165 results on '"E. De Clercq"'
Search Results
2. A scientific career from the early 1960s till 2023: A tale of the various protagonists.
- Author
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De Clercq E
- Subjects
- Humans, History, 20th Century, History, 21st Century, Antiviral Agents history, Antiviral Agents chemistry
- Abstract
In this era spanning more than 60 years (from the early 1960s till today (2023), a broad variety of actors played a decisive role: Piet De Somer, Tom C. Merigan, Paul A. Janssen, Maurice Hilleman, and Georges Smets. Two protagonists (Antonín Holý and John C. Martin) formed with me a unique triangle (the Holý Trinity). Walter Fiers' group (with the help of Jean Content) contributed to the cloning of human β-interferon, and Piet Herdewijn accomplished the chemical synthesis of an array of anti-HIV 2',3'-dideoxynucleoside analogues. Rudi Pauwels, Masanori Baba, Dominique Schols, Johan Neyts, Lieve Naesens, Anita Van Lierde, Graciela Andrei, Robert Snoeck and Dirk Daelemans, as members of my team, helped me in achieving the intended goal, the development of a selective therapy for virus infections. The collaboration with "Lowie" (Guangdi Li) generated a new dimension for the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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3. Unachieved antiviral strategies with acyclic nucleoside phosphonates: Dedicated to the memory of dr. Salvatore "Sam" Joseph Enna.
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De Clercq E, Li G, Zhang Y, Huang J, and Tan L
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- Humans, Animals, Nucleosides chemistry, Nucleosides pharmacology, Virus Diseases drug therapy, Adenine analogs & derivatives, Adenine chemistry, Adenine pharmacology, Tenofovir analogs & derivatives, Organophosphonates chemistry, Organophosphonates pharmacology, Antiviral Agents pharmacology, Antiviral Agents chemistry
- Abstract
Many acyclic nucleoside phosphonates such as cidofovir, adefovir dipivoxil, tenofovir disoproxil fumarate, and tenofovir alafenamide have been marketed for the treatment or prophylaxis of infectious diseases. Here, this review highlights potent acyclic nucleoside phosphonates for their potential in the treatment of retrovirus (e.g., human immunodeficiency virus) and DNA virus (e.g., adeno-, papilloma-, herpes- and poxvirus) infections. If properly assessed and/or optimized, some potent acyclic nucleoside phosphonates can be possibly applied in the control of current and emerging infectious diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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4. In situ click chemistry-based discovery of 1,2,3-triazole-derived diarylpyrimidines as novel HIV-1 NNRTIs by exploiting the tolerant region I in binding pocket.
- Author
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Sun Y, Feng D, Zhou Z, Zhang T, De Clercq E, Pannecouque C, Kang D, Zhan P, and Liu X
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- Reverse Transcriptase Inhibitors pharmacology, Reverse Transcriptase Inhibitors chemistry, Triazoles pharmacology, Triazoles chemistry, Click Chemistry, Drug Design, HIV Reverse Transcriptase, Heterocyclic Compounds, 1-Ring, Structure-Activity Relationship, HIV-1, Anti-HIV Agents pharmacology, Anti-HIV Agents chemistry
- Abstract
HIV-1 reverse transcriptase (RT) is considered as one of the most significant targets for the anti-HIV-1 drug design due to their determined mechanism and well-decoded crystal structure. As a part of our continuous efforts towards the development of potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by exploiting the tolerant region I of NNRTIs binding pocket (NNIBP), the miniaturized parallel synthesis via CuAAC click chemistry reaction followed by in situ biological screening have been performed in this work. The in situ enzyme inhibition screening results showed that 14 compounds exhibited higher or equivalent inhibitory activity compared to the lead K-5a2 and ETR. Anti-HIV-1 activity results indicated that C1N51 displayed the most potent activity (EC
50 = 0.01-0.26 μM) against wild-type and a panel of NNRTIs-resistant strains. Moreover, the molecular simulation demonstrated that the newly introduced triazole ring could develop new hydrogen bonds with Lys103 and Pro236, which explained the feasibility of introducing triazole in the tolerant region I of the RT binding pocket., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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5. Biktarvy for the treatment of HIV infection: Progress and prospects.
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De Clercq E, Zhang Z, Huang J, Zhang M, and Li G
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- Humans, Pyridones, Tenofovir therapeutic use, Heterocyclic Compounds, 3-Ring therapeutic use, Adenine, HIV Infections drug therapy, Anti-HIV Agents therapeutic use, Anti-HIV Agents pharmacology
- Abstract
Bictegravir (BIC), a second-generation integrase strand-transfer inhibitor (INSTI) with high resilience to INSTI-resistance mutations, is integrated as a key component of Biktarvy® - a fixed-dose once-daily triple-drug regimen of bictegravir (BIC), emtricitabine (FTC) plus tenofovir alafenamide (TAF). Based on the accumulated evidence from HIV clinical trials and real-world studies, the clinical effectiveness of BIC + FTC + TAF has been proven non-inferior to other fixed-dose once-daily combinations such as dolutegravir + FTC + TAF and dolutegravir + abacavir + lamivudine. Biktarvy also shows limited drug-drug interactions and a high barrier to drug resistance. According to recent HIV guidelines, BIC + FTC + TAF is recommended as initial and long-term therapy for the treatment of HIV infection. For the pre-exposure prophylaxis, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) remains advisable, but BIC may be possibly added to TDF or TAF. In the development of a long-acting once-monthly regimen, the novel nano-formulation of BIC + FTC + TAF could be possibly developed in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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6. The magic of a methyl group: Biochemistry at the service of medicine.
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De Clercq E
- Subjects
- Epinephrine, Vitamin B 12 metabolism, Cholesterol
- Abstract
A carbon-carbon linkage is created when a methyl group is implanted on dUMP, thus resulting in the formation of dTMP by thymidylate synthase. The methyl group is deleted by aromatase when androgens are converted to estrogens. The methyl group is rearranged with the help of vitamin B12 in the isomerization of methylmalonyl-CoA to succinyl-CoA. S-adenosylmethionine (SAM) serves as the universal methyl donor involved in the biosynthesis of adrenaline and creatine(phosphate). It also interferes with the 5'-mRNA capping and the degradation of catecholamines (i.e. adrenaline, noradrenaline). Cholesterol could be viewed as a conglomeration of methyl groups. Finally, as part of valine, two methyl functions participate in the origin of one of the most frequent hereditary diseases on earth, sickle cell anemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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7. Therapeutic strategies for human poxvirus infections: Monkeypox (mpox), smallpox, molluscipox, and orf.
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De Clercq E, Jiang Y, and Li G
- Subjects
- Humans, Cidofovir therapeutic use, Monkeypox virus, Smallpox drug therapy, Smallpox prevention & control, Variola virus, Mpox (monkeypox) drug therapy, Mpox (monkeypox) epidemiology, Poxviridae Infections drug therapy, Poxviridae Infections prevention & control
- Abstract
Therapeutic and vaccine development for human poxvirus infections (e.g., monkeypox (mpox) virus, variola virus, molluscum contagiosum virus, orf virus) has been largely deserted, especially after the eradication of smallpox by 1980. Human mpox is a self-limited disease confined to Central and West Africa for decades. However, since April 2022, mpox has quickly emerged as a multi-country outbreak, urgently calling for effective antiviral agents and vaccines to control mpox. Here, this review highlights possible therapeutic options (e.g., tecovirimat, brincidofovir, cidofovir) and other strategies (e.g., vaccines, intravenous vaccinia immune globulin) for the management of human poxvirus infections worldwide., Competing Interests: Declaration of competing interest The authors disclose no conflicts., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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8. Indolylarylsulfones bearing phenylboronic acid and phenylboronate ester functionalities as potent HIV‑1 non-nucleoside reverse transcriptase inhibitors.
