Synthesis and Antifungal Activity of Chimonanthus praecox Derivatives
Round 1
Reviewer 1 Report
The manuscript entitled “Synthesis and antifungal activity of cyclotryptamine derivatives” by Jinfeng Chen et al. describes the synthesis of new cyclotryptamine derivatives and the preliminary study for their activity towards six plant pathogen fungi. Overall, the manuscript can not be published in the current form and requires major revision. In addition, I have the following comments and suggestions for the authors:
- The manuscript contains orthographic mistakes and should be corrected. For this purpose, Authors could use Grammarly software.
- Figure 1 is of low quality and should be redrawn.
- Scheme 1. From a chemical point of view, first (compounds 1,2,3) and second (compounds 1,4,5) synthetic ways are the same and should be combined.
- Compounds a1-a20 and b1-b19 have an asymmetric carbon atom in the structure. Thus, the Authors should add information about the chirality of the compounds.
- Antimicrobial activity. Indicate the strains for studied pathogen fungi (for example, Sclerotinia sclerotiorum UFLA1).
- Table 1. The results for Amphotericin B are missing in the table.
- Instruments and Chemicals. NMR spectra were recorded not only in CDCl3; add acetone-d6 and DMSO-d6 to the solvent list.
- Indicate the purity of synthesized compounds. Also, add information about melting or boiling points for the compounds.
- Coupling constants for the quartets of CF3-groups in 13C NMR spectra are missing (compounds b1-b19).
- According to the Reference list, the self-citing is 45% (9 references of 20).
Author Response
Comments and Suggestions for Authors
The manuscript entitled “Synthesis and antifungal activity of cyclotryptamine derivatives” by Jinfeng Chen et al. describes the synthesis of new cyclotryptamine derivatives and the preliminary study for their activity towards six plant pathogen fungi. Overall, the manuscript can not be published in the current form and requires major revision. In addition, I have the following comments and suggestions for the authors:
- The manuscript contains orthographic mistakes and should be corrected. For this purpose, Authors could use Grammarly software.
Response: Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
2. Figure 1 is of low quality and should be redrawn.
Response: Many thanks for the suggestion.
The quality of the structure was improved.
3. Scheme 1. From a chemical point of view, first (compounds 1,2,3) and second (compounds 1,4,5) synthetic ways are the same and should be combined.
Response: Many thanks for the suggestion.
The synthetic ways were combined.
4. Compounds a1-a20 and b1-b19 have an asymmetric carbon atom in the structure. Thus, the Authors should add information about the chirality of the compounds.
Response: Many thanks for the suggestion.
Chiral compounds of the synthesied compoundes are difficult to be separated. We tried to separate isomers, but failed.
5. Antimicrobial activity. Indicate the strains for studied pathogen fungi (for example, Sclerotinia sclerotiorum UFLA1).
Response: Many thanks for the suggestion.
The errors haved been corrected shown in the revised version
6. Table 1. The results for Amphotericin B are missing in the table.
Response: Many thanks for the suggestion.
Amphotericin B was deleted.
7. Instruments and Chemicals. NMR spectra were recorded not only in CDCl3; add acetone-d6 and DMSO-d6 to the solvent list.
Response: Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
8. Indicate the purity of synthesized compounds. Also, add information about melting or boiling points for the compounds.
Response: Many thanks for the suggestion.
The melting points were added.
9. Coupling constants for the quartets of CF3-groups in 13C NMR spectra are missing (compounds b1-b19).
Response: Many thanks for the suggestion.
The coupling constants were added.
10. According to the Reference list, the self-citing is 45% (9 references of 20).
Response: Many thanks for the suggestion.
Our research group has done a lot of work in the synthesis and activity of cyclotryptamine derivatives.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Dear Authors,
You present here a work on synthesis and antifungal activity of some cyclocriptamine derivatives.
You say that the compounds were "designed". What do you mean by that? Please argument and detail.
