Synthesis, Antioxidant, and Antifungal Activities of β-Ionone Thiazolylhydrazone Derivatives and Their Application in Anti-Browning of Freshly Cut Potato

Round 1

Reviewer 1 Report (New Reviewer)

The paper describes the synthesis and characterization of ionone-thiazolyl carbazone derivatives with browning and fungi inhibitory activities. It is well-written and the characterization is supported by complete spectroscopic data. Before it is accepted, the authors are requested to address the following comments.

1. Instead of using browning, please use pigmentation or hyperpigmentation.

2. The screening data would have been more informative and technically better if the compounds were screened against tyrosinase enzymes.

3. Pls express IC50 as uM.

4. The authors must justify in the discussion the choice of the three fungi tested.

5. The potato experiment must precede the screening for antifungal activity since antiox was correlated to pigmentation inhibition.

Minor editing

Author Response

(1) Instead of using browning, please use pigmentation or hyperpigmentation.

Responses: Thanks for the reviewer’s constructive suggestions. After careful discussion, we think that browning is more accurate in this paper, because the compounds we synthesise are mainly used to prevent browning caused by oxidation in plants, pigmentation is primarily aimed at animal splash. 

(2)The screening data would have been more informative and technically better if the compounds were screened against tyrosinase enzymes..

Responses: Thanks for the reviewer’s constructive suggestions. The series of test experiments performed on compounds in this paper belong to the previous work. For compounds on tyrosinase activity test experiment and explore the mechanism of antioxidant, is what we are further research work.

• Pls express IC50 as uM

Responses: Thanks for the reviewer’s constructive suggestions. The units of IC50 values in the articles are all expressed in μM.

(4) The authors must justify in the discussion the choice of the three fungi tested. 

Responses: Thanks for the reviewer’s constructive suggestions. The eight fungi selected for antifungal experiments in this paper are all the most common fungi during plant growth and have been explained in the discussion section of the paper.

(5) The potato experiment must precede the screening for antifungal activity since antiox was correlated to pigmentation inhibition.

Responses: Thanks for the reviewer’s constructive suggestions. The arrangement order of article chapters has been adjusted.

Author Response File: Author Response.doc

Reviewer 2 Report (New Reviewer)

Dayong Peng et al reported that 25 thiazole hydrazone compounds were synthesized and tested invitro antioxidant experiments. Since similar experiments have already been done with similar analogues, it would be better to clearly indicate the difference from that paper. 

 

I recommend for publication after major revision. 

 

Major comments 

1. There is a paper that uses similar derivatives to observe the antioxidat activity and their application in the anti-browning of fresh-cut potatoes, and it would be better to mention the differences and comparisons with this paper in the introduction and in the results. 

 

Synthesis and evaluation of the antioxidant and anti-tyrosinase activities of thiazolyl hydrazone derivatives and their application in the anti-browning of fresh-cut potato 

https://doi.org/10.1016/j.foodchem.2023.135745 

 

Synthesis, antioxidant, antifungal, molecular docking and ADMET studies of some thiazolyl hydrazones 

https://doi.org/10.1016/j.bmcl.2017.06.043 

 

2. Fig.3 For the potatoes in Visual observation of anti-browning, the shapes of the 2d and 3d otatoes in 1k appear to be different. Are you observing on multiple POTATOES without hourly observations on the same POTATOES? Also, it would be better to describe how much the individual differences are. 

 

If the experiment in the color-difference system in Figure 4 has been conducted multiple times, then error bars should be displayed to show how much experimental error there is. Observations in the color-difference system for such a material have a very large error at the position where they are measured 

 

 

Minor comments 

Overall, there were many minor errors. For example, the following is an example, but I think there are many more, so authors should check carefully before submitting their work. 

 

Line 92 

3200cm-1  Need space 

 

Line 99 line 102 

Is there any uniformity in the way the width is written? 

in the renge of about 7.85-7.45 ppm  

in the range of 2.36~1.02 ppm 

 

Line 108 

HRMS (EIS)  

It says EIS, but is it not Electrospray ionization (ESI)? 

 

Line 137  

Table 1 and Line 137 Table 3 

1f 2-NO2  

O with a lowercase 2 after it 

Font is different. 

 

The IC50 in Fig. 1 and Fig. 2 should include units. 

