Synthesis of Antifungal Heterocycle-Containing Mannich Bases: A Comprehensive Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This paper was a well-written manuscript and I am sure it attracts many peoples involved the synthesis and antifungal activity of various Mannich bases chemical compounds usually obtained by the condensation reaction between an amine, a compound with active hydrogens, and an aldehyde, widely known for their wide range of biological activities.

This comprehensive review allows establishing that Mannich bases can be considered as a relevant toxophore/pharmacophore, which can be implemented for the design of new agrochemicals. However, there are many utilities not only in agrochemicals but also in various medicine. Thereby I would like to authors to disguise these two areas to see the reader go through. If authors want to focus on simple agrochemicals, then just write them down in the early part of this manuscript.

In addition, there are chemically simple syntheses of the compounds, In this case tells readers to follow a simple scheme. Other than that, it is fine.

Comments on the Quality of English Language

No editing is necessary

Author Response

Reply to Reviewer 1:

 

We sincerely appreciate your thoughtful review and the valuable suggestions you provided for our manuscript. With meticulous attention, we have addressed each comment and suggestion, resulting in a significantly enhanced version of the manuscript. Changes made have been indicated in yellow in the revised document to facilitate easy identification. As for the comments you raised, we present our responses in a point-to-point manner below:

 

Comment 1: This paper was a well-written manuscript and I am sure it attracts many peoples involved the synthesis and antifungal activity of various Mannich bases chemical compounds usually obtained by the condensation reaction between an amine, a compound with active hydrogens, and an aldehyde, widely known for their wide range of biological activities.

Response: Thanks a lot for your kind depiction and illustration of our manuscript.

 

Comment 2: This comprehensive review allows establishing that Mannich bases can be considered as a relevant toxophore/pharmacophore, which can be implemented for the design of new agrochemicals. However, there are many utilities not only in agrochemicals but also in various medicine. Thereby I would like to authors to disguise these two areas to see the reader go through. If authors want to focus on simple agrochemicals, then just write them down in the early part of this manuscript. In addition, there are chemically simple syntheses of the compounds. In this case tells readers to follow a simple scheme. Other than that, it is fine.

Response: We appreciate so much your kind remark. We think it is a possible confusing direction of our manuscript since our aim was focused on compile information about antifungal Mannich bases against fungal pathogens of plant and animals/humans. Therefore, we explained in the introduction our motivations to deliver a clearer information to readers. In addition, we improved the explanations of schemes as kindly suggested

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The article titled "Synthesis and Bioactivity of Mannich Bases as Antifungal Agents: A Comprehensive Review" by Diego Quiroga and Ericsson Coy-Barrera provides a comprehensive overview of the synthesis and bioactivity of Mannich bases as antifungal agents. The authors aim to present a detailed account of the current knowledge in this field.

The article starts by introducing the Mannich reaction and its significance in medicinal chemistry, particularly in the synthesis of antifungal agents followed by discussing the various synthetic methods employed for the preparation of Mannich bases, including conventional and modern approaches.

Furthermore, the article explores the recent advancements in the development of Mannich bases with improved pharmacokinetic properties, such as enhanced solubility, bioavailability, and reduced toxicity. The authors discuss the strategies employed to achieve these improvements, including prodrug approaches and formulation techniques.

Overall, the review article provides a comprehensive and well-structured overview of the synthesis and bioactivity of Mannich bases as antifungal agents. The authors demonstrate a strong understanding of the subject matter and present the information in a clear and concise manner. This review article serves as a valuable resource for researchers and scientists working in the field of medicinal chemistry and antifungal drug development. However, there are some major questions to address before I recommend it for publication in the journal Organics-

 

1. What are the key factors influencing the regioselectivity of Mannich reactions, and how can selective control over the regio-chemistry be achieved in the synthesis of Mannich bases?
2. What’s the role of catalysts in the Mannich reaction for the synthesis of antifungal Mannich bases? What types of catalysts have been utilized, and how do they affect reaction efficiency and selectivity?
3. Are there any specific stereochemical considerations in the synthesis of chiral Mannich bases as antifungal agents? How does stereochemistry impact their bioactivity and interactions with fungal targets?
4. In terms of structure-activity relationships (SAR), what specific chemical features or functional groups in Mannich bases contribute to their antifungal potency? Are there any general trends or common structural motifs associated with enhanced activity?
5. Can you elaborate on the mechanisms of action of Mannich bases against fungal pathogens? How do they interact with cellular targets or disrupt key biological processes to exhibit antifungal activity?
6. Are there any notable drawbacks or limitations associated with the use of Mannich bases as antifungal agents? How are researchers addressing these challenges to improve the overall efficacy and safety profiles of these compounds?
7. The article discusses the mechanisms of action of Mannich bases as antifungal agents. Can you provide insights into the specific modes of action identified and how they contribute to the antifungal activity of these compounds?
8. A summary table is missing from the article.
9. Following references need to be reformatted in proper way using proper journal name abbreviation-

Reference numbers 3, 15, 18, 21-23, 25, 26, 29, 31, 36, 37, 39, 41-43, 47, 49, 54, 57-62, 64-67, 70.

