Piperidinylethyl, Phenoxyethyl and Fluoroethyl Bromopyridyl Thiourea Compounds with Potent Anti-HIV Activity

2000 ◽  
Vol 11 (5) ◽  
pp. 329-336 ◽  
Author(s):  
TK Venkatachalam ◽  
Elise A Sudbeck ◽  
Chen Mao ◽  
Fatih M Uckun
Keyword(s):  
Reverse Transcriptase ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Phenyl Group ◽  
Piperidine Ring ◽  
Peripheral Blood Mononuclear ◽  
Thiourea Derivatives ◽  
Methyl Substitution ◽  
Anti Hiv ◽  
Hiv 1

Derivatives of piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thioureas were designed and synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT). The anti-HIV activity of these compounds was examined by determining their ability to inhibit the replication of the HIV-1 strain HTLVIIIB in human peripheral blood mononuclear cells. The unsubstituted parent pyridyl thiourea compound N-[2-(1-piperidine)ethyl]-N′-[2-(pyridyl)] thiourea (1) exhibited no anti-HIV activity, even at 100 μM. However, the thiourea derivatives that contain a bromo- or chloro-substituted pyridyl group, compounds 2 and 5, inhibited HIV-1 replication at nanomolar concentrations. The addition of a methyl group onto the piperidine ring significantly altered the potency of these compounds; while methyl substitution at the 3-position of the piperidine ring reduced the activity, methyl substitution at the 2-position enhanced the anti-HIV activity. The IC50 value of the lead piperidinyl compound, N-[2-(2-methylpiperidinylethyl)]-N′-[2-(5-bromopyridyl)] thiourea (4) was >0.001 μM. All three phenoxyethyl derivatives, including the unsubstituted parent phenoxyethyl pyridyl thiourea compound N-[2-(phenoxy)ethyl]-N-[2-(pyridyl)]thiourea (8) and the bromo-/chloro-substituted phenoxyethyl halopyridyl thiourea compounds N-[2-(phenoxy)ethyl]-N-[2-(5-chloropyridyl)]thiourea (9) and N-[2-(phenoxy)ethyl]-N-[2-(5-bromopyridyl)]thiourea (10) exhibited potent anti-HIV activity with nanomolar IC50 values. The corresponding fluoroethyl halopyridyl thiourea compounds β-fluoro[2-phenethyl]-N′[2-(5-chloropyridyl)]thiourea (11) and β-fluoro[2-phenethyl]-N′[2-(5-bromopyridyl)]thiourea (12) inhibited HIV-1 replication in PBMC with subnanomolar IC50 values and selectivity indices <30000. Compared to the corresponding phenoxyethyl thiourea compounds 9 and 10, these compounds were <4–5–fold more active as anti-HIV agents. Notably, the lead fluorothiourea compounds 11 and 12 were both substantially more active against the NNRTI-resistant HIV strains RT-MDR (V106A) and A17 (Y181C) than nevirapine or delavirdine. Taken together, our results provide additional experimental evidence that the structural features of the ‘linker unit” between the pyridyl and phenyl moieties and changes in the phenyl group of PETT-related thiourea compounds significantly affects their biological activity as NNRTIs of HIV-1 RT.

scholarly journals In Vitro Interactions between Apricitabine and Other Deoxycytidine Analogues

2007 ◽  
Vol 51 (8) ◽  
pp. 2948-2953 ◽  
Author(s):  
R. Bethell ◽  
J. De Muys ◽  
J. Lippens ◽  
A. Richard ◽  
B. Hamelin ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
High Performance ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Transcriptase Inhibitor ◽  
Reverse Transcriptase Activity ◽  
Peripheral Blood Mononuclear ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Apricitabine is phosphorylated to its active triphosphate by deoxycytidine kinase, which is also responsible for the intracellular phosphorylation of lamivudine (3TC) and emtricitabine (FTC); hence, in vitro studies were performed to investigate possible interactions between apricitabine and these agents. Human peripheral blood mononuclear cells (PBMC) were incubated for 24 h with various concentrations of 3H-labeled or unlabeled apricitabine, 3TC, or FTC. Intracellular concentrations of parent compounds and their phosphorylated derivatives were measured by high-performance liquid chromatography. In other experiments, viral reverse transcriptase activity was measured in PBMC infected with HIV-1 bearing M184V in the presence of various concentrations of apricitabine and 3TC. [3H]apricitabine and [3H]3TC were metabolized intracellularly to form mono-, di-, and triphosphates. 3TC and FTC (1 to 10 μM) produced concentration-dependent decreases in apricitabine phosphorylation; in contrast, apricitabine at concentrations of up to 30 μM had no effect on the phosphorylation of 3TC or FTC. The combination of apricitabine and 3TC reduced the antiviral activity of apricitabine against HIV-1: apricitabine concentrations producing 50% inhibition of viral reverse transcriptase were increased two- to fivefold in the presence of 3TC. These findings suggest that nucleoside reverse transcriptase inhibitors with similar modes of action may show biochemical interactions that affect their antiviral efficacy. It is therefore essential that potential interactions between combinations of new and existing agents be thoroughly investigated before such combinations are introduced into clinical practice.

scholarly journals Evaluation of PD 404,182 as an Anti-HIV and Anti-Herpes Simplex Virus Microbicide