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Xu S, Song S, Sun L, Gao P, Gao S, Ma Y, Kang D, Cheng Y, Zhang X, Cherukupalli S, De Clercq E, Pannecouque C, Liu X, and Zhan P
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Boronic Acids chemistry, Dose-Response Relationship, Drug, Esters chemistry, HIV Reverse Transcriptase antagonists & inhibitors, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, HIV-1 enzymology, Indoles chemistry, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Solubility, Structure-Activity Relationship, Sulfones chemistry, Water chemistry, Anti-HIV Agents pharmacology, Boronic Acids pharmacology, Esters pharmacology, Indoles pharmacology, Reverse Transcriptase Inhibitors pharmacology, Sulfones pharmacology
- Abstract
To explore the chemical space around the entrance channel of the HIV-1 reverse transcriptase (RT) binding pocket, we innovatively designed and synthesized a series of novel indolylarylsulfones (IASs) bearing phenylboronic acid and phenylboronate ester functionalities at the indole-2-carboxamide as new HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) through structure-based drug design. All the newly synthesized compounds exhibited excellent to moderate potency against wild-type (WT) HIV-1 with EC
50 values ranging from 6.7 to 42.6 nM. Among all, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide and (4-ethylphenyl) boronate ester substituted indole-2-carboxamide were found to be the most potent inhibitors (EC50 = 8.5 nM, SI = 3310; EC50 = 6.7 nM, SI = 3549, respectively). Notably, (3-ethylphenyl)boronic acid substituted indole-2-carboxamide maintained excellent activities against the single HIV-1 mutants L100I (EC50 = 7.3 nM), K103N (EC50 = 9.2 nM), as well as the double mutant V106A/F227L (EC50 = 21.1 nM). Preliminary SARs and molecular modelling studies are also discussed in detail., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2022
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9. Remdesivir: Quo vadis?
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De Clercq E
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- Adenosine Monophosphate administration & dosage, Adenosine Monophosphate chemistry, Adenosine Monophosphate metabolism, Alanine administration & dosage, Alanine chemistry, Alanine metabolism, Animals, Antiviral Agents chemistry, Antiviral Agents metabolism, COVID-19 metabolism, Drug Therapy, Combination, Humans, Protein Structure, Tertiary, SARS-CoV-2 chemistry, SARS-CoV-2 metabolism, Adenosine Monophosphate analogs & derivatives, Alanine analogs & derivatives, Antiviral Agents administration & dosage, SARS-CoV-2 drug effects, COVID-19 Drug Treatment
- Abstract
Remdesivir (GS-5734, Veklury®) has remained the only antiviral drug formally approved by the US FDA for the treatment of Covid-19 (SARS-CoV-2 infection). Its key structural features are the fact that it is a C-nucleoside (adenosine) analogue, contains a 1'-cyano function, and could be considered as a ProTide based on the presence of a phosphoramidate group. Its antiviral spectrum and activity in animal models have been well established and so has been its molecular mode of action as a delayed chain terminator of the viral RdRp (RNA-dependent RNA polymerase). Its clinical efficacy has been evaluated, but needs to be optimized with regard to timing, dosage and duration of treatment, and route of administration. Safety, toxicity and pharmacokinetics need to be further addressed, and so are its potential combinations with other drugs such as corticosteroids (i.e. dexamethasone) and ribavirin., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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10. Exploiting the hydrophobic channel of the NNIBP: Discovery of novel diarylpyrimidines as HIV-1 NNRTIs against wild-type and K103N mutant viruses.
- Author
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Fu Z, Zhang T, Zhou Z, Kang D, Sun L, Gao S, Cherukupalli S, De Clercq E, Pannecouque C, Liu X, and Zhan P
- Subjects
- Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, HIV-1 genetics, Humans, Hydrophobic and Hydrophilic Interactions, Microbial Sensitivity Tests, Molecular Structure, Mutation, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Anti-HIV Agents pharmacology, Drug Discovery, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Reverse Transcriptase Inhibitors pharmacology
- Abstract
To further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), a new series of diarylpyrimidines (DAPYs) were designed and synthesized as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs). The target compounds were evaluated for anti-HIV potency in MT-4 cells. Most of the synthesized DAPYs exhibited moderate to excellent activity against the HIV-1 wild-type (WT) strain with EC
50 values ranging from 16 nM to 0.722 µM. Interestingly, few compounds displayed remarkable activity in inhibiting K103N mutant virus with EC50 values ranging from 39 nM to 1.708 µM. Notably, FS2 (EC50(IIIB) = 16 nM, EC50(K103N) = 39 nM, SI = 294) was identified as the most significant compound, which was considerably more potent than nevirapine, lamivudine, and comparable to zidovudine. Additionally, the HIV-1 RT inhibition assay confirmed their binding target. Preliminary structure-activity relationships (SARs) and molecular modeling studies were also performed, providing significant suggestions for further optimization., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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11. Design, synthesis and anti-HIV evaluation of novel 5-substituted diarylpyrimidine derivatives as potent HIV-1 NNRTIs.
- Author
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Gao P, Song S, Wang Z, Sun L, Zhang J, Pannecouque C, De Clercq E, Zhan P, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cell Line, Tumor, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Reverse Transcriptase Inhibitors, Structure-Activity Relationship, Anti-HIV Agents pharmacology, Drug Design, HIV drug effects, HIV Reverse Transcriptase antagonists & inhibitors, Pyrimidines pharmacology
- Abstract
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. As a continuation of our efforts to discover and develop "me-better" drugs of DAPYs, novel diarylpyrimidine derivatives were designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds demonstrated strong inhibition activity against wide-type HIV-1 strain (III
B ) with EC50 values in the range of 2.5 nM ~ 0.93 μM. Among them, compounds IVB-5-4 and IVB-5-8 were the most potent ones which showed anti-HIV-1IIIB activity much superior than that of Nevirapine, comparable to Efavirenz and Etravirine. What's more, some compounds also showed low nanomole activity against some mutant strains such as K103N and E138K. The selected compound IVB-5-4 was also evaluated for the activity against reverse transcriptase (RT), and exhibited submicromolar IC50 values indicating that this series compounds are specific RT inhibitors. Preliminary structure-activity relationships and modeling studies of these new analogues provide valuable avenues for future molecular optimization., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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12. Novel indolylarylsulfone derivatives as covalent HIV-1 reverse transcriptase inhibitors specifically targeting the drug-resistant mutant Y181C.
- Author
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Gao P, Song S, Frutos-Beltrán E, Li W, Sun B, Kang D, Zou J, Zhang J, Pannecouque C, De Clercq E, Menéndez-Arias L, Zhan P, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, Drug Resistance, Viral drug effects, HIV Reverse Transcriptase genetics, HIV Reverse Transcriptase metabolism, HIV-1 enzymology, Indoles chemical synthesis, Indoles chemistry, Molecular Structure, Mutation, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Sulfones chemical synthesis, Sulfones chemistry, Anti-HIV Agents pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Indoles pharmacology, Reverse Transcriptase Inhibitors pharmacology, Sulfones pharmacology
- Abstract
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. However, emergent and transmitted drug resistance compromise their efficacy in the clinical setting. Y181C is selected in patients receiving nevirapine, etravirine and rilpivirine, and together with K103N is the most prevalent NNRTI-associated mutation in HIV-infected patients. Herein, we report on the design, synthesis and biological evaluation of a novel series of indolylarylsulfones bearing acrylamide or ethylene sulfonamide reactive groups as warheads to inactivate Cys181-containing HIV-1 RT via a Michael addition reaction. Compounds I-7 and I-9 demonstrated higher selectivity towards the Y181C mutant than against the wild-type RT, in nucleotide incorporation inhibition assays. The larger size of the NNRTI binding pocket in the mutant enzyme facilitates a better fit for the active compounds, while stacking interactions with Phe227 and Pro236 contribute to inhibitor binding. Mass spectrometry data were consistent with the covalent modification of the RT, although off-target reactivity constitutes a major limitation for further development of the described inhibitors., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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13. Design, synthesis and biological evaluation of 3-hydroxyquinazoline-2,4(1H,3H)-diones as dual inhibitors of HIV-1 reverse transcriptase-associated RNase H and integrase.
- Author
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Gao P, Cheng X, Sun L, Song S, Álvarez M, Luczkowiak J, Pannecouque C, De Clercq E, Menéndez-Arias L, Zhan P, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Caco-2 Cells, Cell Line, Cell Membrane Permeability drug effects, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, HIV-2 drug effects, Humans, Models, Molecular, Molecular Structure, Quinazolinones chemical synthesis, Quinazolinones chemistry, Ribonuclease H, Human Immunodeficiency Virus metabolism, Structure-Activity Relationship, Anti-HIV Agents pharmacology, Drug Design, Enzyme Inhibitors pharmacology, HIV Integrase metabolism, HIV Reverse Transcriptase antagonists & inhibitors, Quinazolinones pharmacology, Ribonuclease H, Human Immunodeficiency Virus antagonists & inhibitors
- Abstract
A novel series of 3-hydroxyquinazoline-2,4(1H,3H)-diones derivatives has been designed and synthesized. Their biochemical characterization revealed that most of the compounds were effective inhibitors of HIV-1 RNase H activity at sub to low micromolar concentrations. Among them, II-4 was the most potent in enzymatic assays, showing an IC
50 value of 0.41 ± 0.13 μM, almost five times lower than the IC50 obtained with β-thujaplicinol. In addition, II-4 was also effective in inhibiting HIV-1 IN strand transfer activity (IC50 = 0.85 ± 0.18 μM) but less potent than raltegravir (IC50 = 71 ± 14 nM). Despite its relatively low cytotoxicity, the efficiency of II-4 in cell culture was limited by its poor membrane permeability. Nevertheless, structure-activity relationships and molecular modeling studies confirmed the importance of tested 3-hydroxyquinazoline-2,4(1H,3H)-diones as useful leads for further optimization., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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14. Design, synthesis and biological evaluation of novel acetamide-substituted doravirine and its prodrugs as potent HIV-1 NNRTIs.