Author Response

Reply to Reviewer 2:

 

We sincerely appreciate your thoughtful review and the valuable suggestions you provided for our manuscript. With meticulous attention, we have addressed each comment and suggestion, resulting in a significantly enhanced version of the manuscript. Changes made have been indicated in yellow in the revised document to facilitate easy identification. As for the comments you raised, we present our responses in a point-to-point manner below:

 

Comment 0: The article titled "Synthesis and Bioactivity of Mannich Bases as Antifungal Agents: A Comprehensive Review" by Diego Quiroga and Ericsson Coy-Barrera provides a comprehensive overview of the synthesis and bioactivity of Mannich bases as antifungal agents. The authors aim to present a detailed account of the current knowledge in this field. The article starts by introducing the Mannich reaction and its significance in medicinal chemistry, particularly in the synthesis of antifungal agents followed by discussing the various synthetic methods employed for the preparation of Mannich bases, including conventional and modern approaches. Furthermore, the article explores the recent advancements in the development of Mannich bases with improved pharmacokinetic properties, such as enhanced solubility, bioavailability, and reduced toxicity. The authors discuss the strategies employed to achieve these improvements, including prodrug approaches and formulation techniques.

Overall, the review article provides a comprehensive and well-structured overview of the synthesis and bioactivity of Mannich bases as antifungal agents. The authors demonstrate a strong understanding of the subject matter and present the information in a clear and concise manner. This review article serves as a valuable resource for researchers and scientists working in the field of medicinal chemistry and antifungal drug development. However, there are some major questions to address before I recommend it for publication in the journal Organics.

Response: We extend our sincere gratitude to the reviewer for acknowledging the practical value of the information we have presented. Moreover, we deeply appreciate the meticulous review of our manuscript. We have carefully considered the suggestions and questions raised by the reviewer, incorporating them to enhance the quality of our manuscript.

 

Comments 1-3: What are the key factors influencing the regioselectivity of Mannich reactions, and how can selective control over the regio-chemistry be achieved in the synthesis of Mannich bases?

What’s the role of catalysts in the Mannich reaction for the synthesis of antifungal Mannich bases? What types of catalysts have been utilized, and how do they affect reaction efficiency and selectivity?

Are there any specific stereochemical considerations in the synthesis of chiral Mannich bases as antifungal agents? How does stereochemistry impact their bioactivity and interactions with fungal targets?

Response: We appreciate so much your kind remarks, questions, and suggestions. We hold the view that each of these avenues bears immense value and presents a compelling opportunity for exploration. However, the underlying motivations of our review were directed towards describing Mannich bases that are synthesized, exhibit antifungal activity, and are coupled with oxa- or/and aza-heterocycles. We strategically incorporated this focus into the introduction to provide a more defined aim and scope. As authors, we kindly suggest that the reviewer's suggested emphasis will be addressed in a subsequent compilation, specifically tailored to delve into these crucial synthetic aspects/viewpoints.

 

Comment 4: In terms of structure-activity relationships (SAR), what specific chemical features or functional groups in Mannich bases contribute to their antifungal potency? Are there any general trends or common structural motifs associated with enhanced activity?

Response: Thanks a lot for your kind comment. Regrettably, despite a thorough analysis of the compiled information, clear general trends or shared structural motifs linked to heightened activity have not emerged. While certain trends do exist, they lack full confirmation, and discussing them without delving into speculation is challenging. This is due to the limited number of examples available, coupled with variations in microorganisms and their varying susceptibilities. To prevent any misinterpretations, we opt for a descriptive approach in presenting the information.

 

Comments 5-6: Can you elaborate on the mechanisms of action of Mannich bases against fungal pathogens? How do they interact with cellular targets or disrupt key biological processes to exhibit antifungal activity? The article discusses the mechanisms of action of Mannich bases as antifungal agents. Can you provide insights into the specific modes of action identified and how they contribute to the antifungal activity of these compounds?

Response: Thank you very much for your kind remark. While we endeavored to compile information regarding mechanisms of action, the existing data is mostly confined to in vitro assessments, leaving a dearth of literature advancements in that domain. Nevertheless, to provide a comprehensive perspective, we have incorporated a new section, "Future Outlook," which delineates potential advancements and research avenues encompassing the entire spectrum of bioactivity and synthesis concerning these compounds.

 

Comment 7: Are there any notable drawbacks or limitations associated with the use of Mannich bases as antifungal agents? How are researchers addressing these challenges to improve the overall efficacy and safety profiles of these compounds?

Response: Thank you very much for your kind remark. Accordingly, in the new section, we added some explanations about this limitations/challenges regarding selectivity/specificity, toxicity and lack of SAR studies, and how it can be improved.

 

Comment 8: A summary table is missing from the article.

Response: We appreciate so much your kind suggestion. However, given the narrative nature of the review and the diverse range of information gathered, a summary table may not effectively convey clear information. Therefore, as authors, we have chosen to retain the information in its narrative format. We hope the reviewer empathizes with our view as that.