Lines 11, 12, 14: „in vitro”, the names of the pathogen strains should be written in Italic
Why did you choose to synthesis compounds with nicotine functional group? Please detail.
Line 60: please correct „oxidation reaction”
Please enlarge the images presenting the structures of the compounds
Please write all results of your work in past tense
Figure 3 should appear after its citation in text
In the legend of Table 1 you present Amphotericin B as a positive control, but this antifungal drug misses from the table itself
Please detail the results of the antifungal assay.
You present a very superficial structure-activity relationship. Please detail it and transform it into a proper one
In Conclusions, in line 567, you talk about the antibacterial activity, but in manuscript you describe the antifungal activity!
Author Response
Comments and Suggestions for Authors
Dear Authors,
You present here a work on synthesis and antifungal activity of some cyclocriptamine derivatives.
You say that the compounds were "designed". What do you mean by that? Please argument and detail.
Response : Many thanks for the suggestion.
In the past five years, we have completed more than 400 cycliptamine derivatives and found that some of compounds have potent biological activities, some of which are particularly active, which are introduced in the introduction. Therefore, the paper takes cyclotryptamine as the skeleton structure. On the other hand, nicotine compounds have strong biological activities according to the references. Therefore, we want to combine these two parts, hoping to obtain more active compounds.
Lines 11, 12, 14: „in vitro”, the names of the pathogen strains should be written in Italic
Response : Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
Why did you choose to synthesis compounds with nicotine functional group? Please detail.
Response : According to the references, nitrogen-containing compounds have a great impact on biological activity. Nicotine is a kind of nitrogen-containing compounds. We want to investigate the introduction of these compounds in order to improve the biological activity.
Line 60: please correct „oxidation reaction”
Response1: Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
Please enlarge the images presenting the structures of the compounds
Response : Many thanks for the suggestion.
The quality of the images presenting the structures was improved.
Please write all results of your work in past tense
Response : Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
Figure 3 should appear after its citation in text
Response : Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
In the legend of Table 1 you present Amphotericin B as a positive control, but this antifungal drug misses from the table itself
Response : Many thanks for the suggestion.
The errors haved been corrected shown in the revised version. Amphotericin B was deleted.
Please detail the results of the antifungal assay.
Response : Many thanks for the suggestion.
Actually, it is difficult to extract clear structure-activity relationships from the biological data. Some relationships between structure and activity are summarized in the Antifungal Acitivity part.
You present a very superficial structure-activity relationship. Please detail it and transform it into a proper one
Response : Many thanks for the suggestion.
It is difficult to extract clear structure-activity relationships from the biological data.The relationship between structure and activity has been reanalyzed.
In Conclusions, in line 567, you talk about the antibacterial activity, but in manuscript you
Response : Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
Author Response File: Author Response.docx
Reviewer 3 Report
Molecules-1664114-peer-review-v1
Synthesis and Antifungal Activity of Cyclotryptamine Derivatives
The manuscript should be improved in its presentation.
1-Please review the way of writing the scientific names of plants and microorganisms
Section Introduction lines 40-41, page1.
2- Lines 47-48, page 2
The authors write “Compounds j and k revealed potent activity against acetylcholinesterase, with MIC values of 0.01 and 0.1 ng ml−1, respectively[17].”
The paragraph should be improved in its wording. Please include the IC50 values of these compounds against the enzyme acetylcholinesterase. And on the other hand, for those MIC values, indicate against which microorganisms.
Zheng, S.; Zhu, R.; Zhou, X.; Chen, L.; Bai, H.; Zhang, J., Synthesis and biological evaluation of calycanthaceous alkaloid analogs. Bioorgan. Med. Chem. 2019, 27, 115088.
3- Section Results and Discussion
This section should be improved; there is no discussion of the results, only a report of the results obtained.
Please include the agronomic relevance of the strains evaluated. Incorporate some bibliographic references that support your work.
Please include any of the references below to when a compound is potent antimicrobial or not active.
4- Section 3.3. Biological Activity
Please be more specific, review and write this section, incorporating relevant information for potential readers.