- Author
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Wang Z, Yu Z, Kang D, Zhang J, Tian Y, Daelemans D, De Clercq E, Pannecouque C, Zhan P, and Liu X
- Subjects
- Acetamides chemistry, Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Drug Design, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, Humans, Prodrugs chemical synthesis, Prodrugs chemistry, Pyridones chemical synthesis, Pyridones chemistry, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Triazoles chemical synthesis, Triazoles chemistry, Acetamides pharmacology, Anti-HIV Agents pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, Prodrugs pharmacology, Pyridones pharmacology, Reverse Transcriptase Inhibitors pharmacology, Triazoles pharmacology
- Abstract
A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC
50 value of 54.8 nM. Among them, the two most potent compounds 8i (EC50 = 59.5 nM) and 8k (EC50 = 54.8 nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC50 values, being superior to lamivudine (3TC, EC50 = 12.8 μM) and comparable to doravirine (EC50 = 13 nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N + Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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15. Tanovea® for the treatment of lymphoma in dogs.
- Author
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De Clercq E
- Subjects
- Alanine chemistry, Alanine metabolism, Alanine therapeutic use, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Dogs, Lymphoma diagnostic imaging, Lymphoma metabolism, Prodrugs chemistry, Prodrugs metabolism, Purines chemistry, Purines metabolism, Treatment Outcome, Alanine analogs & derivatives, Antineoplastic Agents therapeutic use, Lymphoma drug therapy, Prodrugs therapeutic use, Purines therapeutic use
- Abstract
Tanovea® (first named GS-9219, then VDC-1101, generic name: rabacfosadine) is a pro-prodrug or "double" prodrug of PMEG [9-(2-phosphonylmethoxyethyl)guanine], which has been conditionally approved by the US FDA (Food and Drug Administration) for the treatment of lymphoma in dogs. Tanovea has been demonstrated to be effective against non-Hodgkin's lymphoma (NHL) in dogs, as well as canine cutaneous T-cell lymphoma, spontaneous canine multiple myeloma, naïve canine multicentric lymphoma and relapsed canine B-cell lymphoma. As a double prodrug of PMEG, GS-9219 is first converted intracellularly by hydrolysis to cPr-PMEDAP, then deaminated to PMEG, which is then phosphorylated twice to its active metabolite PMEGpp, acting at the level of the cellular DNA polymerases., (Copyright © 2018 The Author. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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16. Role of tenofovir alafenamide (TAF) in the treatment and prophylaxis of HIV and HBV infections.
- Author
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De Clercq E
- Subjects
- Adenine administration & dosage, Alanine, Drug Resistance, Viral drug effects, Drug Resistance, Viral immunology, Drug Therapy, Combination methods, HIV Infections immunology, Hepatitis B immunology, Humans, Tenofovir analogs & derivatives, Treatment Outcome, Adenine analogs & derivatives, Antiviral Agents administration & dosage, HIV Infections drug therapy, Hepatitis B drug therapy, Pre-Exposure Prophylaxis methods
- Abstract
Tenofovir (TFV) is the cornerstone of the treatment and prophylaxis of HIV infections. It has been routinely used in its prodrug form TDF (tenofovir disoproxil fumarate) combined with emtricitabine ((-)FTC) and other antiretroviral agents. TDF has now been replaced by TAF (tenofovir alafenamide) which allows better uptake by the lymphoid tissue. In combination with elvitegravir (E), cobicistat (C), emtricitabine (F), TAF can be advocated as an STR (single tablet regimen, Genvoya®) for the treatment of HIV infections. In this combination, E and C may in the future be replaced by bictegravir. The prophylaxis of HIV infection is momentarily based upon Truvada®, the combination of F with TDF, which in the future may also be replaced by TAF. TAF (Vemlidy®) has also replaced TDF (Viread®) for the treatment of hepatitis B virus (HBV) infections. Both TDF and TAF offer little or no risk for virus-drug resistance. As compared to TDF, TAF limits the risk for nephrotoxicity and loss of bone mineral density. What remains to be settled, however, before the universal use of TAF could be recommended, is its safety during pregnancy and its applicability in the treatment of tuberculosis, in combination with rifampicin., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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17. The discovery of novel diarylpyri(mi)dine derivatives with high level activity against a wide variety of HIV-1 strains as well as against HIV-2.
- Author
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Lu X, Yang J, Kang D, Gao P, Daelemans D, De Clercq E, Pannecouque C, Zhan P, and Liu X
- Subjects
- Allosteric Regulation, Binding Sites, Drug Design, HIV Reverse Transcriptase chemistry, HIV Reverse Transcriptase metabolism, HIV-1 enzymology, HIV-2 enzymology, Humans, Molecular Docking Simulation, Protein Structure, Tertiary, Pyrimidines metabolism, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors metabolism, Structure-Activity Relationship, HIV-1 drug effects, HIV-2 drug effects, Pyrimidines chemistry, Reverse Transcriptase Inhibitors pharmacology
- Abstract
By means of structure-based molecular hybridization strategy, a series of novel diarylpyri(mi)dine derivatives targeting the entrance channel of HIV-1 reverse transcriptase (RT) were designed, synthesized and evaluated as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs). Encouragingly, all the tested compounds showed good activities against wild-type (WT) HIV-1 (IIIB) with EC
50 in the range of 1.36 nM-29 nM, which is much better than those of nevirapine (NVP, EC50 = 125.42 nM) and azidothymidine (AZT, EC50 = 11.36 nM). Remarkably, these compounds also displayed effective activity against the most of the single and double-mutated HIV-1 strains with low EC50 values, which is comparable to the control drugs. Besides, these compounds were also exhibited favorable enzymatic inhibitory activity. Moreover, preliminary structure-activity relationships (SARs) and molecular modeling study were investigated and discussed in detail. Unexpectedly, four diarylpyrimidines yielded moderate anti-HIV-2 activities. To our knowledge, this is rarely reported that diarylpyrimidine-based NNRTIs have potent activity against both HIV-1 and HIV-2 in cell culture., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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18. Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays.
- Author
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Huang B, Wang X, Liu X, Chen Z, Li W, Sun S, Liu H, Daelemans D, De Clercq E, Pannecouque C, Zhan P, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cell Line, Crystallography, X-Ray, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, Humans, Indoles chemistry, Indoles pharmacology, Microbial Sensitivity Tests, Molecular Structure, Pyrimidines chemistry, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Sulfones chemistry, Sulfones pharmacology, Anti-HIV Agents pharmacology, Drug Discovery, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Crystallographic overlap studies and pharmacophoric analysis indicated that diarylpyrimidine (DAPY)-based HIV-1 NNRTIs showed a similar binding mode and pharmacophoric features as indolylarylsulfones (IASs), another class of potent NNRTIs. Thus, a novel series of DAPY-IAS hybrid derivatives were identified as newer NNRTIs using structure-based molecular hybridization. Some target compounds exhibited moderate activities against HIV-1 IIIB strain, among which the two most potent inhibitors possessed EC
50 values of 1.48μM and 1.61μM, respectively. They were much potent than the reference drug ddI (EC50 =76.0μM) and comparable to 3TC (EC50 =2.54μM). Compound 7a also exhibited the favorable selectivity index (SI=80). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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19. Tenofovir alafenamide (TAF) as the successor of tenofovir disoproxil fumarate (TDF).
