Synthesis and Antiviral Activity of 1,3-Disubstituted Uracils against HIV-1 and HCMV

2003 ◽  
Vol 14 (5) ◽  
pp. 271-279 ◽  
Author(s):  
Tokumi Maruyama ◽  
Shigetada Kozai ◽  
Tetsuo Yamasaki ◽  
Myriam Witvrouw ◽  
Christophe Pannecouque ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Human Cytomegalovirus ◽  
Therapeutic Agents ◽  
Reverse Transcriptase Inhibitors ◽  
Uracil Derivatives ◽  
Immunodeficiency Virus ◽  
Anti Hiv Agents ◽  
Anti Hiv ◽  
Hiv 1

The development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) is an efficient strategy for finding new therapeutic agents against human immunodeficiency virus (HIV). A large number of 6-substituted uracil derivatives have been prepared in order to explore new NNRTIs. However, there are few approaches to anti-HIV agents from 1,3-disubstituted uracil derivatives. Therefore, we tried to prepare several 1,3-disubstituted uracils, which were easily obtainable from uracil by preparation under alkali and Mitsunobu conditions, and examined their antiviral activity against HIV-1 and human cytomegalovirus (HCMV). We found that 1-benzyl-3-(3,5-dimethylbenzyl)uracil and 1-cyanomethyl-3-(3,5-dimethylbenzyl)-4-thiouracil showed powerful inhibition against HCMV and HIV-1, respectively.

scholarly journals In Vitro Antiviral Activity of the Novel, Tyrosyl-Based Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor Brecanavir (GW640385) in Combination with Other Antiretrovirals and against a Panel of Protease Inhibitor-Resistant HIV

2007 ◽  
Vol 51 (9) ◽  
pp. 3147-3154 ◽  
Author(s):  
Richard Hazen ◽  
Robert Harvey ◽  
Robert Ferris ◽  
Charles Craig ◽  
Phillip Yates ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Reverse Transcriptase ◽  
In Vitro Assays ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC50s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC50s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC50s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro.

scholarly journals Synthesis and Evaluation of Some Symmetrical Phosphate Dimer Derivatives of 3′-Modified Nucleosides as Potential anti-HIV Agents

1996 ◽  
Vol 7 (6) ◽  
pp. 330-337 ◽  
Author(s):  
C. McGuigan ◽  
H.-W. Tsang ◽  
N. Mahmood ◽  
A. J. Hay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Analytical Data ◽  
Modified Nucleosides ◽  
Nucleoside Analogues ◽  
Immunodeficiency Virus ◽  
Anti Hiv Agents ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

Novel symmetrical nucIeotide-(5′,5′)-dimers of 3′-O-acetylthymidine, 3′-O-methylthymidine, 3′-O-ethylthymidine, 3′-O-n-propylthymidine and 3′-azido-3′-deoxythymidine (AZT) were synthesized as membrane soluble pro-drugs. These were prepared using phosphorodichloridate chemistry and were characterised by spectroscopic and analytical data. In-vitro evaluation of the derivatives in cells acutely infected with the human immunodeficiency virus (HIV-1) demonstrated a range of activities. These derivatives were generally found to display poor inhibition of HIV proliferation. Derivatives containing AZT moieties were found to be potent, but such compounds were less active than the parent nucleoside. The data indicated that the AZT-containing compounds act primarily via the release of the free nucleoside. However, in some cases, the dimers of certain inactive nucleoside analogues were found to be active. In these cases, release of the nucleoside alone cannot account for the activity.

scholarly journals 1,1,3-Trioxo-2H,4H-Thieno[3,4-e][1,2,4]Thiadiazine (TTD) Derivatives: a New Class of Nonnucleoside Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase Inhibitors with Anti-HIV-1 Activity

