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European Journal of Medicinal Chemistry Jul 2013This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural...
This paper reports the synthesis and antiviral evaluation of a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine the peculiar structural features of diarylpyrimidine derivatives (DAPYs) and benzophenone derivatives (BPs). The DAPY derivatives bearing benzoyl or alkoxyl substitutes on the A-ring showed the inhibitory activity against wild-type HIV-1 at the cellular level within the range of EC50 values from micromolar to nanomolar. Among these compounds, 1u exhibited the most potent anti-HIV-1 activity (EC50 = 0.06 ± 0.01 μM, SI > 6260), which were about 1.8-fold more active than nevirapine (NVP) and delavirdine (DLV). In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these derivatives were also considered for further investigation.
Topics: Anti-HIV Agents; Benzophenones; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Design; HIV Reverse Transcriptase; HIV-1; HIV-2; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pyrimidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship
PubMed: 23707918
DOI: 10.1016/j.ejmech.2013.04.052 -
ChemMedChem Jul 2013In our continued efforts to discover more active and less toxic HIV-1 non-nucleoside reverse transcriptase inhibitors, we recently designed a novel series of...
In our continued efforts to discover more active and less toxic HIV-1 non-nucleoside reverse transcriptase inhibitors, we recently designed a novel series of piperidine-linked pyridine analogues on the basis of diarylpyrimidine derivatives, among which two drugs-etravirine and rilpivirine-are approved for use by the US FDA. The title compounds were evaluated for activity against wild-type and resistant mutant strains of HIV-1 as well as HIV-2 in MT-4 cells. The highly potent compound BD-c1 (EC50 =10 nM, CC50 ≥146 μM, SI≥14 126) displays lower cytotoxicity and higher selectivity than etravirine (EC50 =2.2 nM, CC50 =28 μM, SI=12 884) against wild-type HIV-1. Compound BD-e2 (EC50 =5.1 nM) shows greater antiviral efficacy against wild-type HIV-1 than do the four reference drugs nevirapine, delavirdine, efavirenz, and zidovudine. Many compounds were also found to be active against the frequently observed drug-resistant double mutant (K103N+Y181C) HIV-1 strain. Herein we report the design, synthesis, anti-HIV evaluation, preliminary structure-activity relationships, and molecular simulations of novel piperidine-linked pyridine analogues.
Topics: Anti-HIV Agents; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Discovery; HIV Reverse Transcriptase; HIV-1; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Dynamics Simulation; Molecular Structure; Piperidines; Pyridines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship
PubMed: 23650275
DOI: 10.1002/cmdc.201300130 -
Biochemical Pharmacology Jun 2013Rilpivirine and etravirine are second generation non-nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for... (Comparative Study)
Comparative Study
Rilpivirine and etravirine are second generation non-nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus-1 infection. Pregnane X receptor (PXR) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions. The present study investigated the effects of rilpivirine and etravirine on the activity of human PXR (hPXR), including the mode of activation, and compared them to those of efavirenz, nevirapine, and delavirdine, which are first generation non-nucleoside reverse transcriptase inhibitors. In transiently transfected HepG2 cells, rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, activated human, mouse, and rat PXR. Results from mechanistic studies indicated that rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, bound to the ligand-binding domain of hPXR, as assessed by a transactivation assay and by a competitive ligand-binding assay using time-resolved fluorescence resonance energy transfer; triggered nuclear translocation of a green fluorescence protein-tagged hPXR, as visualized by confocal imaging; and recruited steroid receptor coactivator-1 (SRC-1), SRC-2, and SRC-3 to hPXR, as demonstrated by mammalian two-hybrid assays. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, increased hPXR target gene (CYP3A4) expression in primary cultures of human hepatocytes. In summary, select non-nucleoside reverse transcriptase inhibitors activated human and rodent PXR. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, were identified as agonists of hPXR, as assessed in mechanistic experiments, and inducers of CYP3A4, as determined in primary cultures of human hepatocytes.
Topics: Cell Line, Tumor; Dose-Response Relationship, Drug; Fluorescence Resonance Energy Transfer; Genes, Reporter; Humans; Hydroxylation; Nitriles; Pregnane X Receptor; Pyridazines; Pyrimidines; Real-Time Polymerase Chain Reaction; Receptors, Steroid; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Rilpivirine; Steroid Hydroxylases; Two-Hybrid System Techniques
PubMed: 23583259
DOI: 10.1016/j.bcp.2013.04.002 -
Bioorganic & Medicinal Chemistry Apr 2013In continuation of our efforts toward identification and optimization of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), we have employed a...