 

Line 221  

It would be clearer if you indicate that "d" in Fig. 3 is a day or that it was stored at 20 °C in a caption. 

Author Response

• There is a paper that uses similar derivatives to observe the antioxidat activity and their application in the anti-browning of fresh-cut potatoes, and it would be better to mention the differences and comparisons with this paper in the introduction and in the results.

Responses: Thanks for the reviewer’s constructive suggestions. According to your suggestion, a comparison with two similar articles was added in the introduction in lines 61-65.

 

(2)Fig.3 For the potatoes in Visual observation of anti-browning, the shapes of the 2d and 3d otatoes in 1k appear to be different. Are you observing on multiple POTATOES without hourly observations on the same POTATOES? Also, it would be better to describe how much the individual differences are.

Responses: Thanks for the reviewer’s constructive suggestions. In order to reduce the experimental error, we observed the Browning degree of multiple potatoes at the same time. In order to present the experimental results more intuitively, we selected more representative photos for uploading. The extent of individual differences in potatoes is described in lines 293 - 294.

(3)If the experiment in the color-difference system in Figure 4 has been conducted multiple times, then error bars should be displayed to show how much experimental error there is. Observations in the color-difference system for such a material have a very large error at the position where they are measured.

Responses: Thanks for the reviewer’s constructive suggestions. Experimental values are obtained by averaging multiple measurements, and error lines have been added to Figure 4 according to the actual situation.

• Overall, there were many minor errors. For example, the following is an example, but I think there are many more, so authors should check carefully before submitting their work.

Responses: Thanks for the reviewer’s constructive suggestions. According to your suggestion, we have carefully checked the article and revised many minor errors.

Author Response File: Author Response.doc

Reviewer 3 Report (New Reviewer)

The manuscript was previously submitted to Elsevier in "Tetrahedron". The cover letter is addressed to Tetrahedron. The pre-print is available on the internet but with some different authors from those in this article, as well as a change of author for the correspondence. It is regrettable that it does not state why the article is being submitted to Molecules. (It should explain why the manuscript fits the scope of the journal.)

This study concerns the synthesis of a series of thiazole hydrazone derivatives with antioxidant potential and with anti-browning ability as kojic acid a standard inhibitor. The compounds synthesised are described not in the article but in the supporting information. For some compounds, there are slight differences in the assignment of carbon atoms in the NMR description with the version previously submitted to Elsevier journal. The authors (line 95) point out that they used simulated spectra, and they should specify the program.

In the abstract, line 22 : its IC50 value is 86.525. μmol/L . Don't forget the units. Also remember them in figures 1 and 2. Reading the figures is not made any easier by the change in order of the compounds (1a to 1y).

The authors claimed : « 11 compounds (1a, 1b, 1d, 1e, 1h, 1j, 1k, 1p, 1q, 1t, 1u) have better scavenging effect on DPPH free radical than positive control Trolox. » This is not so obvious for the compounds 1h, 1b, 1u

Line 52. Instead of thiazolizone : thiazole hydrazone  

line 94 : range instead of « resonate in the renge »

In the experimental part :

Line 238 : It is preferable to use the official nomenclature for compound 3 instead of ionone thiosemicarbazone ;(2E)-2-[(3E)-4-(2,6,6-Trimethyl-1-cyclohexen-1-yl)-3-buten-2-ylidene]hydrazinecarbothioamide (3) (The use of the IUPAC nomenclature conventions is preferred)

In the text, reference numbers should be placed in square brackets [ ]. For example (line 299) colorimetric spectrophotometer[39, 40].

Graphical Abstract is missing.

Author Response

(1)The manuscript was previously submitted to Elsevier in "Tetrahedron". The cover letter is addressed to Tetrahedron. The pre-print is available on the internet but with some different authors from those in this article, as well as a change of author for the correspondence. It is regrettable that it does not state why the article is being submitted to Molecules. (It should explain why the manuscript fits the scope of the journal.)