- Author
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De Clercq E
- Subjects
- Adenine administration & dosage, Adenine economics, Adenine therapeutic use, Alanine, Antiviral Agents administration & dosage, Antiviral Agents economics, HIV Infections prevention & control, Humans, Tenofovir administration & dosage, Tenofovir economics, Adenine analogs & derivatives, Antiviral Agents therapeutic use, HIV Infections drug therapy, Tenofovir therapeutic use
- Abstract
Tenofovir alafenamide (TAF) can be considered a new prodrug of tenofovir (TFV), as successor of tenofovir disoproxil fumarate (TDF). It is in vivo as potent against human immunodeficiency virus (HIV) at a 30-fold lower dose (10mg) than TDF (300mg). TAF has been approved in November 2015 (in the US and EU), as a single-tablet regimen (STR) containing 150mg elvitegravir (E), 150mg cobicistat (C), 200mg emtricitabine [(-)FTC] (F) and 10mg TAF, marketed as Genvoya®, on 01 March 2016 in the US as an STR containing 25mg rilpivirine (R), 200mg F and 25mg TAF, marketed as Odefsey®, and on 4 April 2016 in the US, as an STR containing 200mg F and 25mg TAF, marketed as Descovy®, for the treatment of HIV infections. STR combinations containing TAF and emtricitabine could be paired with a range of third agents, for example, darunavir and cobicistat. TAF has a much lower risk of kidney toxicity or bone density changes than TDF, and also offers long-term potential in the pre-exposure prophylaxis (PrEP) of HIV infections. TAF is specifically accumulated in lymphatic tissue, and in the liver, and hence also holds great potential for the treatment of hepatitis B virus (HBV) infections. Akin to TDF, TAF is converted intracellularly to TFV. Its active diphosphate metabolite (TFVpp) is targeted at the RNA-dependent DNA polymerase (reverse transcriptase) of either HIV or HBV., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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20. Arylazolyl(azinyl)thioacetanilides. Part 20: Discovery of novel purinylthioacetanilides derivatives as potent HIV-1 NNRTIs via a structure-based bioisosterism approach.
- Author
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Lu X, Li X, Yang J, Huang B, Kang D, Zhao F, Zhou Z, De Clercq E, Daelemans D, Pannecouque C, Zhan P, and Liu X
- Subjects
- Acetanilides chemistry, Anti-HIV Agents chemistry, Carbon-13 Magnetic Resonance Spectroscopy, Models, Molecular, Proton Magnetic Resonance Spectroscopy, Reverse Transcriptase Inhibitors chemistry, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Acetanilides pharmacology, Anti-HIV Agents pharmacology, HIV-1 drug effects, Reverse Transcriptase Inhibitors pharmacology
- Abstract
By means of structure-based bioisosterism approach, a series of novel purinylthioacetanilide derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the tested compounds were found to be active against wild-type (WT) HIV-1(IIIB) with EC50 in the range of 0.78-4.46μM. Among them, LAD-8 displayed the most potent anti-HIV activity (EC50=0.78μM, SI=24). In addition, LBD-6 showed moderate activity against L100I mutant (EC50=5.64μM) and double mutant strain RES056 (EC50=22.24μM). Preliminary structure-activity relationships (SARs) were discussed in detail. Molecular modeling study was used to predict the optimal conformation in the NNRTI binding site, which may play a guiding role in further rational optimization., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
21. Tumour-specific cytotoxicity and structure-activity relationships of novel 1-[3-(2-methoxyethylthio)propionyl]-3,5-bis(benzylidene)-4-piperidones.
- Author
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Hossain M, Das U, Umemura N, Sakagami H, Balzarini J, De Clercq E, Kawase M, and Dimmock JR
- Subjects
- Animals, Cell Line, Cell Line, Tumor, Cell Survival drug effects, Drug Screening Assays, Antitumor, Humans, Mice, Neoplasms drug therapy, Structure-Activity Relationship, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Piperidones chemistry, Piperidones pharmacology
- Abstract
A series of 1-acyl-3,5-bis(benzylidene)-4-piperidones 3-7 were designed and synthesized as novel cytotoxic agents. These compounds displayed potent cytotoxic properties towards human Molt4/C8, CEM, HSC-2, HSC-3 and HSC-4 neoplasms and also to murine L1210 cells. The majority of the compounds have sub-micromolar or very low micromolar IC50 and CC50 values and are significantly more potent than the reference alkylating drug melphalan. Evaluation of these compounds against non-malignant HGF and HPLF cells revealed the tumour-specific toxicity. In particular, 3e emerged as a promising lead cytotoxic agent which caused apoptosis and PARP1 cleavage in HSC-2 cells., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
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22. A novel family of diarylpyrimidines (DAPYs) featuring a diatomic linker: Design, synthesis and anti-HIV activities.
- Author
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Gu SX, Qiao H, Zhu YY, Shu QC, Liu H, Ju XL, De Clercq E, Balzarini J, and Pannecouque C
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, HIV-1 genetics, HIV-2 genetics, Microbial Sensitivity Tests, Molecular Docking Simulation, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Anti-HIV Agents pharmacology, Drug Design, HIV-1 drug effects, HIV-2 drug effects, Pyrimidines pharmacology
- Abstract
To improve the conformational flexibility and positional adaptability of the traditional diarylpyrimidines (DAPYs), a family of diarylpyrimidines featuring a C-N diatomic linker between the left wing benzene ring and the central pyrimidine was firstly designed, synthesized, and evaluated for in vitro anti-HIV activity. Most of target molecules showed excellent activities against wild-type (WT) HIV-1. Among them the most potent two compounds 12h and 12r displayed extremely potent WT HIV-1 inhibitory activities with an EC50 of 2.6 nM and 3.0 nM, respectively, while their selective index (CC50/EC50) values were both over 1000. Another compound 12b (EC50 14.9 nM) was also noteworthy due to its high SI of 18,614. Moreover, all of compounds were evaluated for their WT HIV-1 reverse transcriptase activities, which shown that the newly synthesized CH2NH-DAPYs bind to HIV-1 RT and belong to the genuine NNRTIs. However, the synthesized compounds lack the activities against HIV-1 double mutant (RES056) and HIV-2 (ROD). Thus it is an upcoming objective to improve the activities against HIV-1 double mutants., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
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23. Hybrid chemistry. Part 4: Discovery of etravirine-VRX-480773 hybrids as potent HIV-1 non-nucleoside reverse transcriptase inhibitors.
- Author
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Wan ZY, Tao Y, Wang YF, Mao TQ, Yin H, Chen FE, Piao HR, De Clercq E, Daelemans D, and Pannecouque C
- Subjects
- Acetanilides chemistry, Anti-HIV Agents chemical synthesis, Cell Line, Chemistry Techniques, Synthetic, Drug Discovery, Drug Evaluation, Preclinical methods, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Humans, Molecular Dynamics Simulation, Nitriles, Pyridazines chemistry, Pyrimidines, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, Triazoles chemistry, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Reverse Transcriptase Inhibitors chemistry
- Abstract
A novel series of etravirine-VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50=0.24 , SI>1225), was more potent than delavirdine (EC50=0.66 μM, SI>67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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24. Anti-HIV diarylpyrimidine-quinolone hybrids and their mode of action.
- Author
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Mao TQ, He QQ, Wan ZY, Chen WX, Chen FE, Tang GF, De Clercq E, Daelemans D, and Pannecouque C
- Subjects
- Anti-HIV Agents chemical synthesis, Binding Sites, Cell Line, Drug Design, Granulocyte Precursor Cells drug effects, Granulocyte Precursor Cells pathology, Granulocyte Precursor Cells virology, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 enzymology, HIV-1 growth & development, Humans, Models, Molecular, Molecular Docking Simulation, Pyrimidines chemical synthesis, Quinolones chemical synthesis, Reverse Transcriptase Inhibitors chemical synthesis, Structure-Activity Relationship, Tetradecanoylphorbol Acetate pharmacology, Virus Latency drug effects, Anti-HIV Agents pharmacology, HIV-1 drug effects, Pyrimidines pharmacology, Quinolones pharmacology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07μM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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25. Synthesis and biological evaluation of DAPY-DPEs hybrids as non-nucleoside inhibitors of HIV-1 reverse transcriptase.
- Author
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Wu HQ, Yao J, He QQ, Chen WX, Chen FE, Pannecouque C, De Clercq E, and Daelemans D
- Subjects
- Anti-HIV Agents pharmacology, Binding Sites, Cell Line, Drug Design, Humans, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, Anti-HIV Agents chemistry, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 enzymology, Pyrimidines chemistry, Reverse Transcriptase Inhibitors chemistry
- Abstract
A series of new DAPY-DPEs hybrids, combined the important pharmacophores of DAPYs and DPEs, has been synthesized and biologically evaluated for their anti-HIV activities against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 and HIV-2 strain ROD in MT-4 cell cultures. Many promising candidates with potent inhibitory activity (wild-type) within the EC50 range from 0.16 to 0.013 μM were obtained. In particular, 3c, 3p, 3r and 3s displayed low nM level EC50 values (35, 13, 50 and 17 nM, respectively) and high selectivity (9342, 25131, 2890 and 11338, respectively), which were much more potent than NVP (EC50=0.31 μM, SI=48), 3TC (EC50=2.24 μM, SI>39), DDI (EC50=23.20 μM, SI>9) and DLV (EC50=0.65 μM, SI>67), and comparable to AZT (EC50=0.0071 μM, SI>13144) and EFV (EC50=0.0062 μM, SI>1014). The HIV-1 reverse transcriptase inhibitory assay confirmed that these DAPY-DPEs hybrids targeted HIV-1 RT. Molecular simulation was performed to investigate the potential binding mode of the newly synthesized compounds. And reasonable explanation for the activity results was discussed with docking method., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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26. Ebola virus (EBOV) infection: Therapeutic strategies.
