Hypecoum spp.—Chemistry and Biological Activity of Alkaloids
Round 1
Reviewer 1 Report
The manuscript entitled “Hypecoum spp. – Chemistry and Biological Activity of Alkaloids (Manuscript ID：diversity-2538404)” reviewed systematically the ethnomedicinal, phytochemical, and pharmacological studies of alkaloids and extracts obtained from Hypecoum plants. The ethnomedicinal, phytochemical, and pharmacological studies of alkaloids and extracts obtained from Hypecoum plants were elucidated by a systematic literature review, including scientific databases, “SCOPUS”, “Google Scholar”, “ISI Web of Knowledge”, “Science Direct”, “PubMed”, and “Wiley Online Library”.. This manuscript is suitable for publishing in Diversity. However, although part of these findings is interesting, this manuscript could not reach the standard for being published on Diversity in its present form. It is suggested to reconsider whether this manuscript is suitable for publication on Diversity after a major revision. Please pay attention to the following points.
1. When the authors reviewed the chemical constituents isolated from Hypecoum plants, the authors should focus on scifinder schoolar: https://scifinder.cas.org/;
2. The chemical structures of isolated compounds in the manuscript is too ugly, they should be redraw using ChemDraw in new ACS document 1996 mode;
3. The author needs to pay attention to the representation of chiral alkaloids and chiral centers;
4. Considering that the total number of isolated and identified compounds from Hypecoum plants is relatively small, it is recommended to review the mechanism of action of active compounds or the total synthesis method of representative compounds.
4. Correction of English is necessary throughout the manuscript line by line.
Author Response
Point 1: When the authors reviewed the chemical constituents isolated from Hypecoum plants, the authors should focus on scifinder schoolar: https://scifinder.cas.org/;
Response 1: Thank you for the suggestion. The aim of our work was to present all chemical structures of the isoquinoline alkaloids that have been reported for genus Hypecoum since 1972. For this purpose, relevant data were collected through all possible scientific databases, as "SCOPUS", "Google Scholar", "ISI Web of Knowledge", "ScienceDirect", "PubMed", "Wiley Online Library". At your suggestion we also included and "SciFinder Scholar".
Point 2: The chemical structures of isolated compounds in the manuscript is too ugly, they should be redraw using ChemDraw in new ACS document 1996 mode;
Response 2: Thank you for your constructive suggestions. We are sorry for our mistake. We have redraw all chemical structures using ChemDraw in ACS document 1996 mode as your suggestion.
Point 3: The author needs to pay attention to the representation of chiral alkaloids and chiral centers;
Response 3: We have carefully revised the chiral alkaloids and have represented their chiral centers in Table 2.
Point 4: Considering that the total number of isolated and identified compounds from Hypecoum plants is relatively small, it is recommended to review the mechanism of action of active compounds or the total synthesis method of representative compounds.
Response 4: Thank you for your recommendation. In this manuscript, we review the chemical structures of natural isoquinoline alkaloids in the poorly studied genus Hypecoum and their biological activities. To enrich the manuscript and the knowledge of natural products, we decided to present the biosynthetic pathway of the isoquinoline alkaloids obtained in the genus Hypecoum and to comment on their possible use for chemotaxonomic purposes. See new point 5. Biosynthesis and chemotaxonomical relevance of isoquinoline alkaloids.
We hope our revised manuscript could meet your satisfaction.
Comments on the Quality of English Language: Correction of English is necessary throughout the manuscript line by line.
Response: We have carefully revised our manuscript and mistakes were corected.
Reviewer 2 Report
This is an organized and comprehensive review that encompasses the alkaloids reported in the last 5 decades in the Hypecoum genus and their potential biological activity. The work is interesting in terms of knowledge as a compilation of the chemical diversity of the Hypecoum genus and the Papaveraceae family. For this reason, I consider that should be crucial to emphasize the chemotaxonomic relevance of those metabolites as markers of the Hypecoum genus, as well as their possible ecological role and the potential relationship with their biological activities. Which was briefly mentioned in the body of the manuscript (4.6. Secoberberine alkaloids), and which should be included in the abstract and the keywords.
The chemical part of the review might be better addressed by focusing on the structural traits of each subgroup of alkaloids, as mentioned before the possible chemotaxonomic importance. Additionally, I suggest pointing out the stereochemistry, indicating chiral centers for each class of alkaloids, when relevant. Likewise, it should be recommendable to homogenize the nomenclature of chiral carbons both in names and in the structures, in fact, some structures (70 and 71) have the absolute configuration in the name but not in the structure, other molecules that have a chiral center do not have the configuration. It would be recommended to use the R, S nomenclature for all the names and structures. All the above, considering the crucial role of stereochemistry at the biological and pharmacological level.
In Table 2, structures 83 to 85 do not correspond to alkaloids, those are amides, therefore I suggest deleting them to avoid further misunderstandings.
On the other hand, several sentences related to biological activity are presented in section 4, to avoid duplicated information might be convenient just to focus on the chemical features in section 4.