In continuation of our efforts toward identification and optimization of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), we have employed a structure-based bioisosterism strategy, with which a new series of diarylpyridazine (DAPD) derivatives were synthesized and evaluated for their anti-HIV-1 (human immunodeficiency virus type 1) activity. Most of the title compounds displayed excellent anti-HIV-1 activity at submicromolar concentrations ranging from 34 nM to 5.08 μM. The most promising compound 8g inhibited HIV-1 IIIB in MT-4 cells at a low EC50 value (0.034 μM), which was lower than the reference drug nevirapine and delavirdine. The structure activity relationships (SARs) were discussed and rationalized by docking simulations.
Topics: Cell Line; Delavirdine; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Nevirapine; Pyridazines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship
PubMed: 23415090
DOI: 10.1016/j.bmc.2012.12.049 -
European Journal of Medicinal Chemistry Dec 2012A series of novel 4,6-diarylpyrimidines (4,6-DAPY) and diarylbenzenes (DABE) compounds were synthesized and evaluated as inhibitors of human immunodeficiency virus...
A series of novel 4,6-diarylpyrimidines (4,6-DAPY) and diarylbenzenes (DABE) compounds were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were 8b, 8d, 14b and 18 (EC(50) = 0.049, 0.381, 0.599 and 0.398 μM, respectively), with HIV-1 inhibitory activity improved or similar to nevirapine (NVP, EC(50) = 0.097 μM) and delavirdine (DEV, EC(50) = 0.55 μM). The other compounds displayed moderate activity (8c, EC(50) = 5.25 μM) or were inactive (8a and 14a) against HIV-1 replication. Molecular modeling studies were performed with the synthesized compounds in complex with the wild-type reverse transcriptase (RT). A correlation was found between the anti-HIV activity and the electrostatic energy of interaction with Lys101 residue. These findings enrich the SAR of these Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) families.
Topics: Anti-HIV Agents; Antineoplastic Agents; Benzene Derivatives; Cell Survival; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HIV Reverse Transcriptase; HIV-1; HIV-2; Humans; Models, Molecular; Molecular Structure; Pyrimidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 23159806
DOI: 10.1016/j.ejmech.2012.10.036 -
Current Medicinal Chemistry 2012In addition to the nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and integrase inhibitors (INIs), nonnucleoside reverse transcriptase... (Review)
Review
In addition to the nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and integrase inhibitors (INIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) have contributed significantly in the treatment of HIV-1 infections. More than 60 structurally different classes of compounds have been identified as NNRTIs, which are specifically inhibiting HIV-1 reverse transcriptase (RT). Five NNRTIs (nevirapine, delavirdine, efavirenz, etravirine and rilpivirine) have been approved by US Food and Drug Administration (FDA) for clinical use. The NNRTIs bind with a specific 'pocket' site of HIV-1 RT (allosteric site) that is closely associated with the NRTI binding site. Due to mutations of the amino acid residues surrounding the NNRTI-binding site, NNRTIs are notorious for rapidly eliciting resistance. Though, the emergence of resistant HIV strains can be circumvented if the NNRTIs are used either alone or in combination with NRTIs (AZT, 3TC, ddI, ddC, TVD or d4T) and PIs (Indinavir, nelfinavir, saquinavir, ritonavir and lopinavir etc.) as shown by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-cells. Here we are going to discuss recent advances in structure activity relationship studies on nevirapine, delavirdine, efavirenz, etravirine, rilpivirine and 4-thiazolidinones (privileged scaffold) HIV-1 NNRTIs.
Topics: Benzoxazines; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Piperazines; Pyrimidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Thiazoles; Triazines
PubMed: 22998569
DOI: 10.2174/092986712803833326 -
European Journal of Medicinal Chemistry May 2012A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed...
A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC(50) values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC(50) values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed.
Topics: Anti-HIV Agents; Cell Line; Chemistry Techniques, Synthetic; HIV Reverse Transcriptase; HIV-1; Inhibitory Concentration 50; Piperidines; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Triazines
PubMed: 22405288
DOI: 10.1016/j.ejmech.2012.02.019 -
AIDS (London, England) Jun 2012Fractures are common and associated with multiple risk factors. We assessed the risks of fracture associated with time-dependent, differential antiretroviral drug...
OBJECTIVES
Fractures are common and associated with multiple risk factors. We assessed the risks of fracture associated with time-dependent, differential antiretroviral drug exposures among a cohort of persons with HIV infection.
DESIGN
Nested case-control study from an HIV cohort of 59,594 medically insured persons with HIV infection enrolled in a medical care between January 1997 and March 2008.
METHODS
Cases were participants with a low-impact, nontraumatic fracture identified by ICD-9-CM codes; noncases were 1:4 matched and without fracture.