1998 ◽  
Vol 42 (3) ◽  
pp. 618-623 ◽  
Author(s):  
M. Witvrouw ◽  
M. E. Arranz ◽  
C. Pannecouque ◽  
R. Declercq ◽  
H. Jonckheere ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Host Cells ◽  
Cross Resistance ◽  
Reverse Transcriptase Inhibitors ◽  
Relationship Analysis ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT We report the development of a new group of nonnucleoside reverse transcriptase inhibitors (NNRTIs). One of the most active congeners of this series of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (TTD) derivatives, i.e., 2-(3-fluorobenzyl)-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine) (QM96639) was found to inhibit human immunodeficiency virus (HIV) type 1 [HIV-1 (IIIB)] replication in MT-4 cells at a concentration of 0.09 μM. This compound was toxic for the host cells only at a 1,400-fold higher concentration. The TTD derivatives proved effective against a variety of HIV-1 strains, including those that are resistant to 3′-azido-3′-deoxythymidine (AZT), but not against HIV-2 (ROD) or simian immunodeficiency virus (SIV/MAC251). HIV-1 strains containing the L100I, K103N, V106A, E138K, Y181C, or Y188H mutations in their reverse transcriptase (RT) displayed reduced sensitivity to the compounds. Their cross-resistance patterns correlated with that of nevirapine. 2-Benzyl-4-cyanomethylen-1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (QM96521) enhanced the anti-HIV-1 activity of AZT and didanosine in a subsynergistic manner. HIV-1-resistant virus containing the V179D mutation in the RT was selected after approximately six passages of HIV-1 (IIIB) in CEM cells in the presence of different concentrations of QM96521. From structure-activity relationship analysis of a wide variety of TTD derivatives, a number of restrictions appeared as to the chemical modifications that were compatible with anti-HIV activity. Modelling studies suggest that in contrast to most other NNRTIs, but akin to nevirapine, QM96521 does not act as a hydrogen bond donor in the RT-drug complex.

3-Hydroxyphthaloyl-β-Lactoglobulin. I. Optimization of Production and Comparison with other Compounds Considered for Chemoprophylaxis of Mucosally Transmitted Human Immunodeficiency Virus Type 1

1997 ◽  
Vol 8 (2) ◽  
pp. 131-139 ◽  
Author(s):  
AR Neurath ◽  
AK Debnath ◽  
N Strick ◽  
Y-Y Li ◽  
K Lin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Chemical Modification ◽  
Elevated Temperatures ◽  
Sexual Transmission ◽  
Immunodeficiency Virus ◽  
Sexual Transmission Of Hiv ◽  
Β Lactoglobulin ◽  
Anti Hiv ◽  
Hiv 1

Modification of the major bovine whey protein, β-lactoglobulin (β-LG) by 3-hydroxyphthalic anhydride (3HP) leads to the generation of a potent inhibitor of infection by human immunodeficiency virus (HIV) types 1 and 2, designated 3HP-β-LG. 3HP-β-LG also has antiviral activity against herpesviruses, albeit at concentrations exceeding those required for inhibition of HIV-1 infection. The topical application of 3HP-β-LG to decrease the rate of sexual transmission of HIV and other sexually transmitted viruses worldwide is being considered. Results presented here: (i) define the conditions for chemical modification of β-LG by 3HP, resulting in 3HP-β-LG with optimum anti-HIV-1 activity; (ii) show that β-LG, prior to chemical modification, or 3HP-β-LG can be exposed to the elevated temperatures used to pasteurize milk without adversely affecting anti-HIV-1 activity; (iii) provide evidence that 3HP-β-LG is a more potent anti-HIV-1 compound than sulphated polysaccharides, other candidate compounds considered as prophylactic agents to prevent sexual transmission of HIV-1; and (iv) confirm that the primary target for 3HP-β-LG is CD4, although binding to the HIV-1 envelope protein gp120 was also observed and contributed to the antiviral activity of 3HP-β-LG.

scholarly journals Preclinical Evaluation of GS-9160, a Novel Inhibitor of Human Immunodeficiency Virus Type 1 Integrase