Include the original reference of the essay. Mention if the assay was performed according to CLSI or EUCAST rules
Include the detailed trial protocol. Mention the company of origin of the reference antibiotics used. Correctly mention the strains of the microorganisms used, origin ATCC or the corresponding strain number. If they are clinical isolates, mention the source organism.
5- Abstract
“Therefore, compounds b15 and b17 were identified as the most promising candidates for further study.”
Please mention which other studies?
- Section Introduction.
Please mention if possible and include reference to the toxicity of the compounds obtained or structurally related to them.
After the suggested changes, the manuscript could be considered for acceptance.
Author Response
Comments and Suggestions for Authors
Molecules-1664114-peer-review-v1
Synthesis and Antifungal Activity of Cyclotryptamine Derivatives
The manuscript should be improved in its presentation.
Response 1: Many thanks for the suggestion.
The manuscript have been improved in the revised version.
1-Please review the way of writing the scientific names of plants and microorganisms
Section Introduction lines 40-41, page1.
Response : Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
2- Lines 47-48, page 2
The authors write “Compounds j and k revealed potent activity against acetylcholinesterase, with MIC values of 0.01 and 0.1 ng ml−1, respectively[17].”
The paragraph should be improved in its wording. Please include the IC50 values of these compounds against the enzyme acetylcholinesterase. And on the other hand, for those MIC values, indicate against which microorganisms.
Zheng, S.; Zhu, R.; Zhou, X.; Chen, L.; Bai, H.; Zhang, J., Synthesis and biological evaluation of calycanthaceous alkaloid analogs. Bioorgan. Med. Chem. 2019, 27, 115088.
Response : Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
3- Section Results and Discussion
This section should be improved; there is no discussion of the results, only a report of the results obtained.
Please include the agronomic relevance of the strains evaluated. Incorporate some bibliographic references that support your work.
Please include any of the references below to when a compound is potent antimicrobial or not active.
Response : Many thanks for the suggestion.
Actually, it is difficult to extract clear structure-activity relationships from the biological data. The relationship between structure and activity has been reanalyzed.
4- Section 3.3. Biological Activity
Please be more specific, review and write this section, incorporating relevant information for potential readers.
Include the original reference of the essay. Mention if the assay was performed according to CLSI or EUCAST rules
Include the detailed trial protocol. Mention the company of origin of the reference antibiotics used. Correctly mention the strains of the microorganisms used, origin ATCC or the corresponding strain number. If they are clinical isolates, mention the source organism.
Response : Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
5- Abstract
“Therefore, compounds b15 and b17 were identified as the most promising candidates for further study.”
Please mention which other studies?
Response : Many thanks for the suggestion.
Compounds 12 and 15 contain Cl atoms in substituents, and Cl atoms are in para position.
The next work will change the skeleton structure and introduce the substituent, hoping to obtain compounds with better activity.
- Section Introduction.
Please mention if possible and include reference to the toxicity of the compounds obtained or structurally related to them.
After the suggested changes, the manuscript could be considered for acceptance.
Response: Many thanks for the suggestion, but We have no conditions to do the toxicity of the compounds research.Sorry.
Author Response File: Author Response.docx
Reviewer 4 Report
Thank you for inviting me to review this article. In the present study, the authors focused on the "Synthesis and Antifungal Activity of Cyclotryptamine Derivatives". On the whole, it is interesting and certainly worth investigating. But to meet the increasingly high-quality standard of Molecules, a careful revision is absolutely necessary before acceptance.
- The quality of Figure 1 is poor. It should be redrawn.
2. There are several grammatical mistakes. Please correct them.
3. It would be great if they added some theoretical studies such as molecular docking and dynamics.
Author Response
Comments and Suggestions for Authors
Thank you for inviting me to review this article. In the present study, the authors focused on the "Synthesis and Antifungal Activity of Cyclotryptamine Derivatives". On the whole, it is interesting and certainly worth investigating. But to meet the increasingly high-quality standard of Molecules, a careful revision is absolutely necessary before acceptance.
