Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease

Al-Wahaibi, Lamya H.; Mostafa, Ahmed; Mostafa, Yaser A.; Abou-Ghadir, Ola F.; Abdelazeem, Ahmed H.; Gouda, Ahmed M.; Kutkat, Omnia; Shama, Noura M. Abo; Shehata, Mahmoud; Gomaa, Hesham A.M.; Abdelrahman, Mostafa H.; Mohamed, Fatma A.M.; Gu, Xuyuan; Ali, Mohamed A.; Trembleau, Laurent; Youssif, Bahaa G.M.

doi:10.1016/j.bioorg.2021.105363

Cited by 14 publications

(11 citation statements)

References 51 publications

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“…Macrocyclic peptides are known for their higher membrane permeability, superior selectivity, and stability, making them a promising privileged structure in drug discovery. Macrocycle 13c has been found to have significant inhibitory activity against SARS‐CoV‐2 3CL pro (IC 50 = 2.58 μM) 127 . Moreover, Johansen‐Leete et al 128 .…”

Section: Synthetic Compoundsmentioning

confidence: 98%

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

Xiong

Zhu

et al. 2022

MedComm

130

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The main proteases (Mpro), also termed 3‐chymotrypsin‐like proteases (3CLpro), are a class of highly conserved cysteine hydrolases in β‐coronaviruses. Increasing evidence has demonstrated that 3CLpros play an indispensable role in viral replication and have been recognized as key targets for preventing and treating coronavirus‐caused infectious diseases, including COVID‐19. This review is focused on the structural features and biological function of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) main protease Mpro (also known as 3CLpro), as well as recent advances in discovering and developing SARS‐CoV‐2 3CLpro inhibitors. To better understand the characteristics of SARS‐CoV‐2 3CLpro inhibitors, the inhibition activities, inhibitory mechanisms, and key structural features of various 3CLpro inhibitors (including marketed drugs, peptidomimetic, and non‐peptidomimetic synthetic compounds, as well as natural compounds and their derivatives) are summarized comprehensively. Meanwhile, the challenges in this field are highlighted, while future directions for designing and developing efficacious 3CLpro inhibitors as novel anti‐coronavirus therapies are also proposed. Collectively, all information and knowledge presented here are very helpful for understanding the structural features and inhibitory mechanisms of SARS‐CoV‐2 3CLpro inhibitors, which offers new insights or inspiration to medicinal chemists for designing and developing more efficacious 3CLpro inhibitors as novel anti‐coronavirus agents.

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Section: Synthetic Compoundsmentioning

confidence: 98%

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

Xiong

Zhu

et al. 2022

MedComm

130

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“…A similar study of an anti-HSV cyclic peptide, aspergillipeptide D, revealed inhibitory activity against SARS-CoV-2, with M pro as a target [157]. It then inspired the synthesis and development of five oxazole-based macrocycles with inhibitory activity against SARS-CoV-2 (NRC-03-nhCoV) in Vero-E6 cells, with an IC 50 of 18.3-63.3 µM [157].…”

Section: Anti-sars-cov-2mentioning

confidence: 98%

Microbial Natural Products with Antiviral Activities, Including Anti-SARS-CoV-2: A Review

et al. 2022

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The SARS-CoV-2 virus, which caused the COVID-19 infection, was discovered two and a half years ago. It caused a global pandemic, resulting in millions of deaths and substantial damage to the worldwide economy. Currently, only a few vaccines and antiviral drugs are available to combat SARS-CoV-2. However, there has been an increase in virus-related research, including exploring new drugs and their repurposing. Since discovering penicillin, natural products, particularly those derived from microbes, have been viewed as an abundant source of lead compounds for drug discovery. These compounds treat bacterial, fungal, parasitic, and viral infections. This review incorporates evidence from the available research publications on isolated and identified natural products derived from microbes with anti-hepatitis, anti-herpes simplex, anti-HIV, anti-influenza, anti-respiratory syncytial virus, and anti-SARS-CoV-2 properties. About 131 compounds with in vitro antiviral activity and 1 compound with both in vitro and in vivo activity have been isolated from microorganisms, and the mechanism of action for some of these compounds has been described. Recent reports have shown that natural products produced by the microbes, such as aurasperone A, neochinulin A and B, and aspulvinone D, M, and R, have potent in vitro anti-SARS-CoV-2 activity, targeting the main protease (Mpro). In the near and distant future, these molecules could be used to develop antiviral drugs for treating infections and preventing the spread of disease.

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“…The potential toxicity of compounds is a vital criterion to evaluate their clinical medical applications. The cytotoxicity of the hydroxamate 1a and thiosemicarbazone 2b (1-400 μM) were assayed by using mouse fibroblast (L929) cells [48] , [49] . As shown in Fig 9 , the cell viability was over 98% in the presence of 25 µM 1a , but only 80% of cells tested maintained viability in the presence of 2b at same concentration, indicating that the hydroxamate has low cytotoxicity, and the thiosemicarbazone has certain cytotoxicity on L929 cells.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

“…The cell supernatant was removed and added MTT solution (10 μL/well) for 4 h, and then added DMSO (100 μL/well) for 20 min. The OD 490 values (optical density) were measured on Microplate Reader [48] .…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals

Chigan

et al. 2022

Bioorganic Chemistry

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Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease

Cited by 14 publications

References 51 publications

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

Microbial Natural Products with Antiviral Activities, Including Anti-SARS-CoV-2: A Review

Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals

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Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease

Cited by 14 publications

References 51 publications

The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19

The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19

Microbial Natural Products with Antiviral Activities, Including Anti-SARS-CoV-2: A Review

Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals

Contact Info

Product

Resources

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The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19

The SARS‐CoV‐2 main protease (M^pro): Structure, function, and emerging therapies for COVID‐19