2008 ◽  
Vol 53 (3) ◽  
pp. 1194-1203 ◽  
Author(s):  
Gregg S. Jones ◽  
Fang Yu ◽  
Ameneh Zeynalzadegan ◽  
Joseph Hesselgesser ◽  
Xiaowu Chen ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Reverse Transcriptase Inhibitors ◽  
Single Mutant ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT GS-9160 is a novel and potent inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN) that specifically targets the process of strand transfer. It is an authentic inhibitor of HIV-1 integration, since treatment of infected cells results in an elevation of two-long terminal repeat circles and a decrease of integration junctions. GS-9160 has potent and selective antiviral activity in primary human T lymphocytes producing a 50% effective concentration (EC50) of ∼2 nM, with a selectivity index (50% cytotoxic concentration/EC50) of ∼2,000. The antiviral potency of GS-9160 decreased by 6- to 10-fold in the presence of human serum. The antiviral activity of GS-9160 is synergistic in combination with representatives from three different classes of antiviral drugs, namely HIV-1 protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors. Viral resistance selections performed with GS-9160 yielded a novel pattern of mutations within the catalytic core domain of IN; E92V emerged initially, followed by L74M. While E92V as a single mutant conferred 12-fold resistance against GS-9160, L74M had no effect as a single mutant. Together, these mutations conferred 67-fold resistance to GS-9160, indicating that L74M may potentiate the resistance caused by E92V. The pharmacokinetic profile of GS-9160 in healthy human volunteers revealed that once-daily dosing was not likely to achieve antiviral efficacy; hence, the clinical development of this compound was discontinued.

Human Immunodeficiency Virus Resistance to AZT in MOLT4/8 Cells is Associated with a Lack of AZT Phosphorylation and is Bypassed by AZT-Monophosphate SATE Prodrugs

1997 ◽  
Vol 8 (4) ◽  
pp. 343-352 ◽  
Author(s):  
J Cinatl ◽  
B Gröschel ◽  
R Zehner ◽  
J Cinatl ◽  
C Périgaud ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Virus Resistance ◽  
Intracellular Accumulation ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Mdr 1 ◽  
Hiv 1 ◽  
Resistant Cells

Human T lymphoid MOLT4/8 cells were grown continuously for more than 2 years in a medium containing 3′-azido-2′,3′-dideoxythymidine (zidovudine; AZT) at a concentration of 250 μM. These cells, designated MOLT-4/8rAZT250, were used to test the cytotoxic and antiviral activity of AZT. Intracellular accumulation of AZT, expression of the multidrug resistance 1 (MDR-1) gene, thymidine kinase (TK) gene and activity of the TK enzyme in cellular extracts were measured. The results showed that both the cytotoxic and antiviral activity of AZT were significantly lower in MOLT4/8rAZT250 than in MOLT4/8 cells; concentrations required to inhibit 50% production of the p24 human immunodeficiency virus type 1 (HIV-1) antigen of two laboratory strains were at least 100-fold higher in resistant cells. The MDR-1 gene was not expressed in the resistant cells. TK mRNA expression was significantly lower in the resistant than in the sensitive cells. TK enzymatic activity for deoxythymidine phosphorylation was impaired in MOLT4/8rAZT250 cells compared to the sensitive cells. AZT was phosphorylated only in the sensitive cells whereas no phosphorylation of AZT was found in the resistant cells. We tested whether several AZT-monophosphate triesters, which bypass cellular TK, could overcome resistance to the cytotoxic and antiviral activity of AZT. The bis( t-butylSATE) phosphotriester derivative of AZT showed comparable cytotoxic and antiviral activity in sensitive and resistant cells. The results demonstrated that MOLT4/8rAZT250 cells exert resistance to the anti-HIV activity of the drug mainly owing to the lack of AZT phosphorylation and that resistance may be bypassed by using AZT-monophosphate SATE prodrugs.

scholarly journals Newly Designed Six-Membered Azasugar Nucleotide-Containing Phosphorothioate Oligonucleotides as Potent Human Immunodeficiency Virus Type 1 Inhibitors