Responses: Thanks for the reviewer’s constructive suggestions. The error in the information in the cover letter was caused by our negligence, and we have corrected it. Was submitted to the Tetrahedron journal article is February, later on we rethink the structure of the article, the problems existing in the compounds added to the number and activity test, and rewrite the much of the content of the article, make the article more rigorous and complete. Referring to the published articles in the Journal Molecule, we believe that this article is appropriate for publication in the Journal Molecule

 

(2)This study concerns the synthesis of a series of thiazole hydrazone derivatives with antioxidant potential and with anti-browning ability as kojic acid a standard inhibitor. The compounds synthesised are described not in the article but in the supporting information. For some compounds, there are slight differences in the assignment of carbon atoms in the NMR description with the version previously submitted to Elsevier journal. The authors (line 95) point out that they used simulated spectra, and they should specify the program.

Responses: Thanks for the reviewer’s constructive suggestions. Due to the large number of compounds synthesized and the long length of the characterization data of the compounds, in order not to affect the reading experience of the readers, the characterization data of the compounds were placed in the supporting file. Following the advice of the tetrahedral reviewers, we modified the small number of characterization data with errors. We have over the use of simulated spectra procedures.

 

(3)In the abstract, line 22 : its IC50 value is 86.525. μmol/L . Don't forget the units. Also remember them in figures 1 and 2. Reading the figures is not made any easier by the change in order of the compounds (1a to 1y).

Responses: Thanks for the reviewer’s constructive suggestions. The abstract of the problem you mentioned has been modified. In order to facilitate reading, in figure 1 and 2 we tag for each value added data

 

(4)The authors claimed : « 11 compounds (1a, 1b, 1d, 1e, 1h, 1j, 1k, 1p, 1q, 1t, 1u) have better scavenging effect on DPPH free radical than positive control Trolox. » This is not so obvious for the compounds 1h, 1b, 1u

Responses: Thanks for the reviewer’s constructive suggestions. We have corrected this description in the article.

 

 

(5)Line 52. Instead of thiazolizone : thiazole hydrazone ,and line 94 : range instead of « resonate in the renge »

Responses: Thanks for the reviewer’s constructive suggestions. We have corrected this description in the article.

(6)Line 238 : It is preferable to use the official nomenclature for compound 3 instead of ionone thiosemicarbazone ;(2E)-2-[(3E)-4-(2,6,6-Trimethyl-1-cyclohexen-1-yl)-3-buten-2-ylidene]hydrazinecarbothioamide (3) (The use of the IUPAC nomenclature conventions is preferred)

In the text, reference numbers should be placed in square brackets [ ]. For example (line 299) colorimetric spectrophotometer[39, 40].

Responses: Thanks for the reviewer’s constructive suggestions. We have corrected this description in the article.

• Graphical Abstract is missing

Responses: Thanks for the reviewer’s constructive suggestions. We have supplemented the Graphical Abstract.

Author Response File: Author Response.doc

Round 2

Reviewer 2 Report (New Reviewer)

The paper has been revised and made better.

Author Response

Thank you very much for your valuable comments on this article and your approval of the revised article.

Reviewer 3 Report (New Reviewer)

The term thiazolizone skeleton is not appropriate. The authors have corrected line 52, but not lines 64, 74, 75. Please make the necessary changes throughout the text .

I couldn't find the graphical abstract in the attachments.

The authors have answered the questions. The manuscript is more fluid. The units have been added. According to the notes to authors, it is preferable not to superscript references in the text.

Author Response

(1) The term thiazolizone skeleton is not appropriate. The authors have corrected line 52, but not lines 64, 74, 75. Please make the necessary changes throughout the text .

Responses: Thanks for the reviewer’s constructive suggestions. We have carefully checked the full text and corrected the description in the article. 

(2)I couldn't find the graphical abstract in the attachments.

反应：感谢审稿人的建设性建议。我们将再次在附件中上传图形摘要。

 

• 根据作者的注释，最好不要在文本中上标参考文献。

反应：感谢审稿人的建设性建议。我们修改了文本中参考文献的标签。

Author Response File: Author Response.doc

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Dear authors,

I have carefully read your manuscript and I have few recommendations and remarks.

Please check your manuscript carefully for spelling, grammar, and punctuation errors.  

Please redraw Scheme 1 and enumerate all the compounds used as well please point out the exact compounds with the corresponding substituents R as required. Please use numbers in order to numerate the compounds and letters to distinguish the different examples with the different substituents. For the reader is very difficult to understand the numeration of the compounds. 

Table 1 needs an explanation. After the table please explain what R is, what is R2, and what is LR. Also, please add a graph plotting both data set results – DPPH and ABTS. This will make it easier to read the results. Also, add a comment explaining the antioxidant effects related to the structural formulas.  