 

Comment 9: Following references need to be reformatted in proper way using proper journal name abbreviation- Reference numbers 3, 15, 18, 21-23, 25, 26, 29, 31, 36, 37, 39, 41-43, 47, 49, 54, 57-62, 64-67, 70.

Response: Thank you very much for your kind remark. Accordingly, we revised these journal abbreviations to fit the correct format.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The review manuscript “Synthesis and Bioactivity of Mannich Bases as Antifungal Agents: A Comprehensive Review” is devoted to Mannich bases containing heterocyclic systems and their antifungal activity against different fungal pests with relevance to agriculture. The manuscript is poorly organized. The review is not clear and comprehensive. The gap in knowledge is not identified. The authors do not discuss similar reviews published recently. However, the topic is interesting and relevant.

In my opinion, the manuscript needs reorganization.

Thus, in my opinion, the manuscript suits to the Organics, and can be accepted after major revision.

Some comments for the authors:

1. The title should be more specific, since the review covers Mannich bases containing heterocyclic systems.

2. The introduction section should contain information on what time period is covered by the review, what other similar reviews were reported, why is this review so important, what gap in knowledge is covered? And something on structure of the review, i.e. how it is organized and what are its sections. And of course it would be nice, if the introduction described how the references for the review were searched.

3. Schemes 4, 5: these does not suit to the section 2.1 since this is not an oxa-heterocycle.

4. I strongly recommend to use subsections which would identify the type of heterocycle discussed (i.e. 2.1.1 Coumarin derivatives and etc.).

5. Section 2.3 should be revised and made more specific.

6. The conclusions are not connected with the manuscript. They deliver general phrases. These should be revised and rewritten.

Author Response

Reply to Reviewer 3:

 

We sincerely appreciate your thoughtful review and the valuable suggestions you provided for our manuscript. With meticulous attention, we have addressed each comment and suggestion, resulting in a significantly enhanced version of the manuscript. Changes made have been indicated in yellow in the revised document to facilitate easy identification. As for the comments you raised, we present our responses in a point-to-point manner below:

 

Comment 0: The review manuscript “Synthesis and Bioactivity of Mannich Bases as Antifungal Agents: A Comprehensive Review” is devoted to Mannich bases containing heterocyclic systems and their antifungal activity against different fungal pests with relevance to agriculture. The manuscript is poorly organized. The review is not clear and comprehensive. The gap in knowledge is not identified. The authors do not discuss similar reviews published recently. However, the topic is interesting and relevant. In my opinion, the manuscript needs reorganization. Thus, in my opinion, the manuscript suits to the Organics, and can be accepted after major revision.

Response: We thank the reviewer for his/her comments, perception and scrutiny on our manuscript. We are sure that addressing those remarks would end up in an improved version.

 

Comment 1: The title should be more specific, since the review covers Mannich bases containing heterocyclic systems.

Response: We appreciate so much your kind remark. Accordingly, we modified the title to be more specific, as suggested.

 

Comment 2: The introduction section should contain information on what time period is covered by the review, what other similar reviews were reported, why is this review so important, what gap in knowledge is covered? And something on structure of the review, i.e. how it is organized and what are its sections. And of course it would be nice, if the introduction described how the references for the review were searched.

Response: Thanks a lot for your kind suggestion. Accordingly, we modified the introduction section, adding the topics suggested by the reviewer regarding time, similar reviews, the gap, motivations, review structure, and source searching.

 

Comment 3: Schemes 4, 5: these does not suit to the section 2.1 since this is not an oxa-heterocycle.

Response: Thank you very much for your kind remark. Accordingly, we restructured such a text regarding Schemes 4 and 5 (allylphenol derivatives), and the section was renamed as “2. Heterocyclic-based and/or oxygenated Mannich bases”.

 

Comment 4: I strongly recommend to use subsections which would identify the type of heterocycle discussed (i.e. 2.1.1 Coumarin derivatives and etc.).

Response: We thank for your kind suggestion. Accordingly, we added subheadings to locate the different heterocycles compiled.

 

Comment 5: Section 2.3 should be revised and made more specific.

Response: We appreciate so much your kind observation. Consequently, we added subheadings to subdivide this section into morpholine and oxadiazole derivatives to made it more specific, as suggested.

 

Comment 6: The conclusions are not connected with the manuscript. They deliver general phrases. These should be revised and rewritten.

Response: Thanks a lot for your kind suggestion. Accordingly, we reorganized and rewritten the conclusions section to connect it with the manuscript body.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I am pleased to accept the submitted article for publication. The author's responses to my questions and concerns have been comprehensive and satisfactory. Their efforts in addressing the issues raised during the review process have significantly improved the quality and clarity of the manuscript. The research presented in this article contributes valuable insights to the field and meets the standards of the journal for publication. I look forward to seeing this work published and shared with the scientific community.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors provided necessary changes, the manuscript is ready for acceptance.