2005 ◽  
Vol 49 (10) ◽  
pp. 4110-4120 ◽  
Author(s):  
Dong-Seong Lee ◽  
Kyeong-Eun Jung ◽  
Cheol-Hee Yoon ◽  
Hong Lim ◽  
Yong-Soo Bae
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Broad Spectrum ◽  
Mononuclear Cells ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT A series of modified oligonucleotides (ONs), characterized by a phosphorothioate (P═S) backbone and a six-membered azasugar (6-AZS) as a sugar substitute in a nucleotide, were newly synthesized and assessed for their ability to inhibit human immunodeficiency virus type 1 (HIV-1) via simple treatment of HIV-1-infected cultures, without any transfection process. While unmodified P═S ONs exhibited only minor anti-HIV-1 activity, the six-membered azasugar nucleotide (6-AZN)-containing P═S oligonucleotides (AZPSONs) exhibited remarkable antiviral activity against HIV-1/simian-human immunodeficiency virus (SHIV) replication and syncytium formation (50% effective concentration = 0.02 to 0.2 μM). The AZPSONs exhibited little cytotoxicity at concentrations of up to 100 μM. DBM 2198, one of the most effective AZPSONs, exhibited antiviral activity against a broad spectrum of HIV-1, including T-cell-tropic, monotropic, and even drug-resistant HIV-1 variants. The anti-HIV-1 activities of DBM 2198 were similarly maintained in HIV-1-infected cultures of peripheral blood mononuclear cells. When we treated severely infected cultures with DBM 2198, syncytia disappeared completely within 2 days. Taken together, our results indicate that DBM 2198 and other AZPSONs may prove useful in the further development of safe and effective AIDS-therapeutic drugs against a broad spectrum of HIV-1 variants.

scholarly journals Anti-Human Immunodeficiency Virus Interactions of SCH-C (SCH 351125), a CCR5 Antagonist, with Other Antiretroviral Agents In Vitro

2002 ◽  
Vol 46 (5) ◽  
pp. 1336-1339 ◽  
Author(s):  
Cécile L. Tremblay ◽  
Françoise Giguel ◽  
Christopher Kollmann ◽  
Yongbiao Guan ◽  
Ting-Chao Chou ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Protease Inhibitors ◽  
Reverse Transcriptase Inhibitors ◽  
Antiretroviral Agents ◽  
Synergistic Interactions ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT SCH-C (SCH 351125) is a small-molecule antagonist of the human immunodeficiency virus type 1(HIV-1) coreceptor CCR5. It has in vitro activity against R5 viruses with 50% inhibitory concentrations ranging from 1.0 to 30.9 nM. We have studied anti-HIV-1 interactions of SCH-C with other antiretroviral agents in vitro. Synergistic interactions were seen with nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine), nonnucleoside reverse transcriptase inhibitors (efavirenz), and protease inhibitors (indinavir) at all inhibitory concentrations evaluated. We have also studied antiviral interactions between the HIV-1 fusion inhibitor T-20 and SCH-C against a panel of R5 HIV-1 isolates. We found synergistic interactions against all the viruses tested, some of which harbored resistance mutations to reverse transcriptase and protease inhibitors. Anti-HIV-1 synergy was also observed between SCH-C and another R5 virus inhibitor, aminooxypentane-RANTES. These findings suggest that SCH-C may be a useful anti-HIV drug in combination regimens and that a combination of chemokine coreceptor/fusion inhibitors may be useful in the treatment of multidrug-resistant viruses.

Design, Synthesis and Antiviral Activity of New Pyridinone Derivatives

1997 ◽  
Vol 8 (2) ◽  
pp. 161-172 ◽  
Author(s):  
F Jourdan ◽  
J Renault ◽  
C Fossey ◽  
R Bureau ◽  
D Ladurée ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Hybrid Structure ◽  
Design Synthesis ◽  
Structural Correlation ◽  
Immunodeficiency Virus ◽  
Structural And Electronic Properties ◽  
Anti Hiv ◽  
Hiv 1

A molecular modelling study was carried out in order to compare the structural and electronic properties of the pyridinone L-696,229 and the HEPT derivative EBPU. This comparison led to a hybrid structure, 3-(benzyloxymethyl)-5-ethyl-6-methylpyridin-2-one [18a], which revealed a good structural correlation with the models. A series of 2-[(arylmethyl)oxymethyl]pyridin-2-ones related to [18a] was synthesized and tested for antiviral activity against human immunodeficiency virus type 1 (HIV-1). Compound [18a] and four other derivatives showed anti-HIV-1 activity.

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