transcriptase, and moderate activity was found for target compound 1.