Thiourea inhibitors of herpes viruses. Part 2: N-Benzyl-N′-arylthiourea inhibitors of CMV

Bloom, Jonathan D.; Dushin, Russell G.; Curran, Kevin J.; Donahue, Fran; Norton, Emily B.; Terefenko, Eugene A.; Jones, Thomas R.; Ross, Adma A.; Feld, Boris; Lang, Stanley A.; DiGrandi, Martin J.

doi:10.1016/j.bmcl.2004.04.093

Cited by 62 publications

(32 citation statements)

References 7 publications

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“…The bis-(aryl)thiourea inhibitor WY1768 is a potent inhibitor of HCMV fusion in FBs (3,33) and retains its activity on VR1814 strain infections of ECs (50% infective dose in ECs, 1.96 Ϯ 0.06 nM [mean Ϯ standard deviation {SD}; n ϭ 4] [data not shown]), suggesting that the affected mechanism is essential for HCMV entry in both cell types. When the lipid mixing assay was performed in the presence of 2 M WY1768, the VR1814 virus failed to transfer R18 fluorescence to either ECs or HELFs.…”

Section: Resultsmentioning

confidence: 99%

Cytomegalovirus UL131-128 Products Promote gB Conformational Transition and gB-gH Interaction during Entry into Endothelial Cells

Patrone

Secchi

Bonaparte

et al. 2007

J Virol

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Herpesviruses use gB and gH-gL glycoproteins to execute fusion. Other virus-specific glycoproteins are required for receptor binding and fusion activation. The human cytomegalovirus (HCMV) UL131-128 proteins are essential for the infection of leukocytes, endothelial cells (ECs), and many epithelial cell lines. Here we show that UL131-128 play a role in a chain of events involving gB and gH during HCMV entry into ECs. An HCMV strain bearing the wild-type (wt) UL131-128 locus exhibited a gB transition from a protease-resistant to protease-sensitive form, a conformational change that was suppressed by a thiourea inhibitor of fusion (WY1768); in contrast, gH was susceptible to proteolysis throughout entry. Moreover, gB and gH transiently interacted, and a lipid mixing assay showed that the wt strain had carried out fusion by 60 min postinfection. However, these events were greatly altered when UL131-128-defective strains were used for infection or when there was an excess of soluble pUL128 during wt infection: the gB conformational change became WY1768 resistant, the gB-gH complex was no longer observed, and fusion was prevented. Both gB and gH in this case showed late protease resistance, related to their endocytic uptake. Our data point to the involvement of UL131-128 proteins in driving gB through a WY1768-sensitive fold transition, thus promoting a short-lived gB-gH complex and fusion; they also suggest that HCMV fuses with the EC plasma membrane and that endocytosis ensues only when the virus cannot trigger UL131-128-dependent steps.Human cytomegalovirus (HCMV), the prototypical member of the Betaherpesvirinae subfamily, is the leading infectious cause of congenital defects, a major opportunist in transplant recipients and immunocompromised patients, and a suspected cofactor for cardiovascular diseases, systemic sclerosis, and gastrointestinal cancer (7,27,29,41,42,49). Clinical isolates of HCMV infect various cell types in vitro, including endothelial cells (ECs), thus replicating the broad cell type tropism observed in HCMV infections of immunocompromised subjects (EC-tropic strains). However, laboratory propagation in fibroblasts (FBs) restricts viral tropism (FB-tropic strains), and mutations causing the loss of tropism for ECs, epithelial cells, polymorphonuclear leukocytes, and dendritic cells (DCs) have been mapped to the contiguous UL131, UL130, and UL128 open reading frames (ORFs) (13,25,18,56).There is considerable indirect evidence indicating that UL131-128 proteins act as regulators of virus-cell fusion: (i) FB-tropic strains fail to transfer tegument pp65-UL83 protein to EC nuclei (18), which suggests that infection stops before virus uncoating; (ii) an HCMV deletion mutant lacking the UL128-UL150 ORFs infects retinal pigment epithelial cells after exposure to polyethylene glycol in order to force fusion between viral and cellular membranes (50); and (iii) EC-tropic strains are syncytiogenic at a high multiplicity of infection (18,56).The membrane-spanning glycoproteins gB and gH and the soluble gL...

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Section: Resultsmentioning

confidence: 99%

Cytomegalovirus UL131-128 Products Promote gB Conformational Transition and gB-gH Interaction during Entry into Endothelial Cells

Patrone

Secchi

Bonaparte

et al. 2007

J Virol

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“…Some thiourea compounds were reported to be non-nucleoside inhibitors (NNIs) of the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV) [1]. High throughput screening studies revealed that certain bis(aryl)thioureas carrying an amide functionality, as exemplified by the structure shown below, could be considered as inhibitors of herpes viruses such as HSV, CMV and VZV [2]. In addition, some thiourea derivatives were reported to be potent inhibitors of influenza virus neuraminidase, Coxsackie virus B4 and thymidine kinase positive varicella-zoster virus (TK þ VZV, OKA strain) [3,4].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antiviral and anticancer activity of some novel thioureas derivedfrom N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide

Karakuş

Küçükgüzel

et al. 2009

European Journal of Medicinal Chemistry

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“…[1][2][3][4] Numerous compounds containing thiourea group are selective ligands for 5-HT family receptors, including 5-HT 2A , 5-HT 2B and 5-HT 2C . [5][6][7][8][9] The drug-elicited head twitch response (HTR) 10,11) is a selective behavioral model for 5-HT 2 agonist activity in rodents, and several previous studies have established that direct and indirect 5-HT agonists induce this effect.12-19) Additionally, 5-HT 2 receptor antagonists selectively block HTR, [19][20][21] and their potency is highly correlated with the antagonist's affinity for 5-HT 2 receptors. …”

