Phototoxicity of Quinolones and Fluoroquinolones: A Mechanistic Review About Photophysical and Photochemical Pathways
, Denisse de Loera 1, Gabriela Navarro-Tovar 1 and Lluvia I. López 2Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript is scientifically robust and thoroughly researched, presenting a valuable and comprehensive synthesis of the current literature on the photochemistry and phototoxicity of quinolones and fluoroquinolones. It effectively integrates fundamental studies, offering the readers a well-contextualized understanding of this important class of compounds.
The section on photophysical and photochemical mechanisms is particularly strong, providing detailed mechanistic insights supported by references to key experimental studies, such as those utilizing laser flash photolysis (LFP) and pulse radiolysis. These references not only strengthen the discussion but also guide readers to critical primary sources.
The authors elegantly connect the molecular structure to photochemical behavior, and thoughtfully discuss how specific substituents and electronic configurations influence reactivity, excited-state lifetimes, and potential clinical outcomes. This structure–activity relationships are crucial in understanding both the therapeutic potential and the risks associated with these compounds.
Overall, the article is both informative and engaging, offering clarity in presentation and depth in scientific analysis. It will be a valuable resource for researchers in photochemistry, medicinal chemistry, and pharmaceutical sciences.
However, to maximize its impact and readability, the authors should:
Refine the language and more clearly link structure to photochemical consequences and clinical implications.
Edits and suggestions
‘Photophysical and Photochemical Properties of Quinolones and Fluoroquinolones and Their Role in Phototoxicity’
The title accurately reflects the major focus of the review but could be improved for clarity and scope. Consider a more specific phrasing such as:
“Phototoxicity of Quinolones and Fluoroquinolones: A Mechanistic Review of Photophysical and Photochemical Pathways”
The abstract needs to be revised for grammar and add a concluding sentence to emphasize relevance to medicinal chemistry and phototoxicity mitigation.
The introduction could be enhanced by focusin more sharply on the phototoxicity problem.
In the results the explanation of equilibrium species and pKa behavior could be more structured with diagrams or tables.
Some paragraphs are long and difficult to follow; consider restructuring for better readability.
The section on Photophysical and Photochemical Mechanisms has excellent mechanistic detail with references to key studies (e.g., LFP, pulse radiolysis). However, there is some redundancy in describing ISC, singlet oxygen formation, and electron transfer.
Phototoxicity and Biological Interactions: The discusses both direct and indirect mechanisms (Type I and II), and it highlights photobinding, DNA damage, and protein cross-linking with literature support.
Quantitative comparisons (e.g., quantum yields, ROS rates) are scattered. These should be consolidated into a summary table for clarity.
In vivo data and their correlation with in vitro findings could be more explicitly connected.
Recent Developments and Structure-Phototoxicity Relationships. Shows evolution of Qs and FQs with structural modifications.
The Conclusion is elegant, but slightly repetitive of the introduction. The authors could add sentences on more future-focused, emphasizing opportunities for photochemistry-informed drug design.
Author Response
Responses to Reviewer#1
However, to maximize its impact and readability, the authors should:
Refine the language and more clearly link structure to photochemical consequences and clinical implications.
Response:
-The language has been refined throughout the manuscript.
-The link between structure and photochemical consequences is presented in section 3.
Edits and suggestions
“Photophysical and Photochemical Properties of Quinolones and Fluoroquinolones and Their Role in Phototoxicity’ The title accurately reflects the major focus of the review but could be improved for clarity and scope. Consider a more specific phrasing such as:
“Phototoxicity of Quinolones and Fluoroquinolones: A Mechanistic Review of Photophysical and Photochemical Pathways”
Response: The title has been changed.
The abstract needs to be revised for grammar and add a concluding sentence to emphasize relevance to medicinal chemistry and phototoxicity mitigation.
Response: The abstract has been changed and corrected.
The introduction could be enhanced by focusin more sharply on the phototoxicity problem.
Response: The introduction has been changed and corrected.
In the results the explanation of equilibrium species and pKa behavior could be more structured with diagrams or tables.
Response: A sentence and reference has been included.
Some paragraphs are long and difficult to follow; consider restructuring for better readability.