- Author
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De Clercq E
- Subjects
- Africa, Western epidemiology, Animals, Antiviral Agents pharmacology, Ebolavirus physiology, Hemorrhagic Fever, Ebola epidemiology, Humans, Antiviral Agents therapeutic use, Ebolavirus drug effects, Hemorrhagic Fever, Ebola drug therapy, Hemorrhagic Fever, Ebola transmission
- Abstract
Within less than a year after its epidemic started (in December 2013) in Guinea, Ebola virus (EBOV), a member of the filoviridae, has spread over a number of West-African countries (Guinea, Sierra Leone and Liberia) and gained allures that have been unprecedented except by human immunodeficiency virus (HIV). Although EBOV is highly contagious and transmitted by direct contact with body fluids, it could be counteracted by the adequate chemoprophylactic and -therapeutic interventions: vaccines, antibodies, siRNAs (small interfering RNAs), interferons and chemical substances, i.e. neplanocin A derivatives (i.e. 3-deazaneplanocin A), BCX4430, favipiravir (T-705), endoplasmic reticulum (ER) α-glucosidase inhibitors and a variety of compounds that have been found to inhibit EBOV infection blocking viral entry or by a mode of action that still has to be resolved. Much has to be learned from the mechanism of action of the compounds active against VSV (vesicular stomatitis virus), a virus belonging to the rhabdoviridae, that in its mode of replication could be exemplary for the replication of filoviridae., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
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27. Arylazolyl(azinyl)thioacetanilides. Part 16: Structure-based bioisosterism design, synthesis and biological evaluation of novel pyrimidinylthioacetanilides as potent HIV-1 inhibitors.
- Author
-
Li X, Lu X, Chen W, Liu H, Zhan P, Pannecouque C, Balzarini J, De Clercq E, and Liu X
- Subjects
- Acetanilides chemical synthesis, Acetanilides chemistry, Anti-HIV Agents chemical synthesis, Dose-Response Relationship, Drug, HIV-1 growth & development, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Virus Replication drug effects, Acetanilides pharmacology, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Drug Design, HIV-1 drug effects, Pyrimidines pharmacology
- Abstract
A series of novel pyrimidinylthioacetanilides were designed, synthesized, and evaluated for their biological activity as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Most of the tested compounds were proved to be effective in inhibiting HIV-1 (IIIB) replication with EC50 ranging from 0.15 μM to 24.2 μM, thereinto compound 15 was the most active lead with favorable inhibitory activity against HIV-1 (IIIB) (EC50=0.15 μM, SI=684). Besides, compound 6 displayed moderate inhibition against the double-mutated HIV-1 strain (K103N/Y181C) (EC50=3.9 μM). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships (SCRs) data, and molecular modeling studies were discussed as well, which may provide valuable insights for further optimizations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
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28. Synthesis and biological evaluation of CHX-DAPYs as HIV-1 non-nucleoside reverse transcriptase inhibitors.
- Author
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Yan ZH, Wu HQ, Chen WX, Wu Y, Piao HR, He QQ, Chen FE, De Clercq E, and Pannecouque C
- Subjects
- Cell Survival drug effects, Cells, Cultured, HIV-1 drug effects, Humans, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Nitriles, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma virology, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Virus Replication drug effects, Anti-HIV Agents chemical synthesis, Anti-HIV Agents pharmacology, Benzamides chemical synthesis, Benzamides pharmacology, Drug Design, HIV Reverse Transcriptase antagonists & inhibitors, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors pharmacology
- Abstract
A series of new diarylpyrimidines (DAPYs) characterized by a halogen atom on the methylene linker between wing I and the central pyrimidine ring was synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. The two most promising compounds 7f and 7g showed excellent activity against wild-type HIV-1 with low nanomolar EC50 values of 0.005 and 0.009 μM, respectively, which were comparable to or more potent than all the reference drugs zidovudine (AZT), lamivudine (3TC), nevirapine (NEV), efavirenz (EFV), delaviridine (DLV) and etravirine (ETV). In particular, 7g also displayed strong activity against the double mutant strain 103N + 181C with an EC50 value of 8.2 μM. The preliminary structure-activity relationship (SAR) and molecular docking analysis of this new series of CHX-DAPYs were also investigated., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
29. Current race in the development of DAAs (direct-acting antivirals) against HCV.
- Author
-
De Clercq E
- Subjects
- Animals, Antiviral Agents adverse effects, Antiviral Agents chemistry, Antiviral Agents therapeutic use, Drug Resistance, Viral, Drug Therapy, Combination, Enzyme Inhibitors adverse effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Hepacivirus enzymology, Hepatitis C drug therapy, Hepatitis C virology, Humans, Molecular Targeted Therapy, Antiviral Agents pharmacology, Drug Discovery, Hepacivirus drug effects, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
The direct-acting antivirals (DAAs) currently in development for treatment of hepatitis C fall into four categories: (i) NS3/4A protease inhibitors: ABT-450/r, faldaprevir, asunaprevir, GS-9256, vedroprevir (GS-9451), danoprevir, MK-5172, vaniprevir, sovaprevir, ACH-2684, narlaprevir and simeprevir, in addition to those that are already developed [telaprevir (Incivek®) and boceprevir (Victrelis®)], (ii) NS5A protein inhibitors: ABT-267, daclatasvir, ledipasvir, ACH-2928, ACH-3102, PPI-668, AZD-7295, MK-8742, and GSK 2336805; (iii) NS5B (nucleoside-type) polymerase inhibitors: sofosbuvir (now approved by the FDA since 6 December 2013), GS-0938, mericitabine, VX-135, ALS 2158 and TMC 649128; (iv) NS5B (non-nucleoside-type) polymerase inhibitors: VX-222, ABT-072, ABT-333, deleobuvir, tegobuvir, setrobuvir, VCH-916, VCH-759, BMS-791325 and TMC-647055. Future drug combinations will likely exist of two or more DAAs belonging to any of the 4 categories, with the aim to achieve (i) pan-genotypic hepatitis C virus (HCV) activity, (ii) little or no risk for resistance; (iii) short duration (i.e. 12 weeks) of treatment, and (iv) a sustained viral response (SVR) and definite cure of the disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
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30. Structural modifications of CH(OH)-DAPYs as new HIV-1 non-nucleoside reverse transcriptase inhibitors.
- Author
-
Yan ZH, Huang XY, Wu HQ, Chen WX, He QQ, Chen FE, De Clercq E, and Pannecouque C
- Subjects
- Binding Sites, Cell Line, HIV Reverse Transcriptase metabolism, Humans, Molecular Docking Simulation, Protein Structure, Tertiary, Pyrimidines chemistry, Pyrimidines metabolism, Reverse Transcriptase Inhibitors metabolism, Structure-Activity Relationship, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 enzymology, Reverse Transcriptase Inhibitors chemistry
- Abstract
A series of CR2(OH)-diarylpyrimidine derivatives (CR2(OH)-DAPYs) featuring a hydrophobic group at CH(OH) linker between wing I and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. All the target compounds except for compound 3k displayed inhibitory activity against HIV-1 wild-type with EC50 values ranging from 7.21±1.99 to 0.067±0.006 μM. Among them, compound 3d showed the most potent anti-HIV-1 activity (EC50=0.067±0.006 μM, SI>592), which was approximately 2-fold more potent than the reference drugs nevirapine (NVP) and delaviridine (DLV) in the same assay. In addition, the binding modes with HIV-1 RT and the preliminary SAR studies of these new derivatives were also investigated., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
31. Fused heterocyclic compounds bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 1: design, synthesis and biological evaluation of novel 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives.
- Author
-
Tian Y, Du D, Rai D, Wang L, Liu H, Zhan P, De Clercq E, Pannecouque C, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, Drug Design, HIV Reverse Transcriptase metabolism, Heterocyclic Compounds chemical synthesis, Heterocyclic Compounds chemistry, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Nitrogen chemistry, Pyrazoles chemical synthesis, Pyrazoles chemistry, Pyrimidines chemical synthesis, Pyrimidines chemistry, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Anti-HIV Agents pharmacology, HIV drug effects, HIV Reverse Transcriptase antagonists & inhibitors, Heterocyclic Compounds pharmacology, Pyrazoles pharmacology, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[1,5-a]pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07μM. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07μM against wild-type HIV-1 and very high selectivity index (SI, 3999). Compound 5a was more effective than the reference drugs nevirapine (by 2-fold) and delavirdine (by 2-fold). In order to further confirm their binding target, an HIV-1 RT inhibitory assay was also performed. Furthermore, SAR analysis among the newly synthesized compounds was discussed and the binding mode of the active compound 5a was rationalized by molecular modeling studies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
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32. Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays.