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confidence: 99%

“…Chemistry The preparation of new nineteen thiourea and urea derivatives of 10-isopropyl-8-methyl-4-azatricyclo[5.2.2.0 2,6 ]undec-8-ene-3,5-dione, 1-isopropyl-7-methyl-4-azatricyclo[5.2.2.0 2,6 ]undec-8-ene-3,5-dione and 1,7,8,9,10-pentamethyl-4-azatricyclo[5.2.1.0 2,6 ]dec-8-ene-3,5-dione (Chart 1) is described.…”

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confidence: 99%

“…10-Isopropyl-8-methyl-4-azatricyclo-[5.2.2.0 2,6 ]undec-8-ene-3,5-dione was obtained in reaction of enantiomeric (R)-(Ϫ)-a-phellandrene with pyrrole-2,5-dione, 23) 1-isopropyl-7-methyl-4-azatricyclo[5.2.2.0 2,6 ]undec-8-ene-3,5-dione in reaction of a-terpinene with pyrrole-2,5-dione 23) and 1,7,8,9,10-pentamethyl-4-azatricyclo[5.2.1.0 2,6 ]-dec-8-ene-3,5-dione in reaction 1,2,3,4,5-pentamethylcyclopentadiene with pyrrole-2,5-dione. 24) The obtained tricyclic imides reacted with hydrazine (80% aqueous solution).…”

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confidence: 99%

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Synthesis and Pharmacological Activity of Urea and Thiourea Derivatives of 4-Azatricyclo[5.2.2.0<sup>2,6</sup>]undec-8-ene-3,5-dione

Struga¹,

Kossakowski²,

Kędzierska

et al. 2007

Chem. Pharm. Bull.

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Thiourea and urea derivatives show a broad spectrum of biological activities as anti-HIV, antiviral, HDL-elevating, antibacterial, analgesic properties. [1][2][3][4] Numerous compounds containing thiourea group are selective ligands for 5-HT family receptors, including 5-HT 2A , 5-HT 2B and 5-HT 2C . [5][6][7][8][9] The drug-elicited head twitch response (HTR) 10,11) is a selective behavioral model for 5-HT 2 agonist activity in rodents, and several previous studies have established that direct and indirect 5-HT agonists induce this effect.12-19) Additionally, 5-HT 2 receptor antagonists selectively block HTR, [19][20][21] and their potency is highly correlated with the antagonist's affinity for 5-HT 2 receptors. 12,22)Here we report the synthesis of compounds h2, h2a, d2, d2a, k2, k2a-h4, h4a, d4, d4a, k4, k4a which composed of thiourea or urea system attached to policyclic imide.Chemistry The preparation of new nineteen thiourea and urea derivatives of 10-isopropyl-8-methyl-4-azatricyclo[5.2.2.0 2,6 ]undec-8-ene-3,5-dione, 1-isopropyl-7-methyl-4-azatricyclo[5.2.2.0 2,6 ]undec-8-ene-3, 5-dione and 1,7,8,9,10-pentamethyl-4-azatricyclo[5.2.1.0 2,6 ]dec-8-ene-3,5-dione (Chart 1) is described.Imides obtained in Diels-Alder reaction were used as starting material. 10-Isopropyl-8-methyl-4-azatricyclo- ]-dec-8-ene-3,5-dione in reaction 1,2,3,4,5-pentamethylcyclopentadiene with pyrrole-2,5-dione. 24)The obtained tricyclic imides reacted with hydrazine (80% aqueous solution). Afterwards the compounds were subjected to the reaction with phenyl, 4-methoxyphenyl, cyclohexyl isocyanate or isothiocyanate in order to be transformed into the corresponding urea or thiourea derivatives.All final compounds were characterized by 1 H-NMR spectra which corresponded with the proposed structures.The general synthetic pathway is given in Chart 1. Pharmacology Acute toxicity of tested compound was lower than 2000 mg/kg i.p. and therefore LD 50 ϭ2000 mg/kg was accepted for the continuation of the studies. Spontaneous motor activity, amphetamine-induced hyperactivity, motor coordination and body temperature, were not changed by k1a. This compound did not protect from clonic seizures and tonic convulsions evoked by pentetrazole and from abdominal constriction induced by i.p. administration of the acetic acid solution.Only the head-twitch responses to 5-HTP were significantly decreased by 77.88% ( pϽ0.05), from 14.13Ϯ4.24 to 3.125Ϯ1.007, by k1a (Fig. 1). The result seems to point out some connection with 5-HT the system. Since it appears that head shakes induced by 5-HTP are mediated by 5-HT 2 recep- Chart 1. Synthesis of the Obtained Compounds h2, h2a, d2, d2a, k2, k2a-h4, h4a, d4, d4a, k4, k4a

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Thiourea inhibitors of herpes viruses. Part 2: N-Benzyl-N′-arylthiourea inhibitors of CMV

Cited by 62 publications

References 7 publications

Cytomegalovirus UL131-128 Products Promote gB Conformational Transition and gB-gH Interaction during Entry into Endothelial Cells

Cytomegalovirus UL131-128 Products Promote gB Conformational Transition and gB-gH Interaction during Entry into Endothelial Cells

Synthesis, antiviral and anticancer activity of some novel thioureas derivedfrom N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide

Synthesis and Pharmacological Activity of Urea and Thiourea Derivatives of 4-Azatricyclo[5.2.2.0<sup>2,6</sup>]undec-8-ene-3,5-dione

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