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Article
Peer-Review Record

Structural Requirements for Antimicrobial Activity of Phenolic Nor-Triterpenes from Celastraceae Species

Appl. Sci. 2019, 9(15), 2957; https://doi.org/10.3390/app9152957
by Laila Moujir 1, Manuel R. López 1, Carolina P. Reyes 2, Ignacio A. Jiménez 2 and Isabel L. Bazzocchi 2,*
Reviewer 1: Anonymous
Reviewer 2: Anonymous
Reviewer 3: Anonymous
Reviewer 4: Anonymous
Appl. Sci. 2019, 9(15), 2957; https://doi.org/10.3390/app9152957
Submission received: 27 June 2019 / Revised: 18 July 2019 / Accepted: 19 July 2019 / Published: 24 July 2019
(This article belongs to the Special Issue Biological Activity and Applications of Natural Compounds)

Round  1

Reviewer 1 Report

Prof. Bazzocchi and co-workers presented a comprehensive report on the chemistry and biology of phenolic nor-triterpene natural products from Celastraceae species. The authors provided a detailed review of study of related natural products from peers and their own lab. Synthesis of derivatives were outlined, and structures of products were fully characterized by essential methods, including HRMS, NMRs (1D and 2D), and IRs. Specifically, the authors were using extensive 2D NMR technologies to unambiguously assign the connections, as well as the stereo-outcomes. With the library of analogues in hand, they screened the compounds in MIC assay with a few bacteria lines, from which they tried to draw conclusion for the SAR. Though still vague, the authors did best to elaborate relationships between functionalities and anti-prolierative effects. The phenol group, non-conjugated alkenes, and etc are necessary to maintain the bacteria killing effect. The manuscript was written well, and results are presented clearly in appropriate scientific way.  If possible, this reviewer would like to see that another,detailed figure in the main body which includes generalized structures and corresponding biological data (SAR). Overall, this reviewer recommend acceptance as it is. 

Author Response

As suggested by the reviewer, a more detailed Figure (Figure 4, pg 8) in the main body including generalized structures and corresponding biological data (SAR), has been added to the revised manuscript.


Reviewer 2 Report

The manuscript "Structural Requirements for Antimicrobial Activity of Phenolic nor-Triterpenes from Celastraceae species" is well written and reports interesting findings, it can be suitable for publication in Applied Sciences. However, I would encourage authors to revise a few minor concerns before publication:

- A figure with the structures of the compounds cited in the introduction (celastrol, pristimerin, tingenone, netzahualcoyone...) would be welcomed as it will help readers to situate better, and could improve the quality of presentation and overall merit of the manuscript.

- The text of the template of Molecules (lines 195-197) must be deleted.

- In the Table 1, authors could highlight (i.e. bold) those compound values that improve the activity of the positive control, so that readers can detect them better.

Author Response

1. A Figure (Figure 1, pg 2) with the compounds cited in the introduction has been included in the revised manuscript as suggested by the reviewer.

2. This item has been corrected.

3. Compounds with improved activity in comparison with the positive control are highlighted in Table 1 in the revised manuscript.


Reviewer 3 Report

Recommendation:

Taking into account that authors proposed a  hypothetical compound, 4-carboxy-6α-hydroxy-pristimerol, that would have a zeylasterone A-ring (as in studied compound 14), an un-conjugated B-ring (as in 6 and 24) and a pristimerin E-ring as being the most active  against Bacillus and Staphylococcus spp., they could estimate clogP values of this compound for comparison with data obtained for synthesized and studied compounds using as given in Reference list, 34. Software-predicted lipophilicity of the compounds was calculated with the ALOGPS 2.1 program (www.vcclab.org/lab/ alogps/) accessible via internet on-line Lipophilicity/Aqueous Solubility Calculation Softvare.

Author Response

As suggested by the reviewer, the clog P for the hypothetical compound, 4-carboxy-6α-hydroxy-pristimerol (clog P x) has been calculated (pg 9, line 315).


Reviewer 4 Report

This is an interesting manuscript that addresses the critical public health issue of identifying new antimicrobial drugs. As such, I believe this manuscript will be a valuable contribution to the field and of interest to the readers. However, there are some changes that I believe could be made to improve the readability and merit.

First, there are some English language errors throughout the manuscript. A thorough grammar and spelling check would improve the readability of the manuscript.

Second, while the conclusions are interesting and seem to be well-supported by the results, the current presentation of the conclusions makes them difficult to follow. I would suggests adding several tables or graphs to help make the conclusions stand out more clearly. For example, the authors discuss the impact of varying substituents at the C4 position on the overall activity of the various molecules tested. Rather than simply discussing this in text, the authors could show this quickly and clearly using a graph or table showing the average activity versus functional group. The authors could also use some quantitative and statistical comparisons to strengthen their conclusions. For example, the average change in activity with acetylation and methylation of the compounds could be calculated from each of the compounds listed in the comparison.

Finally, in their discussion, the authors made a very interesting proposal regarding a potential ideally effective anti-microbial compound based on the properties of the compounds that they found most effective against the tested bacteria. While the authors may consider this outside of the scope of their current study, testing the antimicrobial activity of this proposed ideal compound, 4-carboxy-6α-hydroxy-pristimerol, would be a very interesting addition to their work, and would add significantly to the impact of the paper.

Author Response

1. A grammar and spelling check of the manuscript has been carried out.

2. The authors think that Figure 3 summarizes and gives a quick and clear idea of the results of the SAR studies. Despite this, a more detailed Figure (Figure 4, pg 8) including generalized structures and corresponding biological data (SAR), has been added to the revised manuscript.

3. As mentioned in the manuscript, the 4-carboxy-6α-hydroxy-pristimerol is a proposed, ideal compound based on the SAR studies, therefore, it does not exist and it is not possible to test its antimicrobial activity. To do that, the compound would have to be synthesized, which is not the aim of the present work.


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