- Author
-
Chen W, Zhan P, Rai D, De Clercq E, Pannecouque C, Balzarini J, Zhou Z, Liu H, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Crystallization, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, HIV-1 enzymology, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Pyridones chemical synthesis, Pyridones chemistry, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Anti-HIV Agents pharmacology, Drug Discovery, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Pyridones pharmacology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by molecular hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC₅₀=0.15-0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform molecular modeling studies to predict the binding mode of these 2-pyridone derivatives., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
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33. Design, synthesis and preliminary SAR studies of novel N-arylmethyl substituted piperidine-linked aniline derivatives as potent HIV-1 NNRTIs.
- Author
-
Zhang L, Zhan P, Chen X, Li Z, Xie Z, Zhao T, Liu H, De Clercq E, Pannecouque C, Balzarini J, and Liu X
- Subjects
- Aniline Compounds chemistry, Anti-HIV Agents pharmacology, Drug Design, HIV-1 genetics, Humans, Models, Molecular, Piperidines chemistry, Structure-Activity Relationship, Aniline Compounds chemical synthesis, Anti-HIV Agents chemical synthesis, HIV-1 metabolism, Piperidines chemical synthesis
- Abstract
A series of novel N-arylmethyl substituted piperidine-linked aniline derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. All the new compounds showed moderate to potent activities against wild-type (wt) HIV-1 with an EC₅₀ range from 0.022 to 2.1 μM. Among them, compound 5a6 (EC₅₀=0.022 ± 0.0091 μM, SI >10,770) was confirmed to be the most potent and selective inhibitor, which proved more potent than DDI and DLV in a cell-based assay against wt HIV-1, and more efficient than NVP in an RT (reverse transcriptase) assay. Besides, it is worth noting that compound 7a1 retained moderate inhibitory activity (EC₅₀=4.8 ± 0.95 μM) against the HIV-1 double RT mutant strain (K103N/Y181C). The preliminary structure-activity relationship was discussed and rationalized by molecular simulation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
34. Design, synthesis and biological evaluation of 3-benzyloxy-linked pyrimidinylphenylamine derivatives as potent HIV-1 NNRTIs.
- Author
-
Rai D, Chen W, Tian Y, Chen X, Zhan P, De Clercq E, Pannecouque C, Balzarini J, and Liu X
- Subjects
- Cell Line, Drug Design, HIV Infections virology, HIV Reverse Transcriptase metabolism, HIV-1 enzymology, Humans, Molecular Docking Simulation, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology, Structure-Activity Relationship, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, HIV Infections drug therapy, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Pyrimidines chemistry, Pyrimidines pharmacology
- Abstract
A novel series of 3-benzyloxy-linked pyrimidinylphenylamine derivatives (8a-8s) was designed, synthesized and evaluated for their in vitro anti-HIV activity in MT-4 cell cultures. Most of the compounds inhibited wild-type (wt) HIV-1 replication in the lower micromolar concentration range (EC(50)=0.05-35 μM) with high selectivity index (SI) values (ranged from 10 to >4870). In particular, 8h and 8g displayed excellent antiretroviral activity against wt HIV-1 with low cytotoxicity (EC(50)=0.07 μM, CC(50) >347 μM, SI >4870; EC50=0.05 μM, CC(50)=42 μM, SI=777, respectively), comparable to that of the marked drug nevirapine (EC(50)=0.113 μM, CC(50) >15 μM, SI >133). In order to confirm the binding target, 8h was selected to perform the anti-HIV-1 RT assay. Additionally, preliminary structure activity relationship (SAR) analysis and molecular docking studies of newly synthesized compounds were also discussed, as well as the predicted physicochemical properties., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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35. Dancing with chemical formulae of antivirals: A panoramic view (Part 2).
- Author
-
De Clercq E
- Subjects
- Humans, Antiviral Agents chemistry, Antiviral Agents therapeutic use, Virus Diseases drug therapy
- Abstract
In this second part of "Dancing with antivirals as chemical formulae" I will focus on a number of chemical compounds that in the last few years have elicited more than common attraction from a commercial viewpoint: (i) favipiravir (T-705), as it is active against influenza, but also several other RNA viruses; (ii) neuraminidase inhibitors such as zanamivir and oseltamivir; (iii) peramivir and laninamivir octanoate, which might be effective against influenza virus following a single (intravenous or inhalation) administration; (iv) sofosbuvir, the (anticipated) cornerstone for the interferon-free therapy of HCV infections; (v) combinations of DAAs (direct antiviral agents) to achieve, in no time, a sustained virus response (SVR) against HCV infection; (vi) HIV protease inhibitors, the latest and most promising being darunavir; (vii) the integrase inhibitors (INIs) (raltegravir, elvitegravir, dolutegravir), representing a new dimension in the anti-HIV armamentarium; (viii), a new class of helicase primase inhibitors (HPIs) that may exceed acyclovir and the other anti-herpes compounds in both potency and safety; (ix) CMX-001, as the latest of Dr. Antonín Holý's legacy for its activity against poxviruses and CMV infections, and (x) noroviruses for which the ideal antiviral compounds are still awaited for., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
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36. Design, synthesis and biological evaluation of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives as HIV-1 NNRTIs.
- Author
-
Chen W, Zhan P, De Clercq E, Pannecouque C, Balzarini J, Jiang X, and Liu X
- Subjects
- Binding Sites, Cell Line, HIV Reverse Transcriptase metabolism, HIV-1 enzymology, Humans, Inhibitory Concentration 50, Molecular Docking Simulation, Protein Structure, Tertiary, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Triazines chemical synthesis, Drug Design, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Pyrroles chemistry, Reverse Transcriptase Inhibitors pharmacology, Triazines chemistry, Triazines pharmacology
- Abstract
A series of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives (PTTDs) was designed and synthesized by a facile route. The biological assay results showed that five most potent compounds displayed inhibitory activity against HIV-1 at low micromolar concentrations (EC50=5.1-8.9 μM). Structure-activity relationship analysis indicated that N2-(3-halogenated-benzyl) analogues were more potent than N2-(unsubstituted-benzyl) analogues. The N4-substitutions contributed to the antiviral activity in the following order: 2-/3-cyano substituted benzyl > 2-/3-halogenated benzyl > non-substituted benzyl > 4-halogenated benzyl. Docking studies of the representative compound revealed the binding conformation of these compounds and provided critical insights for the further development of PTTD analogues., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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37. Towards new C6-rigid S-DABO HIV-1 reverse transcriptase inhibitors: synthesis, biological investigation and molecular modeling studies.
- Author
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Wu HQ, Yan ZH, Chen WX, He QQ, Chen FE, De Clercq E, Balzarini J, Daelemans D, and Pannecouque C
- Subjects
- Binding Sites, HIV Reverse Transcriptase metabolism, Humans, Molecular Docking Simulation, Protein Binding, Protein Structure, Tertiary, Pyrimidines chemical synthesis, Pyrimidines metabolism, Pyrimidinones chemistry, Pyrimidinones metabolism, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors metabolism, Structure-Activity Relationship, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 enzymology, Pyrimidines chemistry, Pyrimidinones chemical synthesis, Reverse Transcriptase Inhibitors chemical synthesis
- Abstract
A series of C6-rigid S-DABO analogs characterized by a substituted benzoyl group at C6 position of the pyrimidine ring has been synthesized and biological evaluation as NNRTIs against wild-type HIV-1 strain IIIB, double RT mutant (K103N+Y181C) strain RES056 as well as HIV-2 strain ROD in MT-4 cell cultures. Most of the compounds exhibited moderate antiviral activities. Among them, compound 7q displayed the highest anti-HIV-1 activity with an EC50 value of 0.26μM and a selectivity index (SI) of 541. The preliminary structure-activity relationship (SAR) of these new S-DABOs was investigated, the target RT was confirmed and docking study was performed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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38. Dancing with chemical formulae of antivirals: a personal account.
