Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication

Andrew V Stachulski; Chandrakala Pidathala; Eleanor C Row; Raman Sharma; Neil G Berry; Alexandre S Lawrenson; Shelley L Moores; 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/jm201264t

Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication

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

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

41 Citations (Scopus)

Abstract

We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.

Original language	English
Pages (from-to)	8670-80
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	24
DOIs	https://doi.org/10.1021/jm201264t
Publication status	Published - 22 Dec 2011

Keywords

Amides
Antiviral Agents
Cell Line
Hepacivirus
Humans
Quantitative Structure-Activity Relationship
Thiazoles
Virus Replication

UN SDGs

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

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10.1021/jm201264t

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Stachulski, A. V., Pidathala, C., Row, E. C., Sharma, R., Berry, N. G., Lawrenson, A. S., Moores, S. L., 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. 2. Inhibition of hepatitis C virus replication. Journal of Medicinal Chemistry, 54(24), 8670-80. https://doi.org/10.1021/jm201264t

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title = "Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication",

abstract = "We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.",

keywords = "Amides, Antiviral Agents, Cell Line, Hepacivirus, Humans, Quantitative Structure-Activity Relationship, Thiazoles, Virus Replication",

author = "Stachulski, {Andrew V} and Chandrakala Pidathala and Row, {Eleanor C} and Raman Sharma and Berry, {Neil G} and Lawrenson, {Alexandre S} and Moores, {Shelley L} and Mazhar Iqbal and Joanne Bentley and Allman, {Sarah A} and Geoffrey Edwards and Alison Helm and Jennifer Hellier and Korba, {Brent E} and Semple, {J Edward} and Jean-Francois Rossignol",

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doi = "10.1021/jm201264t",

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Stachulski, AV, Pidathala, C, Row, EC, Sharma, R, Berry, NG, Lawrenson, AS, Moores, SL, Iqbal, M, Bentley, J, Allman, SA, Edwards, G, Helm, A, Hellier, J, Korba, BE, Semple, JE & Rossignol, J-F 2011, 'Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication', Journal of Medicinal Chemistry, vol. 54, no. 24, pp. 8670-80. https://doi.org/10.1021/jm201264t

TY - JOUR

T1 - Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication

AU - Stachulski, Andrew V

AU - Pidathala, Chandrakala

AU - Row, Eleanor C

AU - Sharma, Raman

AU - Berry, Neil G

AU - Lawrenson, Alexandre S

AU - Moores, Shelley L

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 - 2011/12/22

Y1 - 2011/12/22

N2 - We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.

AB - We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.

KW - Amides

KW - Antiviral Agents

KW - Cell Line

KW - Hepacivirus

KW - Humans

KW - Quantitative Structure-Activity Relationship

KW - Thiazoles

KW - Virus Replication

U2 - 10.1021/jm201264t

DO - 10.1021/jm201264t

M3 - Article

C2 - 22059983

SN - 0022-2623

VL - 54

SP - 8670

EP - 8680

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 24

ER -

Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication

Abstract

Keywords

UN SDGs

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