RESULTS
Cases included 2,477 persons with HIV infection with fractures, who were risk-set matched to 9,144 persons with HIV infection without fractures. Exposure to antiretroviral therapy by drug class and by duration (any drug/class) was associated with reduced risk for fracture. Drug-specific antiretroviral exposures over time identified an increased risk for fracture associated with darunavir, delavirdine and saquinavir, whereas reduced risk was associated with efavirenz, emtricitabine, lamivudine, tenofovir, and zidovudine. An initial null risk became a reduced risk with increased duration for nevirapine. In a similar pattern, abacavir, didanosine, nelfinavir, ritonavir and stavudine were initially associated with increased risk for fracture, after which the risk became null with increased duration of exposure. Null or uncertain risk for fracture was associated with amprenavir, atazanavir, enfuvirtide, fosamprenavir, indinavir, lopinavir, tipranavir, and zalcitabine.
CONCLUSION
Our findings suggest an overall reduced risk for facture in persons treated versus not treated with antiretroviral drugs for HIV infection. Differential drug-specific exposure-response relationships for fracture will need to be further evaluated in other study populations.
Topics: Adult; Anti-HIV Agents; Case-Control Studies; Female; Fractures, Bone; HIV Infections; Humans; Male; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome
PubMed: 22301413
DOI: 10.1097/QAD.0b013e328351997f -
Virologica Sinica Dec 2011This study aimed to evaluate emerging trends of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors...
This study aimed to evaluate emerging trends of drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) among 290 former blood donor HIV-1 infected patients in Hubei, China, from 2004 to 2006, all of whom had received anti-HIV-1 therapy. The presence of NRTI- and NNRTI-associated mutations were established by sequencing; genotypic and predicted phenotypic drug resistance were evaluated using HIVdb Program version 5.0.1 (http://hivdb.stanford.edu/pages/algs/HIVdb.html ). Genotypic drug resistance analysis showed significant increases in percentages of patients carrying HIV-1 strains with M41L, T215Y/F, D67N, K103N, G190A/S, Y181C/F or L210W mutations. Of the variants' predicted phenotypic drug resistance, highly significant increases were detected in percentages of patients carrying HIV-1 with high resistance to zidovudine (AZT) or stavudine (D4T) in NRTIs, and to delavirdine (DLV), efavirenz (EFV) or nevirapine (NVP) in NNRTIs; intermediate resistance to abacavir (ABC), AZT, D4T, didanosine (DDI) or tenofovir disoproxil fumarate (TDF) in NRTIs, and to etravirine (ETR) in NNRTIs; and low and potential low resistance to lamivudine (3TC), ABC, emtricitabine (FTC) or TDF in NRTIs, and to ETR in NNRTIs.
Topics: Adult; Blood Donors; China; Drug Resistance, Viral; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Mutation; Reverse Transcriptase Inhibitors; Sentinel Surveillance
PubMed: 22160938
DOI: 10.1007/s12250-011-3210-0 -
Indian Journal of Medical Sciences Nov 2011In the era of free HAART, accessibility and availability of ARV has been dramatically increased in India. However, rates of treatment literacy and adherence appear to be...
CONTEXT
In the era of free HAART, accessibility and availability of ARV has been dramatically increased in India. However, rates of treatment literacy and adherence appear to be sub-optimal. Therefore, it is essential to monitor the extent of primary drug resistance in such settings.
MATERIALS AND METHODS
Between July and October 2006, 18 anti-retroviral-naοve individuals were identified as recent infected by the BED-Capture enzyme immunoassay in a VCTC clinic in Chennai. Specimens from these individuals were subjected to genotypic drug resistance testing. Phylogenetic trees were generated using MEGA for Windows version 4.0 using neighbor-joining method. The significant differences in polymorphic mutation frequencies between the study specimens and established subtype C-specific polymorphisms were examined using the Chi-square test.
RESULTS
Amino acid substitution (K103N and V106MV) at drug resistance positions occurred in two (11%) isolates, conferring high-level resistance to the non-nucleoside reverse-transcriptase inhibitors nevirapine (NVP), efavirenz (EFV), delavirdine (DLV) and notably extensive genetic variations were observed. K122E (94.4%) and K49R/KR (11.1%) polymorphisms identified in this study have not been previously described in established subtype-C specific polymorphisms. The rate of polymorphisms showed marked difference at the locations V60, D121, V35, and D123 (P < 0.0001). All the sequences showed maximum homology with Indian HIV-1 subtype C reference strain C.IN.95IN21068.
CONCLUSIONS
The finding of resistance to NNRTIs is of public health importance. There is an urgent need to establish surveillance for primary drug resistance in large scale. Further studies are required to determine the phenotype impact of newer polymorphic mutations in relation to drug resistance and viral fitness.
Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Delavirdine; Drug Resistance, Viral; Genotype; HIV Infections; HIV-1; Humans; India; Nevirapine; Polymorphism, Genetic; Reverse Transcriptase Inhibitors; Tertiary Care Centers
PubMed: 23525026
DOI: No ID Found