- Author
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De Clercq E
- Subjects
- Humans, Antiviral Agents chemistry, Antiviral Agents therapeutic use, Virus Diseases drug therapy
- Abstract
A chemical structure is a joy forever, and this is how I perceived the chemical structures of a number of antiviral compounds with which I have been personally acquainted over the past 3 decades: (1) amino acid esters of acyclovir (i.e. valaciclovir); (2) 5-substituted 2'-deoxyuridines (i.e. brivudin); (3) 2',3'-dideoxynucleoside analogues (i.e. stavudine); (4) acyclic nucleoside phosphonates (ANPs) (i.e. cidofovir, adefovir); (5) tenofovir disoproxil fumarate (TDF) and drug combinations therewith; (6) tenofovir alafenamide (TAF, GS-7340), a new phosphonoamidate prodrug of tenofovir; (7) pro-prodrugs of PMEG (i.e. GS-9191 and GS-9219); (8) new ANPs: O-DAPy and 5-aza-C phosphonates; (9) non-nucleoside reverse transcriptase inhibitors (NNRTIs): HEPT and TIBO derivatives; and (10) bicyclam derivatives (i.e. AMD3100)., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
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39. Synthesis and biological evaluation of pyridazine derivatives as novel HIV-1 NNRTIs.
- Author
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Li D, Zhan P, Liu H, Pannecouque C, Balzarini J, De Clercq E, and Liu X
- Subjects
- Cell Line, Delavirdine pharmacology, HIV Infections virology, HIV Reverse Transcriptase metabolism, HIV-1 enzymology, Humans, Nevirapine pharmacology, Pyridazines chemical synthesis, Reverse Transcriptase Inhibitors chemical synthesis, Structure-Activity Relationship, HIV Infections drug therapy, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Pyridazines chemistry, Pyridazines pharmacology, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology
- Abstract
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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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40. Antivirals: past, present and future.
- Author
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De Clercq E
- Subjects
- Antiviral Agents pharmacology, Microbial Sensitivity Tests, Viruses drug effects, Antiviral Agents therapeutic use, Virus Diseases drug therapy
- Abstract
Vaccination is possible to prevent infections with some viruses: hepatitis B virus (HBV), varicella-zoster virus (VZV), influenza A and B viruses, Yellow fever virus and poliovirus; but not for others: human immunodeficiency virus (HIV), hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), and most hemorrhagic fever viruses (HFV) (except for Yellow fever virus). Antiviral therapy is obviously needed to control those infections that are not amenable to prophylaxis by vaccination, but is also highly desirable for those infections where vaccination has not been implemented or did not fulfill its premises for complete protection., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
41. Arylazolyl(azinyl)thioacetanilides. Part 10: design, synthesis and biological evaluation of novel substituted imidazopyridinylthioacetanilides as potent HIV-1 inhibitors.
- Author
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Li X, Zhan P, Liu H, Li D, Wang L, Chen X, Liu H, Pannecouque C, Balzarini J, De Clercq E, and Liu X
- Subjects
- Acetanilides chemical synthesis, Acetanilides chemistry, Anti-HIV Agents chemistry, Cell Line, Dose-Response Relationship, Drug, HIV-1 physiology, Humans, Imidazoles chemistry, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship, Virus Replication drug effects, Acetanilides pharmacology, Anti-HIV Agents chemical synthesis, Anti-HIV Agents pharmacology, Drug Design, HIV-1 drug effects, Imidazoles chemical synthesis, Imidazoles pharmacology
- Abstract
In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with novel structures, we have employed a scaffold hopping strategy to explore the chemically diversed space of bioactive compounds. The original arylazolylthioacetanilide platform was replaced with different imidazopyridinylthioacetanilide scaffolds to yield the optimal pharmacophore moieties in order to generate novel NNRTIs with desirable potency. Some of the new compounds proved able to inhibit HIV-1 replication in the low micromolar range. In particular, compound 5b16 displayed the most potent anti-HIV-1 activity (EC(50) = 0.21 ± 0.06 μM), inhibiting HIV-1 IIIB replication in MT-4 cells more effectively than dideoxycytidine (EC(50) = 1.4 ± 0.1 μM) and similarly with nevirapine (EC(50) = 0.20 ± 0.10 μM). Preliminary structure-activity relationship (SAR) of the newly synthesized congeners is discussed, and molecular modeling study is performed to rationalize the SAR conclusions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
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42. Where rilpivirine meets with tenofovir, the start of a new anti-HIV drug combination era.
- Author
-
De Clercq E
- Subjects
- Adenine administration & dosage, Animals, Deoxycytidine administration & dosage, Drug Combinations, Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination, Emtricitabine, Emtricitabine, Rilpivirine, Tenofovir Drug Combination, HIV Infections epidemiology, Humans, Rilpivirine, Tenofovir, Adenine analogs & derivatives, Anti-HIV Agents administration & dosage, Deoxycytidine analogs & derivatives, Drug Therapy, Combination trends, HIV Infections drug therapy, HIV-1 drug effects, Nitriles administration & dosage, Organophosphonates administration & dosage, Oxazines administration & dosage, Pyrimidines administration & dosage
- Abstract
The triple-drug once-daily combination pill containing tenofovir, emtricitabine and rilpivirine for HIV treatment was launched in 2011, both in the USA (Complera) and the E.U. (Eviplera). The active ingredients of Complera or Eviplera are the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir, the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine, and the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine. Rilpivirine originated from a collaborative research I had started with Dr. Paul Janssen in 1987, whereas tenofovir emanated from a collaborative research with Dr. Antonin Holý and Gilead Sciences. Exactly twenty-five years later rilpivirine and tenofovir joined each other, together with emtricitabine, in the same "combo" pill, representing a full treatment regimen for AIDS (HIV infection) based on a single once-daily pill., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
43. Design, synthesis, anti-HIV evaluation and molecular modeling of piperidine-linked amino-triazine derivatives as potent non-nucleoside reverse transcriptase inhibitors.
- Author
-
Chen X, Zhan P, Liu X, Cheng Z, Meng C, Shao S, Pannecouque C, De Clercq E, and Liu X
- Subjects
- Amines chemistry, Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cell Line, Tumor, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Piperidines chemistry, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Triazines chemistry, Anti-HIV Agents pharmacology, Drug Design, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, HIV-2 drug effects, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors pharmacology
- Abstract
A novel series of piperidine-linked amino-triazine derivatives were designed, synthesized and evaluated for in vitro anti-HIV activity as non-nucleoside reverse transcriptase inhibitors on the basis of our previous work. Screening results indicated that most compounds showed excellent activity against wild-type HIV-1 with EC(50) values in low nanomolar concentration range (especially compound 6b3, EC(50) = 4.61 nM, SI = 5945) and high activity against K103N/Y181C resistant mutant strain of HIV-1 with EC(50) values in low micromolar concentration range. In addition, preliminary structure-activity relationship and molecular modeling of these new analogs were detailed in this manuscript., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
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44. Protection of pigs against genital Chlamydia trachomatis challenge by parenteral or mucosal DNA immunization.
- Author
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Schautteet K, De Clercq E, Jönsson Y, Lagae S, Chiers K, Cox E, and Vanrompay D
- Subjects
- Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic genetics, Administration, Inhalation, Administration, Intravaginal, Animals, Bacterial Vaccines administration & dosage, Chlamydia trachomatis genetics, Disease Models, Animal, Female, Lymphogranuloma Venereum immunology, Plasmids administration & dosage, Swine, Vaccines, DNA administration & dosage, Bacterial Vaccines immunology, Chlamydia trachomatis immunology, Immunity, Mucosal, Immunization methods, Lymphogranuloma Venereum prevention & control, Vaccines, DNA immunology
- Abstract
The current study evaluates combined aerosol-vaginal delivery of a MOMP-based Chlamydia trachomatis (serovar E) DNA vaccine in a pig genital challenge model. Most non-replicating antigens are rather poor mucosal immunogens in comparison to replicating antigens. Therefore, a mucosal administered DNA vaccine, which actually mimics a live vaccine, could be promising. Protection was promoted by plasmids encoding the porcine granulocyte macrophage-colony stimulating factor (pcDNA3.1zeo::GM-CSF), the Escherichia coli thermo-labile enterotoxin (LT) subunit A (plasmid PJV2004::LTa) and subunit B (plasmid PJV2005::LTb). Mucosal C. trachomatis DNA vaccination induced significant protection against genital C. trachomatis challenge although the infection could not be eradicated. Intradermal immunization was significantly less efficient in protecting experimentally infected pigs. Protection was correlated with efficient T cell priming and significantly higher serum IgA titers following primo vaccination., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
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45. Synthesis and structure-activity relationship of novel diarylpyrimidines with hydromethyl linker (CH(OH)-DAPYs) as HIV-1 NNRTIs.