- The quality of Figure 1 is poor. It should be redrawn.
Response : Many thanks for the suggestion.
The quality of Figure 1 was improved.
- There are several grammatical mistakes. Please correct them.
Response : Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
- It would be great if they added some theoretical studies such as molecular docking and dynamics.
Response : Many thanks for the suggestion, but We have no conditions to do theoretical research.Sorry.
Round 2
Reviewer 1 Report
Manuscript Version # 2.
Comments and Suggestions for Authors:
- Scheme 1. From a chemical point of view, first (compounds 1,2,3) and second (compounds 1,4,5) synthetic ways are the same and should be combined. Also, check the object settings of Figures 1, 2, and 3 (bond length, spacing, etc.).
- Antimicrobial activity. Indicate the strains for studied pathogen fungi (for example, Sclerotinia sclerotiorum UFLA1).
- Table 1. The results for Amphotericin B are missing in the table.
- The self-citing is 45% (9 references of 20). Authors could add information about modern antifungal studies to the Introduction.
Author Response
Comments and Suggestions for Authors:
- Scheme 1. From a chemical point of view, first (compounds 1,2,3) and second (compounds 1,4,5) synthetic ways are the same and should be combined. Also, check the object settings of Figures 1, 2, and 3 (bond length, spacing, etc.).
Response: Many thanks for the suggestion.
The revision showed in the revised version.
- Antimicrobial activity. Indicate the strains for studied pathogen fungi (for example, Sclerotinia sclerotiorum UFLA1).
Response: Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
Verticillium dahliae：ACCC 36211
Colletotrichum orbiculare：SAUM 0321
Cytospora juglandis：ACCC36357
Curvularia lunata：SAUM 1373
Sclerotinia sclerotiorum：ACCC34236
Altenaria solani：SAUM 1275
- Table 1. The results for Amphotericin B are missing in the table.
Response: Many thanks for the suggestion.
The results for Amphotericin B was added in the revised version.
- The self-citing is 45% (9 references of 20). Authors could add information about modern antifungal studies to the Introduction.
Response: Many thanks for the suggestion.
The problem is solved by adding the literature on Synthesis of Cyclotryptamine and deleting some of its own literature shown in the revised version.
Author Response File: Author Response.docx
Reviewer 2 Report
Dear authors,
Thank you for considering my suggestions and for making the corrections.
Still, you present the results of the antifungal assay as MICs and you deleted Amphotericin from the table, after I told you that there is no result for Amphotericin in the table. This is not the good solution, because you need an antifungal drug as reference for your assay. Therefore, please compare the results obtained for your compounds with MIC values of the antifungal used and put these data in the table.
Author Response
Thank you for considering my suggestions and for making the corrections.
Still, you present the results of the antifungal assay as MICs and you deleted Amphotericin from the table, after I told you that there is no result for Amphotericin in the table. This is not the good solution, because you need an antifungal drug as reference for your assay. Therefore, please compare the results obtained for your compounds with MIC values of the antifungal used and put these data in the table.
Response: Many thanks for the suggestion.
The results for Amphotericin B was added in the revised version.
Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for Authors second revision
Molecules-1664114-peer-review-v2
Synthesis and Antifungal Activity of Cyclotryptamine Derivatives
The authors have made some changes, however there are suggestions that should be considered and incorporated into a new revision, after which the manuscript could be considered for acceptance.
1-Please review the way of writing the scientific names of plants according
chimonanthus praecox
Chimonanthus praecox (L.) Link
http://www.theplantlist.org/
http://www.worldfloraonline.org/
Please include the full name of the microorganisms used, for example
Streptococcus agalactiae-MQ3,
Streptococcus pyogenes-MQ4;
Escherichia coli ATCC 25922,
2- Please include any of the references below to when a compound is potent antimicrobial or not active.