2013 ◽  
Vol 58 (2) ◽  
pp. 687-697 ◽  
Author(s):  
Ana M. Chamoun-Emanuelli ◽  
Michael Bobardt ◽  
Bernard Moncla ◽  
Marie K. Mankowski ◽  
Roger G. Ptak ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
High Stability ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Synthetic Compound ◽  
Peripheral Blood Mononuclear ◽  
Simplex Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTPD 404,182 (PD) is a synthetic compound that was found to compromise HIV integrity via interaction with a nonenvelope protein viral structural component (A. M. Chamoun et al., Antimicrob. Agents Chemother. 56:672–681, 2012). The present study evaluates the potential of PD as an anti-HIV microbicide and establishes PD's virucidal activity toward another pathogen, herpes simplex virus (HSV). We show that the anti-HIV-1 50% inhibitory concentration (IC50) of PD, when diluted in seminal plasma, is ∼1 μM, similar to the IC50determined in cell culture growth medium, and that PD retains full anti-HIV-1 activity after incubation in cervical fluid at 37°C for at least 24 h. In addition, PD is nontoxic toward vaginal commensalLactobacillusspecies (50% cytotoxic concentration [CC50], >300 μM), freshly activated human peripheral blood mononuclear cells (CC50, ∼200 μM), and primary CD4+T cells, macrophages, and dendritic cells (CC50, >300 μM). PD also exhibited high stability in pH-adjusted Dulbecco's phosphate-buffered saline with little to no activity loss after 8 weeks at pH 4 and 42°C, indicating suitability for formulation for transportation and storage in developing countries. Finally, for the first time, we show that PD inactivates herpes simplex virus 1 (HSV-1) and HSV-2 at submicromolar concentrations. Due to the prevalence of HSV infection, the ability of PD to inactivate HSV may provide an additional incentive for use as a microbicide. The ability of PD to inactivate both HIV-1 and HSV, combined with its low toxicity and high stability, warrants additional studies for the evaluation of PD's microbicidal candidacy in animals and humans.

Effects of Aryl Substituents on the Anti-HIV Activity of the Arylphosphoramidate Derivatives of Stavudine

2002 ◽  
Vol 13 (3) ◽  
pp. 197-203 ◽  
Author(s):  
Fatih M Uckun ◽  
P Samuel ◽  
S Qazi ◽  
C Chen ◽  
S Pendergrass ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Peripheral Blood Mononuclear ◽  
Chemical Hydrolysis ◽  
Blood Mononuclear Cells ◽  
Alkaline Conditions ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

We compared the anti-HIV activity of 13 phenyl phosphate derivatives of stavudine (2′,3′-didehydro-2′,3′-dideoxythymidine/d4T) by examining their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells. Our results show that the introduction of electron-withdrawing substituents enhances the activity of these phosphoramidate derivatives. The rate of chemical hydrolysis under alkaline conditions (but not the lipophilicity) predicted the potency of the compounds.

scholarly journals Enhancement of Human Immunodeficiency Virus Type 1 Replication Is Not Intrinsic to All Polyanion-Based Microbicides

2009 ◽  
Vol 53 (8) ◽  
pp. 3565-3568 ◽  
Author(s):  
Secondo Sonza ◽  
Adam Johnson ◽  
David Tyssen ◽  
Tim Spelman ◽  
Gareth R. Lewis ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Sexual Transmission ◽  
Intrinsic Property ◽  
Enhancement Effect ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Polyanion-based microbicides have been developed to prevent the sexual transmission of human immunodeficiency virus (HIV). Recent data suggest that polyanions have the capacity to enhance HIV type 1 (HIV-1) replication at threshold antiviral concentrations. Evaluation of the microbicide candidates SPL7013 and PRO 2000 revealed no specific enhancement of two CCR5 HIV-1 strains in human peripheral blood mononuclear cells compared to enfuvirtide (Fuzeon). The enhancement effect is likely to be a function of the assay conditions and is not an intrinsic property of these polyanions.

scholarly journals Reverse Transcriptase Inhibitors as Potential Colorectal Microbicides

2009 ◽  
Vol 53 (5) ◽  
pp. 1797-1807 ◽  
Author(s):  
Carolina Herrera ◽  
Martin Cranage ◽  
Ian McGowan ◽  
Peter Anton ◽  
Robin J. Shattock
Keyword(s):  
Reverse Transcriptase ◽  
Rational Design ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Single Point ◽  
Point Mutations ◽  
Peripheral Blood Mononuclear ◽  
Rectal Microbicides ◽  
The Individual ◽  
Hiv 1

ABSTRACT We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.

scholarly journals N-[2-(4-Methylphenyl)Ethyl]-N′-[2-(5-Bromopyridyl)]-Thiourea as a Potent Inhibitor of NNRTI-Resistant and Multidrug-Resistant Human Immunodeficiency Virus Type 1

2000 ◽  
Vol 11 (2) ◽  
pp. 135-140 ◽  
Author(s):  
Fatih M Uckun ◽  
Chen Mao ◽  
Sharon Pendergrass ◽  
Danielle Maher ◽  
Dan Zhu ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Binding Pocket ◽  
Transcriptase Inhibitor ◽  
Multidrug Resistant ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

The composite non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket model was used to study a number of thiourea analogues with different substitutions at the 4-phenyl position including N-[2-(4-methylphenyl)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea (compound HI-244), which inhibited recombinant RT better than trovirdine or compound HI-275 with an unsubstituted phenyl ring. HI-244 effectively inhibited the replication of HIV-1 strain HTLVIIIB in human peripheral blood mononuclear cells with an IC50 value of 0.007 μM, which is equal to the IC50 value of trovirdine. Notably, HI-244 was 20 times more effective than trovirdine against the multidrug-resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74 V, 41L and 215Y) and seven times more potent than trovirdine against the NNRTI- resistant HIV-1 strain A17 with a Y181C mutation.

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