Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication

Andrew V Stachulski; Chandrakala Pidathala; Eleanor C Row; Raman Sharma; Neil G Berry; Mazhar Iqbal; Joanne Bentley; Sarah A Allman; Geoffrey Edwards; Alison Helm; Jennifer Hellier; Brent E Korba; J Edward Semple; Jean-Francois Rossignol

doi:10.1021/jm200153p

Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication

Andrew V Stachulski, Chandrakala Pidathala, Eleanor C Row, Raman Sharma, Neil G Berry, Mazhar Iqbal, Joanne Bentley, Sarah A Allman, Geoffrey Edwards, Alison Helm, Jennifer Hellier, Brent E Korba, J Edward Semple, Jean-Francois Rossignol

University of Liverpool

Research output: Contribution to journal › Article › peer-review

58 Citations (Scopus)

Abstract

We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 μm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.

Original language	English
Article number	N/A
Pages (from-to)	4119-4132
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	12
DOIs	https://doi.org/10.1021/jm200153p
Publication status	Published - 23 Jun 2011

Keywords

Amides
Animals
Antiviral Agents
Dogs
Glucuronides
Hep G2 Cells
Hepatitis B virus
Humans
Prodrugs
Quantitative Structure-Activity Relationship
Rats
Salicylamides
Thiazoles
Virion
Virus Replication

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/jm200153p

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Stachulski, A. V., Pidathala, C., Row, E. C., Sharma, R., Berry, N. G., Iqbal, M., Bentley, J., Allman, S. A., Edwards, G., Helm, A., Hellier, J., Korba, B. E., Semple, J. E., & Rossignol, J.-F. (2011). Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication. Journal of Medicinal Chemistry, 54(12), 4119-4132. Article N/A. https://doi.org/10.1021/jm200153p

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abstract = "We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 μm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.",

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AU - Stachulski, Andrew V

AU - Pidathala, Chandrakala

AU - Row, Eleanor C

AU - Sharma, Raman

AU - Berry, Neil G

AU - Iqbal, Mazhar

AU - Bentley, Joanne

AU - Allman, Sarah A

AU - Edwards, Geoffrey

AU - Helm, Alison

AU - Hellier, Jennifer

AU - Korba, Brent E

AU - Semple, J Edward

AU - Rossignol, Jean-Francois

PY - 2011/6/23

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N2 - We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 μm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.

AB - We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 μm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.

KW - Amides

KW - Animals

KW - Antiviral Agents

KW - Dogs

KW - Glucuronides

KW - Hep G2 Cells

KW - Hepatitis B virus

KW - Humans

KW - Prodrugs

KW - Quantitative Structure-Activity Relationship

KW - Rats

KW - Salicylamides

KW - Thiazoles

KW - Virion

KW - Virus Replication

U2 - 10.1021/jm200153p

DO - 10.1021/jm200153p

M3 - Article

C2 - 21553812

SN - 0022-2623

VL - 54

SP - 4119

EP - 4132

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 12

M1 - N/A

ER -

Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication

Abstract

Keywords

UN SDGs

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