Please see and include the following bibliographic reference
"Regarding edible plant extracts or their parts, it is estimated that they are very active if they show MIC values < 100 µg/mL, significantly active if MICs 100-512 µg/mL, moderately active if 512 < MICs 2048 µg/mL and not very active if MIC > 2048 µg/mL (Tamokou et al., 2017).
See highly active, significantly active, moderately active, low active and inactive in Tamokou, J.D.D., Mbaveng, A.T., Kuete, V. (2017). Antimicrobial activities of African medicinal spices and vegetables. Medicinal spices and vegetables from Africa, 207-237. doi:10.1016/b978-0-12-809286-6.00008-x. pages218, 219, section 3.4.
3- Section Results and Discussion
This section should be improved; there is no discussion of the results, only a report of the results obtained.
Please include the agronomic relevance of the strains evaluated. Incorporate some bibliographic references that support your work.
4- Section 3.3. Biological Activity
Please be more specific, review and write this section, incorporating relevant information for potential readers.
Include the original reference of the essay. Mention if the assay was performed according to CLSI or EUCAST rules. Include the detailed trial protocol. Mention the company of origin of the reference antibiotics used. Correctly mention the strains of the microorganisms used, origin ATCC or the corresponding strain number. If they are clinical isolates, mention the source organism.
After the suggested changes, the manuscript could be considered for acceptance.
Author Response
Comments and Suggestions for Authors second revision
Molecules-1664114-peer-review-v2
Synthesis and Antifungal Activity of Cyclotryptamine Derivatives
The authors have made some changes, however there are suggestions that should be considered and incorporated into a new revision, after which the manuscript could be considered for acceptance.
1-Please review the way of writing the scientific names of plants according
chimonanthus praecox
Chimonanthus praecox (L.) Link
http://www.theplantlist.org/
http://www.worldfloraonline.org/
Please include the full name of the microorganisms used, for example
Response: Many thanks for the suggestion.
The errors haved been corrected shown in the revised version.
Verticillium dahliae-ACCC 36211
Colletotrichum orbiculare-SAUM 0321
Cytospora juglandis-ACCC36357
Curvularia lunata-SAUM 1373
Sclerotinia sclerotiorum-ACCC34236
Altenaria solani-SAUM 1275
2- Please include any of the references below to when a compound is potent antimicrobial or not active.
Please see and include the following bibliographic reference
"Regarding edible plant extracts or their parts, it is estimated that they are very active if they show MIC values < 100 µg/mL, significantly active if MICs 100-512 µg/mL, moderately active if 512 < MICs 2048 µg/mL and not very active if MIC > 2048 µg/mL (Tamokou et al., 2017).
See highly active, significantly active, moderately active, low active and inactive in Tamokou, J.D.D., Mbaveng, A.T., Kuete, V. (2017). Antimicrobial activities of African medicinal spices and vegetables. Medicinal spices and vegetables from Africa, 207-237. doi:10.1016/b978-0-12-809286-6.00008-x. pages218, 219, section 3.4.
Response: Many thanks for the suggestion.
The two references have been added in the revised version.
3- Section Results and Discussion
This section should be improved; there is no discussion of the results, only a report of the results obtained.
Please include the agronomic relevance of the strains evaluated. Incorporate some bibliographic references that support your work.
Response: Many thanks for the suggestion.
The problem is solved by adding the literature .
4- Section 3.3. Biological Activity
Please be more specific, review and write this section, incorporating relevant information for potential readers.
Include the original reference of the essay. Mention if the assay was performed according to CLSI or EUCAST rules. Include the detailed trial protocol. Mention the company of origin of the reference antibiotics used. Correctly mention the strains of the microorganisms used, origin ATCC or the corresponding strain number. If they are clinical isolates, mention the source organism.
Response: Many thanks for the suggestion.
Verticillium dahliae：ACCC 36211
Colletotrichum orbiculare：SAUM 0321
Cytospora juglandis：ACCC36357
Curvularia lunata：SAUM 1373
Sclerotinia sclerotiorum：ACCC34236
Altenaria solani：SAUM 1275
Author Response File: Author Response.docx
