Benzothiazole-Based Therapeutics: FDA Insights and Clinical Advances^†

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The paper presented by the authors is a review of some FDA-approved drugs containing the benzothiazole base structure. The manuscript is generally well-structured and well-written. However, the reviewer recommends some clarifications and additions before accepting the manuscript.

a) Figure 1 is incorrect because a tautomer is not being depicted; only a resonant form is shown. It is recommended to delete it.

b) The section on 'Synthetic Accessibility and Structural Tunability' could be enriched by exploring more advanced strategies. These could include transition-metal-catalyzed cyclization, green chemistry techniques, and biocatalysis. By incorporating these innovative methods, the manuscript could provide a more forward-looking perspective on the synthesis of benzothiazole-based drugs.

c) In line 102, it is mentioned that the incorporation of electron-withdrawing groups at the C5 and C6 positions enhances biological activity. It is crucial to indicate in which particular cases this occurs, as it will provide a more comprehensive understanding of the factors influencing biological activity in benzothiazole-based drugs.

d) The review would be enriched by including some additional examples of recently published benzothiazole core molecules with demonstrated biological activity (e.g. https://doi.org/10.1021/acs.jmedchem.2c01597, https://doi.org/10.3390/molecules30010107).

Author Response

Response to Reviewer Comments

The paper presented by the authors is a review of some FDA-approved drugs containing the benzothiazole base structure. The manuscript is generally well-structured and well-written. However, the reviewer recommends some clarifications and additions before accepting the manuscript.

We sincerely thank the Editor and Reviewers for their valuable comments and suggestions. All the points raised by them are important for the betterment of the manuscript. We have addressed all the reviewers' comments and revised the manuscript accordingly. All the changes are highlighted in yellow in the revised manuscript. Herein, we provide point-by-point responses to all comments (comments are in blue, and responses are in black text). 

Reviewer: 1

Point-by-point response letter:

Comment: 1

Figure 1 is incorrect because a tautomer is not being depicted; only a resonant form is shown. It is recommended to delete it.

Response:

Thanks for your comment and we agree with the reviewer’s observation. We modified and included in the manuscript based on other referee suggestions.

Comment: 2

The section on 'Synthetic Accessibility and Structural Tunability' could be enriched by exploring more advanced strategies such as transition-metal-catalyzed cyclization, green chemistry techniques, and biocatalysis.

Response:

We are very thankful to the reviewer for this suggestion, and we appreciate this valuable comment. The section has been revised and expanded to include recent advances in synthetic strategies for benzothiazole derivatives. We have discussed transition-metal-catalyzed cyclization, green chemistry approaches, and biocatalytic methods, with appropriate literature references to reflect the current trends and enhance the forward-looking perspective (included with Figure 3 and highlighted as yellow—page 3, 4-5).

Comment: 3

 In line 102, it is mentioned that the incorporation of electron-withdrawing groups at the C5 and C6 positions enhances biological activity. It is crucial to indicate in which particular cases this occurs.

Response:

Thank you for your suggestions and pointing this out. We have now clarified in which electron-withdrawing groups at the C5 and C6 positions positively influence biological activity, including anticancer and antimicrobial derivatives. References have been added to support this explanation (highlighted as yellow—page 3, 4-5).

1. d) The review would be enriched by including some additional examples of recently published benzothiazole core molecules with demonstrated biological activity.

Response:

Thanks for valuable suggestion regarding recent reports, we agree and have added several examples of benzothiazole derivatives published between 2020 and 2025 with confirmed biological activity (Figure 11). The references suggested by the reviewer (DOI: 10.1021/acs.jmedchem.2c01597 and 10.3390/molecules30010107) have also been included and discussed in the revised version with detailed way. (highlighted as yellow—Figure 11/page 21).

We hope that these revisions address all of the reviewer’s concerns. We are grateful for the helpful feedback and believe that the revised manuscript is significantly improved.

Sincerely,
Dr. SR Cheekatla

 

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

A file is attached

Comments for author File: Comments.pdf

Author Response

 

 

 

The review deals with the presentation of the well-known FDA-approved, or under clinical or preclinical evaluation benzothiazoles, by presenting some general structural characteristics and some aspects regarding their activity (including some information of their mechanism of activity). It is useful and could be helpful for those who would like to get the first idea for the presented benzothiazoles. Some comments are listed below:

 

We sincerely thank the Editor and Reviewers for their valuable comments and suggestions. All the points raised by them are important for the betterment of the manuscript. We have addressed all the comments of the reviewers and revised the manuscript accordingly. All the changes are highlighted in yellow in the revised manuscript. Herein, we write the point-by-point responses for all the comments (the comments are in blue, and the responses are in black text). 

 

 

Reviewer: 2

We sincerely thank Reviewer 2 for the constructive comments and suggestions. Below, we address each point raised by referee 2:

 

Point-by-point response letter:

Comment: 1

Figure 1 is not correct. The tautomeric forms of the benzothiazolyl core are the following:

 

Response:

We appreciate this correction. Figure 1 has been updated to correctly depict the tautomeric forms of the benzothiazolyl core, as illustrated by the reviewer’s suggestions. This correction is now reflected in the revised manuscript.  (page 2)

 

Comment: 2

Some explanation is needed for compounds 3, 4 to show the connection with benzothiazole core. e.g. that they are 4,5,6,7-tetrahydro-1,3-benzothiazoles. For saccharine 5, a benzosulfimide, the general core is categorized in Section 4.5 as a “benzisothiazole-1,1-dioxide core”. Some structural features should be discussed closer to Figure 3, to explain the relationship. The use of the IUPAC name “1H-1λ6,2-Benzothiazole-1,1,3(2H)-trione” to show the similarity would be helpful.

Response:

Thank you for highlighting this important point. We have addressed explanation for compounds 3 and 4 in the relevant section of the manuscript, clarifying that they are 4,5,6,7-tetrahydro-1,3-benzothiazoles. Additionally, for compound 5 (saccharine), we now describe its classification as a benzisothiazole-1,1-dioxide and have added a note on its structural relationship to benzothiazoles. The IUPAC name “1H-1λ⁶,2-benzothiazole-1,1,3(2H)-trione” has been included to support the structural discussion. (page 8-10)

 

Comment: 3

Is there a reason to split the presented molecules into two Figures (Figure 3 and Figure 5)?

Response:

Thanks, and we agree with this comment. In Figure 4 (revised) we discussed most of the compounds approved drugs and the other figure 6 (revised) clinical drugs.

 

Comment: 4

Check again if Phortress is still in clinical trials. It seems that the latest clinical

trials have been abandoned. You could check if there are any planned clinical

trials.
Response:

Thank you for this comment. We have reviewed the current clinical trial status of Phortress and confirmed that the latest trials have indeed been discontinued. We have updated the text accordingly (page 13).

 

Comment: 5

English is fine. In Line 19 of the abstract, you should possibly remove “and” (or rephrase).

Response:

Thank you for the suggestion. We have rephrased the sentence in Line 19 of the abstract to improve clarity and readability.  (page 1, line 19-21)

 

We thank the reviewer once again for the valuable feedback, which has significantly strengthened our manuscript.

Yours Sincerely,

Dr.SR Cheekatla

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have clearly improved their manuscript, and all of my concerns have been addressed. Therefore, the paper is now suitable for publication