1-(3-Chlorophenyl)-3-(6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexyl)thiourea

Round 1

Reviewer 1 Report

According to a SciFinder search, the compound studied is hitherto unpublished. Hence, the present work should be suitable for publication as a one-compound short note in Molbank. The manuscript, however, is in need of revision.

- Only the first letter in the title should be capitalized.

- The compound name should contain the E configuration of the imine double bond, provided this has been proven.

- The final sentence of the abstract is more speculative than informative. That aside, "thiourea" is misspelled. The authors should improve the abstract. I recommend following the structure suggested in the MDPI article template, i.e. background (which could be inhibition of soluble epoxide hydrolase),  methods, results and so on. The abstract should contain, for example, how the title compound was prepared.

- The use of the term "scaffold" in Figure 1 is somewhat inappropriate. In medicinal chemistry, the term refers to a core structure to which different groups are bonded. Thus, I reckon in Figure 1 urea would be the scaffold to which adamantyl, bornyl or trifluormethoxy groups are attached.

- "The present study is aimed at" should be "the present study aimed at".

- "And last but not least" seems a bit colloquial and inappropriate in a scientific manuscript.

- I find the colours in Scheme 1 rather disturbing. If you want to maintain colours, I suggest turning the red colour to black and just keep the blue colour. That should suffice to highlight the building blocks.

- I wonder why it is stated that the starting material is poorly soluble specifically in hexane and diethl ether. Why not other solvents?

- I suppose that treatment of the product with 1 N aqueous HCl might also cause hydrolysis of the imine.

- "spectra were taken" should perhaps be "spectra were recorded".

- As far as I see, the source of the starting materials has not been mentioned. Can the E configuration of the imine double bond (as drawn) be confirmed?

- There appears to be mix of compound names and numbers. Once a number for a compound has been introduced (e.g. 1, 2, 3), the number should be used throughout thereafter.

- Usually, assigments for ¹³C NMR signals should only be made on the basis of 2D NMR spectra.

- The Conclusions section is not very conclusive. I think a conclusions section is not mandatory for the short note format and can probably be omitted here.

The English is understandable. Some minor editing as indicated above should be undertaken.

Author Response

According to a SciFinder search, the compound studied is hitherto unpublished. Hence, the present work should be suitable for publication as a one-compound short note in Molbank. The manuscript, however, is in need of revision.

Thank you for the review!

- Only the first letter in the title should be capitalized.

Sorry, but this correction was made by the editor. In the initially submitted manuscript there was only one capital letter “C” in the title. Corrected.

- The compound name should contain the E configuration of the imine double bond, provided this has been proven.

E/Z configuration of imine double bond was not determined. Thus we corrected the representation of the structures with crossed double bond.

- The final sentence of the abstract is more speculative than informative. That aside, "thiourea" is misspelled. The authors should improve the abstract. I recommend following the structure suggested in the MDPI article template, i.e. background (which could be inhibition of soluble epoxide hydrolase),  methods, results and so on. The abstract should contain, for example, how the title compound was prepared.

Final sentence was removed since another reviewer also highlighted its controversy. Abstract was revised.

- The use of the term "scaffold" in Figure 1 is somewhat inappropriate. In medicinal chemistry, the term refers to a core structure to which different groups are bonded. Thus, I reckon in Figure 1 urea would be the scaffold to which adamantyl, bornyl or trifluormethoxy groups are attached.

Term “scaffold” was changed to “fragment”.

- "The present study is aimed at" should be "the present study aimed at".

Corrected.

- "And last but not least" seems a bit colloquial and inappropriate in a scientific manuscript.

Changed to “Finally”.

- I find the colours in Scheme 1 rather disturbing. If you want to maintain colours, I suggest turning the red colour to black and just keep the blue colour. That should suffice to highlight the building blocks.

We changed red colour to black.

- I wonder why it is stated that the starting material is poorly soluble specifically in hexane and diethl ether. Why not other solvents?

These are the most common solvents for the urea synthesis. Most of amines usually soluble in these solvents and ureas not, which simplifies the isolation. Unlike the DMF these solvent could be easily removed. Some researchers sometimes use DCM but we encountered decent solubility of ureas in this solvent.

- I suppose that treatment of the product with 1 N aqueous HCl might also cause hydrolysis of the imine.

We suppose that imines are not so easily hydrolysed in mild conditions. Previously we used salt formation for the isolation of other imines and no traceable hydrolysis was observed.

- "spectra were taken" should perhaps be "spectra were recorded".

Corrected.

- As far as I see, the source of the starting materials has not been mentioned. Can the E configuration of the imine double bond (as drawn) be confirmed?

E/Z configuration of imine double bond was not determined. Thus we corrected the representation of the structures with crossed double bond.

- There appears to be mix of compound names and numbers. Once a number for a compound has been introduced (e.g. 1, 2, 3), the number should be used throughout thereafter.