- Author
-
Gu SX, He QQ, Yang SQ, Ma XD, Chen FE, De Clercq E, Balzarini J, and Pannecouque C
- Subjects
- Aniline Compounds chemistry, Aniline Compounds toxicity, Cell Line, Chlorine chemistry, HIV Reverse Transcriptase genetics, HIV Reverse Transcriptase metabolism, Humans, Mutation, Pyrimidines chemical synthesis, Pyrimidines toxicity, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors toxicity, Structure-Activity Relationship, Aniline Compounds chemical synthesis, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 enzymology, Pyrimidines chemistry, Reverse Transcriptase Inhibitors chemical synthesis
- Abstract
A series of 26 diarylpyrimidines, characterized by the hydroxymethyl linker between the left wing benzene ring and the central pyrimidine, were synthesized and evaluated for in vitro anti-HIV activity. Most of the compounds exhibited moderate to excellent activities against wild-type HIV-1. Among them, compound 10i, bearing a chlorine atom at the C-2 position of left benzene ring, was the best congener and showed potent activity against wild-type HIV-1 with an EC(50) value of 0.009 μM, along with moderate activities against the double RT mutant (K103N+Y181C) HIV-1(III(B)) and HIV-2(ROD) with an EC(50) value of 6.2 and 6.0 μM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
46. Synthesis and biological evaluation of novel 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors.
- Author
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Zhang J, Zhan P, Wu J, Li Z, Jiang Y, Ge W, Pannecouque C, De Clercq E, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cell Line, Tumor, Crystallography, X-Ray, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, HIV-2 drug effects, Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Pyrimidinones chemical synthesis, Pyrimidinones chemistry, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Stereoisomerism, Structure-Activity Relationship, Virus Replication drug effects, Anti-HIV Agents pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, Pyrimidinones pharmacology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
A series of novel S-DABO analogues of 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were compounds 6c1,6c6, and 6b1 (EC(50)=0.24 ± 0.05, 0.38 ± 0.13, 0.39 ± 0.05 μM, respectively), which possess improved or similar HIV-1 inhibitory activity compared with nevirapine (NVP) (EC(50)=0.21 μM) and delavirdine (DLV) (EC(50)=0.32 μM). None of these compounds were active against HIV-2 replication. Furthermore, enzyme inhibitory assays were performed with selected derivatives against HIV-1 wtRT, confirming that the main target of these compounds is the HIV-1 RT and these new S-DABOs are acting as NNRTIs. The preliminary structure-activity relationship (SAR) of these new congeners is discussed briefly and rationalized by docking studies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
47. The clinical potential of the acyclic (and cyclic) nucleoside phosphonates: the magic of the phosphonate bond.
- Author
-
De Clercq E
- Subjects
- Adenine analogs & derivatives, Adenine therapeutic use, Antineoplastic Agents pharmacology, Antiviral Agents pharmacology, Cidofovir, Cytosine analogs & derivatives, Cytosine therapeutic use, Guanosine analogs & derivatives, Guanosine therapeutic use, HIV Infections drug therapy, HIV Infections prevention & control, Hepatitis B drug therapy, Humans, Organophosphonates pharmacology, Prodrugs therapeutic use, Structure-Activity Relationship, Tenofovir, Antineoplastic Agents therapeutic use, Antiviral Agents therapeutic use, Organophosphonates therapeutic use
- Abstract
The use of the acyclic nucleoside phosphonates, starting with (S)-HPMPA as the prototype, yielded three clinically approved antiviral drugs, cidofovir for the treatment of CMV retinitis in AIDS patients, adefovir dipivoxil for the treatment of chronic hepatitis B and tenofovir disoproxil fumarate for the treatment of HIV infections (AIDS) and HBV infections. This era has now grown to many more acyclic (and cyclic) nucleoside phosphonates (such as the "open ring" DAPy and Fd4A phosphonates) and alkoxyalkyl and phosphonoamidate prodrugs thereof, as well as new clinical applications, including new drug combination regimens for the treatment of AIDS, the chemoprophylaxis of HIV infections, and the anticancer potential against some malignant disorders., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
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48. Synthesis and antiviral activity of N9-[3-fluoro-2-(phosphonomethoxy)propyl] analogues derived from N6-substituted adenines and 2,6-diaminopurines.
- Author
-
Baszczyňski O, Jansa P, Dračínský M, Klepetářová B, Holý A, Votruba I, de Clercq E, Balzarini J, and Janeba Z
- Subjects
- 2-Aminopurine analogs & derivatives, 2-Aminopurine chemical synthesis, 2-Aminopurine chemistry, 2-Aminopurine pharmacology, 3T3 Cells, Adenine chemistry, Adenine pharmacology, Animals, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Antiviral Agents pharmacology, Cells, Cultured, Crystallography, X-Ray, Dose-Response Relationship, Drug, HIV-1 drug effects, HIV-2 drug effects, Humans, Mice, Mice, Inbred C3H, Moloney murine sarcoma virus drug effects, Organophosphonates chemical synthesis, Organophosphonates chemistry, Organophosphonates pharmacology, Purines chemistry, Purines pharmacology, Structure-Activity Relationship, Adenine analogs & derivatives, Adenine chemical synthesis, Purines chemical synthesis
- Abstract
An efficient method for the synthesis of N(9)-[3-fluoro-2-(phosphonomethoxy)propyl] (FPMP) derivatives of purine bases has been developed. Both (R)- and (S)-enantiomers of the N(6)-substituted FPMP derivatives of adenine and 2,6-diaminopurine were prepared and their anti-human immunodeficiency virus (HIV) and anti-Moloney murine sarcoma virus (MSV) activity was evaluated. Whereas none of the 6-substituted FPMPA derivatives showed any antiviral activity, several FPMPDAP derivatives had a moderate antiretroviral activity. Moreover, the data obtained from the study of the substrate activity of the active derivatives towards N(6)-methyl-AMP aminohydrolase support the notion that the studied N(6)-substituted FPMPDAP derivatives act as prodrugs of the antiretroviral FPMPG analogues., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
49. Hybrid diarylbenzopyrimidine non-nucleoside reverse transcriptase inhibitors as promising new leads for improved anti-HIV-1 chemotherapy.
- Author
-
Zeng ZS, He QQ, Liang YH, Feng XQ, Chen FE, De Clercq E, Balzarini J, and Pannecouque C
- Subjects
- Cell Line, Cell Survival drug effects, HIV Reverse Transcriptase antagonists & inhibitors, HIV Reverse Transcriptase chemistry, Humans, Models, Molecular, Nitriles, Protein Binding, Pyridazines chemistry, Pyridazines pharmacology, Pyrimidines, Quinazolines chemistry, Quinazolines pharmacology, Structure-Activity Relationship, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, HIV Infections drug therapy, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Molecular hybridization of the known anti-HIV-1 template DPC083 and etravirine based on docking model overlay has been generated a novel series of diarylbenzopyrimidine analogues (DABPs) (5a-z). These new hybrids were assessed for their activity against HIV in MT-4 cell cultures. Most of these compounds showed good activity against wild-type HIV-1 and mutant viruses. In particular, compound 5r showed the most potent activity against wild-type HIV-1 with an EC50 value of 1.8 nM, and with a selectivity index up to 111,954. It also proved more active against mutant L100I, K103N, Y188L, and K103N+Y181C RT HIV-1 strains than efavirenz., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
50. Synthesis and biological evaluation of 4-(hydroxyimino)arylmethyl diarylpyrimidine analogues as potential non-nucleoside reverse transcriptase inhibitors against HIV.
- Author
-
Feng XQ, Zeng ZS, Liang YH, Chen FE, Pannecouque C, Balzarini J, and De Clercq E
- Subjects
- Cell Line drug effects, Cell Survival drug effects, HIV-2 drug effects, Humans, Indicators and Reagents, Stereoisomerism, Structure-Activity Relationship, Anti-HIV Agents chemical synthesis, Anti-HIV Agents pharmacology, HIV-1 drug effects, HIV-1 enzymology, Pyrimidines chemical synthesis, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors pharmacology
- Abstract
A series of novel diarylpyrimidine analogues featuring a hydroxyiminomethyl group between the pyrimidine scaffold and the aryl wing I have been synthesized and tested in MT-4 cells culture as non-nucleoside reverse transcriptase inhibitors against human immunodeficiency virus (HIV). Most of these new congeners exhibited moderate to excellent activity against wild-type virus with an EC(50) value ranging from 0.569microM to 0.005microM. 4-(4-((Hydroxyimino) (3-methoxyphenyl)methyl)pyrimidin-2-ylamino)benzonitrile (12n) was identified as the most active compound of this new series (EC(50)=0.025microM, SI >1223) associated with moderate activity against HIV-1 double mutant strains (K103N+Y181C) (EC(50)=8.72microM) in addition to its anti-HIV-2 activity with an EC(50) value of 8.31microM. Preliminary structure-activity relationship (SAR) among the newly synthesized DAPYs was also investigated., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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