Regarding the biological activity, I strongly suggest including concise data such as concentrations, doses, percentages of inhibition, etc, particularly for the Anti-inflammatory, cytotoxic and antibacterial reports (5.1, 5.2, 5.3). Also, it would be enriching for the manuscript to include a critical analysis of the mentioned studies, limitations, and future potential.
A few sentences require small modifications and improvements.
Author Response
Point 1: The work is interesting in terms of knowledge as a compilation of the chemical diversity of the Hypecoum genus and the Papaveraceae family. For this reason, I consider that should be crucial to emphasize the chemotaxonomic relevance of those metabolites as markers of the Hypecoum genus, as well as their possible ecological role and the potential relationship with their biological activities. Which was briefly mentioned in the body of the manuscript (4.6. Secoberberine alkaloids), and which should be included in the abstract and the keywords.
Response 1: Thank you for your constructive suggestions. The chemotaxonomic relevance of isoquinoline alkaloids as markers of the Hypecoum genus is added in a new section 5. “Biosynthesis and chemotaxonomical relevance of isoquinoline alkaloids”, as well as in the abstract and the keywords.
Point 2: The chemical part of the review might be better addressed by focusing on the structural traits of each subgroup of alkaloids, as mentioned before the possible chemotaxonomic importance.
Response 2: The chemotaxonomic data are excluded from section 4.6. Secoberberine alkaloids and are added in a new section 5.
Point 3: Additionally, I suggest pointing out the stereochemistry, indicating chiral centers for each class of alkaloids, when relevant. Likewise, it should be recommendable to homogenize the nomenclature of chiral carbons both in names and in the structures, in fact, some structures (70 and 71) have the absolute configuration in the name but not in the structure, other molecules that have a chiral center do not have the configuration. It would be recommended to use the R, S nomenclature for all the names and structures. All the above, considering the crucial role of stereochemistry at the biological and pharmacological level.
Response 3: We carefully revised the chiral alkaloids and represented their chiral centers using R,S nomenclature, both in names and structures (Table 2).
Point 4: In Table 2, structures 83 to 85 do not correspond to alkaloids, those are amides, therefore I suggest deleting them to avoid further misunderstandings.
Response 4: The amides (83-85) are delited from Table 2 and from the text.
Point 5: On the other hand, several sentences related to biological activity are presented in section 4, to avoid duplicated information might be convenient just to focus on the chemical features in section 4.
Response 5: In section 4, we have presented the chemical characteristics of the identified classes of isoquinoline alkaloids and the most important biological activities of the main alkaloids in individual groups are briefly mentioned.
Point 6: Regarding the biological activity, I strongly suggest including concise data such as concentrations, doses, percentages of inhibition, etc, particularly for the Anti-inflammatory, cytotoxic and antibacterial reports (5.1, 5.2, 5.3). Also, it would be enriching for the manuscript to include a critical analysis of the mentioned studies, limitations, and future potential.
Response 6: We have included the data you recommended, such as concentrations, doses, percentages of inhibition, etc., in Section 6. (6.1, 6.2, 6.3) (highlighted in yellow). A critical analysis of the mentioned studies, limitations and future potential is included in Section 7. Conclusion and Future Perspectives.
Reviewer 3 Report
Authors made a very good review of this litlle known genus regarding their bioactivities. The manuscript is well writen and I include some suggestions for their improve.
Comments for author File: 
Comments.pdf
The English grammar can be improved
Author Response
Point 1: Authors made a very good review of this litlle known genus regarding their bioactivities. The manuscript is well writen and I include some suggestions for their improve.
Response 1: Thank you for your constructive suggestions. The corrections we made and the answers to your questions are in the attached file.
Author Response File: Author Response.pdf
Reviewer 4 Report
In this manuscript, the authors reviewed the traditional use data, chemistry and biological activity of the alkaloids of the relative poorly studied genus Hypecoum.
The manuscript is suitable for publication after minor revision.
The numbering of the skeleton is missing in case of the spiro-compound procumbine (50) and peshawarine (59).
line 118. Their structures include…
line 128: N-methyl function (N should be written in Italic.)
line 191: The authors studied… (instead of investigated)
line 311: The researchers Bustani et al. [61] studied 29 medicinal plants…
line 118. Their structures include…
line 191: The authors studied… (instead of investigated)
line 311: The researchers Bustani et al. [61] studied 29 medicinal plants…
Author Response
Point 1: In this manuscript, the authors reviewed the traditional use data, chemistry and biological activity of the alkaloids of the relative poorly studied genus Hypecoum.
The manuscript is suitable for publication after minor revision.
The numbering of the skeleton is missing in case of the spiro-compound procumbine (50) and peshawarine (59).
line 118. Their structures include…
line 128: N-methyl function (N should be written in Italic.)
line 191: The authors studied… (instead of investigated)
line 311: The researchers Bustani et al. [61] studied 29 medicinal plants…
Response 1: Thank you for pointing out our mistakes. Your suggestions are constructive for our manuscript.
The numbering of the skeleton of the spiro-compound procumbine (50) and peshawarine (59) have added.
The mistakes you mentioned (line: 118, 128, 191 and 311) were carefully corrected.
Round 2
Reviewer 2 Report
Most of the suggestions were considered and adequately addressed in this manuscript version.
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