Corrected.

- Usually, assignments for 13C NMR signals should only be made on the basis of 2D NMR spectra.

Assignments for 1H and 13C of the bornylidene fragment were made according to [13]. In that manuscript assignments were made according to “combination of 1D and 2D experiments (COSY, COLOC, HSCQ, HMBC)”. We can remove assignments if it’s important, but we think it’s possible to leave it in its current form.

- The Conclusions section is not very conclusive. I think a conclusions section is not mandatory for the short note format and can probably be omitted here.

We looked through several recent Molbank papers. Some of them in fact to not have conclusions. The other have conclusions similar to our one. We added more data to the conclusions and would like to keep this section.

Reviewer 2 Report

This short note describes the synthesis of a new compound, the 1-(3-chlorophenyl)-3-(6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexyl)thiourea. The synthesis method is simple and well described with enough detail to be reproduced.

The compound was characterized by NMR (1H and 13C) and by FTIR. I would recommend adding mass spectrometry, and X-ray to complete the characterization of this compound.

I also recommend to present the assignment of 1H and 13C signals in a different and more usual format: 0.68 (s, 3H, H-9), 0.84 (s, 3H, H-9’)… 12.2 (C-8), 19.5 (C-9), 19.9 (C-9’), 27.0 (C-12). Note that for 13C NMR shifts it is not necessary to use two decimal points.

In the abstract the authors stated that this thourea could serve as an inhibitor of soluble epoxide hydrolase (sEH) and possess analgesic and antiviral activity. However, in the paper there are no evidence of this type of activities for the described compound.

I recommend the addition of the results regarding epoxide hydrolase (sEH) inhibition and analgesic and antiviral activity. The addition of these results may contribute to improve the significance of the content, its scientific soundness and interest to readers. Otherwise, the statement “this thourea could serve as an inhibitor of soluble epoxide hydrolase (sEH) and possess analgesic and antiviral activity” should be removed from the abstract.

There are also some typos that need to be corrected:

Abstract: change possess by possesses

Page 1, last paragraph correct the sentence “…adamantylcontaning 1,3-disubti￾tuted thioureas…” as “…adamantly-contaning 1,3-disubstituted thioureas…”.

Page 2: correct the sentence “…or at least are significantly posess higher water solubility…” by deleating “are”.

Please check if the author name Burmisrov is correct.

English language is fine. Only minor editing of some few typos are necessary.

Author Response

This short note describes the synthesis of a new compound, the 1-(3-chlorophenyl)-3-(6-((1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene)amino)hexyl)thiourea. The synthesis method is simple and well described with enough detail to be reproduced.

Thank you for the review!

The compound was characterized by NMR (1H and 13C) and by FTIR. I would recommend adding mass spectrometry, and X-ray to complete the characterization of this compound.

We added mass spectre of reported compound to the manuscript. Unfortunately we were not able to prepare crystal of reported compound suitable for X-ray diffraction analysis.

I also recommend to present the assignment of 1H and 13C signals in a different and more usual format: 0.68 (s, 3H, H-9), 0.84 (s, 3H, H-9’)… 12.2 (C-8), 19.5 (C-9), 19.9 (C-9’), 27.0 (C-12). Note that for 13C NMR shifts it is not necessary to use two decimal points.

Corrected

In the abstract the authors stated that this thourea could serve as an inhibitor of soluble epoxide hydrolase (sEH) and possess analgesic and antiviral activity. However, in the paper there are no evidence of this type of activities for the described compound.

I recommend the addition of the results regarding epoxide hydrolase (sEH) inhibition and analgesic and antiviral activity. The addition of these results may contribute to improve the significance of the content, its scientific soundness and interest to readers. Otherwise, the statement “this thourea could serve as an inhibitor of soluble epoxide hydrolase (sEH) and possess analgesic and antiviral activity” should be removed from the abstract.

Data on the sEH inhibition activity will be published for the whole series of compounds as soon as these tests will be completed. Statement was removed from the abstract.

There are also some typos that need to be corrected:

Abstract: change possess by possesses

Whole sentence was removed.

Page 1, last paragraph correct the sentence “…adamantylcontaning 1,3-disubtituted thioureas…” as “…adamantly-contaning 1,3-disubstituted thioureas…”.

Corrected

Page 2: correct the sentence “…or at least are significantly posess higher water solubility…” by deleating “are”.

Corrected

Please check if the author name Burmisrov is correct.

Corrected

Round 2

Reviewer 2 Report

Dear Authors,

In the final version of the paper, please correct the C=N double bond of the structures presented in Scheme 1 and Figure 2.

English language is fine. Only minor editing of English language may be necessary.

Author Response

This change in the structure (scheme 1 and fig 2) was requested by another reviewer. Reported molecule could be in two forms (E) and (Z). And as soon as we do not prove specific form (most likely there is a mixture) we should use this crossed bond.