In table 1 instead of/for the Trolox R-value add a simple dash “-”. 

In the Table 1 title please check the punctuation. 

The conclusion on the Results and discussion part is very lean and short. Please re-write in deep. 

In table 2 - no need for red color. If you would like to point some values out - please make the numbers bold. 

In the Synthesis part. Please add the quantities of the reagent together with the equivalents. After the % yield is given, please give the amount in mg/g you obtained. In the infrared spectroscopy data - please add the type of bond vibration. For the NMR data – no need for red color. Please change it to black. 

For the HRMS data – please calculate and include the mass error in ppm. Please enter four decimal places in the predicted mass, too.

The formulas for calculating DPPH and ABTS look odd. Please make sure all letters are the same size. 

I would like to offer to reconsider the article again after major revision.

 

 Best regards, 

 

 

 

Author Response

Please see the detail in the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

After reading the article entitled "Synthesis, Antioxidant activity and Anti-fungal activity of β-ionone thiazolylhydrazone derivatives" dealing with the synthesis and biological evaluation of several new β-ionone thiazolylhydrazones, I listed below several issues to be revised.

However, the chemistry is very simple and the results of testing are not impactful. Also, authors have not properly argued how they choose their synthetic targets.

 Scheme 1. The general structure of 2-bromoacetophenone is wrong. Also, change the way you present the substituents at phenyl ring, it is very confusing

 Spectral data

For HRMS data, give the calculated HMRS with 4 decimals as in case of found value.

Moreover, looking at supplementary MS spectra, all found values for HRMS given in paper are different of the one I can see in spectra. No information about the MS spectrometer and the ionization source and mode. Check and correct/add all these information. It looks like you did not get [M+H]⁺ ions in the presented spectra, but [M-H]^_

 FTIR data: give the wavenumbers with no decimals

 NMR: for some of the compounds proton NMR was recorded in CDCl3 and carbon NMR in DMSO-d6. Is it real? Why?

 ¹³C-NMR: for compound containing fluorine, add the description of the split signals and the corresponding coupling constants

 Table 1

There are columns in this table (R² and LR) with no information in manuscript about. What are R2 and LR ? Why they are relevant for your work? Discuss them...

 

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

The work is nice, In my opinion this synthesis is comes under eco favor approche. because in this method only ethanol and heat used. AS we know spirit itself as a green solvent.  For this add some discussion part about green chemistry synthetic published methods discussion at introduction.

Title can improve like .."eco-friendly synthesis of......

to get potentiality of this paper to publish., For your easy work use following latest references and write their discussion at introduction 

1. 2019, In: Journal of Saudi Chemical Society. 23, 3, p. 263-273 

2.  2019, In: Journal of Heterocyclic Chemistry. 56, 5, p. 1661-1666 

 

 

 

 

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Dear Authors, 

I think now your manuscript looks much better. Thank you for considering all my points. 

Kind regards,

Reviewer 2 Report

Dear Editor,

Of course, I found that manuscript is improved by comparison with the first version, but I still mantain my initial opinion that the novelty and impact are not enough in this manuscript to be published in Molecules.

 

Moreover there are some aspects that were not properly corrected, listed below:

There is no scheme 1 in the main manuscript. I found only the title of scheme, but the scheme is missing.

The scheme 1 is given only in supplementary material, but in the same confusing way as I wrote in my first report. The author corrected only the structure of 2-bromoacetophenone.

Anyway this scheme should be improved and given in the main manuscript.

 

Spectral data

 

For HRMS data, some of the interpretration of spectral data are wrong.

You have some spectra recorded in positive mode, and spectra recorded in negative mode. Therefore in some spectra you obtained positive ions, in some other you obtained negative ions.

Just few examples, but you need to check all:

-For compound 1f, you have [M-H]^- ion in HRMS spectra, not as you claim, the positive M⁺ ion; the same for 1j;

-for compound 1g, you have M+H ion, it is double because you have the two bromine isotopes 79 and 81 present; the same for 1k (you have M+H =444/446)

 

¹³C-NMR: for compound containing fluorine 1b, add the description of the split signals and the corresponding coupling constants.

Also the interpretation of ¹³C-NMR signals for compound 1q is wrong. You should have two doublets with about 250 Hz splitting for the two C-F, etc