The section on Photophysical and Photochemical Mechanisms has excellent mechanistic detail with references to key studies (e.g., LFP, pulse radiolysis). However, there is some redundancy in describing ISC, singlet oxygen formation, and electron transfer.
Phototoxicity and Biological Interactions: It discusses both direct and indirect mechanisms (Type I and II), and it highlights photobinding, DNA damage, and protein cross-linking with literature support.
Response: the complete manuscript has been corrected.
Quantitative comparisons (e.g., quantum yields, ROS rates) are scattered. These should be consolidated into a summary table for clarity.
Response: Quantitative comparisons (e.g., quantum yields and ROS rates) have been consolidated in two tables (1 and 2).
In vivo data and their correlation with in vitro findings could be more explicitly connected.
Response: A paragraph about this issue has been included.
Recent Developments and Structure-Phototoxicity Relationships. Shows evolution of Qs and FQs with structural modifications.
A section on this issue has been included
The Conclusion is elegant, but slightly repetitive of the introduction. The authors could add sentences on more future-focused, emphasizing opportunities for photochemistry-informed drug design.
The conclusion has been modified to include structure modifications and perspectives.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe review provides a thorough analysis of quinolone photochemistry and phototoxicity, emphasizing the significance of molecular design in optimizing safety. However, several suggestions for improvement are noted:
Structural Adjustment: The authors should restructure the content by first introducing the "Structure and Biological Properties of Qs" section before discussing photochemistry and phototoxicity. This flow would better establish the foundational context for understanding the subsequent mechanistic discussions.
Clarification on Fluorination at C-6: The review states that introducing a fluorine atom at the C-6 position in second-generation quinolones enhances activity against Gram-positive bacteria, not Gram-negative bacteria. This correction is important for accurate representation of structure-activity relationships.
Withdrawal Reasons for Sparfloxacin: While the review mentions phototoxicity as a reason for withdrawal of drugs like sparfloxacin, it should also acknowledge that cardiotoxicity (e.g., QT interval prolongation) contributed to their removal from the market, in addition to phototoxicity. A more comprehensive discussion of multiple adverse effects would improve the review’s accuracy.
Scheme Representation in Phototoxicity Mechanisms: The review uses schemes to illustrate phototoxicity mechanisms effectively, but there is a structural inaccuracy in Scheme 7. The notation "FQ*" should be revised to reflect structures similar to "1*" as presented in Photochemistry and Photobiology 1998, 68, 666–674.
Author Response
RESPONSE TO REVIEWER 2.
The review provides a thorough analysis of quinolone photochemistry and phototoxicity, emphasizing the significance of molecular design in optimizing safety. However, several suggestions for improvement are noted:
Structural Adjustment: The authors should restructure the content by first introducing the "Structure and Biological Properties of Qs" section before discussing photochemistry and phototoxicity. This flow would better establish the foundational context for understanding the subsequent mechanistic discussions.
Response: A section on Structure and Biological Properties has already been included. It is presented on page 16.
Clarification on Fluorination at C-6: The review states that introducing a fluorine atom at the C-6 position in second-generation quinolones enhances activity against Gram-positive bacteria, not Gram-negative bacteria. This correction is important for accurate representation of structure-activity relationships.
Response: It has been corrected.
Withdrawal Reasons for Sparfloxacin: While the review mentions phototoxicity as a reason for withdrawal of drugs like sparfloxacin, it should also acknowledge that cardiotoxicity (e.g., QT interval prolongation) contributed to their removal from the market, in addition to phototoxicity. A more comprehensive discussion of multiple adverse effects would improve the review’s accuracy.
Response: This review is centered on phototoxicity. There many recent reviews about diverse adverse effects.
Scheme Representation in Phototoxicity Mechanisms: The review uses schemes to illustrate phototoxicity mechanisms effectively, but there is a structural inaccuracy in Scheme 7. The notation "FQ*" should be revised to reflect structures similar to "1*" as presented in Photochemistry and Photobiology 1998, 68, 666–674.
Response: In the article by Fassani et al., they select to represent the estabilization using lomefloxacin. We use another structure with similar structural elements to avoid using using the same figure of the article by Fassani. But we reference Fassani et al. in the text.
