5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors

Arasappan, Ashok; Bennett, Frank; Girijavallabhan, Vinay; Huang, Yuhua; Huelgas, Regina; Álvarez, Carmen; Chen, Lei; Gavalas, Stephen; Kim, Seong‐Heon; Kosinski, Aneta; Pinto, Patrick; Rizvi, Razia; Rossman, Randall; Shankar, B. B.; Tong, Ling; Velázquez, Francisco; Venkatraman, Srikanth; Verma, Vishal; Kozlowski, Joseph A.; Shih, Neng‐Yang; Piwinski, John J.; MacCoss, Malcolm; Kwong, Cecil D.; Clark, Jeremy L.; Fowler, Anita T.; Geng, Feng; Kezar, Hollis S.; Roychowdhury, Abhijit; Reynolds, Robert C.; Maddry, Joseph A.; Ananthan, Subramaniam; Secrist, John A.; Li, Cheng; Chase, Robert A.; Curry, Stephanie; Huang, Hsiao‐Ching; Tong, Xiao; Njoroge, F. George

doi:10.1016/j.bmcl.2012.03.036

Cited by 13 publications

(5 citation statements)

References 12 publications

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“…The C-2 position resulted in identification of compound (131) very good replicon potency, selectivity and rodent plasma/target organ concentration. Compound (131) also displayed good plasma level concentrations and oral bioavailability in dogs [165]. The pyridothiazole group replacement by BTA moiety, these modifications led to yield compounds (132,133) which displayed good potency and selectivity profiles while demonstrating good PK in multiple animal species [166].…”

Section: Bta As Hepatitis C Virus (Hcv) Inhibitorsmentioning

confidence: 97%

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Keri

Patil

et al. 2015

European Journal of Medicinal Chemistry

466

238

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Section: Bta As Hepatitis C Virus (Hcv) Inhibitorsmentioning

confidence: 97%

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Keri

Patil

et al. 2015

European Journal of Medicinal Chemistry

466

238

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“…Furthermore, pyrimidine substituted with benzothiazole inhibited the growth of various viral cells and enzymes, Figure . Compound B showed optimal inhibition against HCV with a low EC 50 value and selectivity index greater than 550 . Additionally, with low IC 50 and high CC 50 values, compounds C and D demonstrated remarkable viral reduction in the range of 70 to 90% and inhibitory activity against the Hsp90α protein with IC 50 comparable to acyclovir, as a standard drug, Figure .…”

Section: Introductionmentioning

confidence: 92%

“…Compound B showed optimal inhibition against HCV with a low EC 50 value and selectivity index greater than 550. 17 Additionally, with low IC 50 and high CC 50 values, compounds C and D demonstrated remarkable viral reduction in the range of 70 to 90% and inhibitory activity against the Hsp90α protein with IC 50 comparable to acyclovir, as a standard drug, 18 Figure 2 . Moreover, the thiophene ring and its derivatives are considered to be one of the most significant types of heterocyclic molecules with remarkable applications in the field of medicinal chemistry.…”

Section: Introductionmentioning

confidence: 99%

Novel Thiophene Thioglycosides Substituted with the Benzothiazole Moiety: Synthesis, Characterization, Antiviral and Anticancer Evaluations, and NS3/4A and USP7 Enzyme Inhibitions

2022

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Novel derivatives of benzothiazole-2-thiophene Sglycoside were synthesized and tested for their antiviral and anticancer potency and NS3/4A and USP7 enzyme inhibitions. The ring system was formed by first synthesizing new derivatives of 5-mercaptothiophene substituted with the benzothiazole moiety, followed by coupling with various halo sugar derivatives. New compounds were tested in vitro for the cytotoxic effect on five types of normal cell lines and for antiviral activity using a plaque reduction assay against CBV4, HSV-1, HCVcc genotype 4 viruses, HAV HM 175, and HAdV7. Notably, three compounds demonstrated substantial IC 50 , CC 50 , and SI values against HSV-1 with a viral reduction of 80% or more. Two substances have demonstrated a reduction of more than 50% in CBV4 and HCVcc viruses. The effectiveness of the compounds against HSV-1 and HCVcc was tested for their capability to inhibit NS3/4A protease and USP7 enzyme. Additionally, a panel of 60 human cancer cells was used to investigate the ability of the newly synthesized compounds to inhibit the in vitro tumor growth. The results revealed that two compounds, 6a and 6c, have an inhibitory effect on most cancer types, whereas 6d and 6f inhibited only three and two cell lines, respectively.

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“…The 4-methyl derivative emerged with enhanced rat in vivo profile demonstrating a very good replicon potency, selectivity and rodent plasma/target organ concentration. [43] Further, introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor, resulted in the discovery of more potent pyridothiazole analogues (19) ( Figure 7). [44] HCV replicon inhibitors HCV replication in cell lines was practically impossible before the development of subgenomic replicons which replicate freely in the human hepatoma cell line Huh-7.…”

Section: Hcv Ns3 Helicase Inhibitorsmentioning

confidence: 99%

Benzothiazoles as potential antiviral agents

Asiri

Alsayari

Muhsinah

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives The recent viral pandemic poses a unique challenge for healthcare providers. Despite the remarkable progress, the number of novel antiviral agents in the pipeline is woefully inadequate against the evolving virulence and drug resistance of current viruses. This highlights the urgent need for new and improved vaccines, diagnostics and therapeutic agents to obviate the viral pandemic. Key findings Benzothiazole plays a pivotal role in the design and development of antiviral drugs. This is evident from the fact that it comprises many clinically useful agents. The current review is aimed to provide an insight into the recent development of benzothiazole-based antiviral agents, with a special focus on their structure-activity relationships and lead optimisation. One hundred and five articles were initially identified, and from these studies, 64 potential novel lead molecules and main findings were highlighted in this review. Summary We hope this review will provide a logical perspective on the importance of improving the future designs of novel broad-spectrum benzothiazolebased antiviral agents to be used against emerging viral diseases. Benzothiazoles as antiviral agents Yahya I. Asiri et al.

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5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors

Cited by 13 publications

References 12 publications

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

Novel Thiophene Thioglycosides Substituted with the Benzothiazole Moiety: Synthesis, Characterization, Antiviral and Anticancer Evaluations, and NS3/4A and USP7 Enzyme Inhibitions

Benzothiazoles as potential antiviral agents

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