Design and Synthesis of New Boron-Based Benzo[c][1,2,5]oxadiazoles and Benzo[c][1,2,5]thiadiazoles as Potential Hypoxia Inhibitors
Round 1
Reviewer 1 Report
The article has an interesting theme, the research leading to the synthesis of 17 new compounds as potential inhibitors of hypoxia.
However, I believe that the authors did not prepare the article carefully. First, the Materials and Methods chapter is missing from the article, but it is wrongly included in Supplementary Material.
I also think the article should be completed with tests of biological activity as hypoxia inhibitors.
I believe that the article has potential for publication if it will be carefully reviewed by the authors and completed to increase its scientific level.
Author Response
Reviewer 1:
Overall Comment: The article has an interesting theme, the research leading to the synthesis of 17 new compounds as potential inhibitors of hypoxia. I believe that the article has potential for publication if it will be carefully reviewed by the authors and completed to increase its scientific level.
Response: Thank you to reviewer 1 for accepting our article and appreciating the theme of our research program. We carefully reviewed our article according to reviewer’s comments and resubmitting for your kind approval.
Query: However, I believe that the authors did not prepare the article carefully. First, the Materials and Methods chapter is missing from the article, but it is wrongly included in Supplementary Material.
Response: Materials and Methods chapter has been removed from Supplementary Material and included in the revised manuscript (page 6-14) as suggested by reviewer.
Query: I also think the article should be completed with tests of biological activity as hypoxia inhibitors.
Response: Thanks to the reviewer’s for advice. We heartily appreciate reviewer’s suggestion. Partially we did some testing (not all compounds) with our old hypoxia chambers, due to some technical cell contamination, we couldn’t able to get good results. We are in the process to purchase new chambers and it will take some time to test all these compounds. Our ultimate aim to do in-vivo work, but in this paper we would like to publish the synthetic methodologies so these new compounds. This methodology and compounds will be very attractive to Inorganic and organic and Medicinal Chemistry community.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Indeed, boron-based hetereocycles are being established as vital templates in the field of medicinal chemistry after the FDA approval ofnew boron-based drugs (e.g. Vaborbactam, Ixazomib, crisaborole, tavaborole and bortezomib)
Tavaborole –2014 FDA approved,
Bortezomib – 2003-2006 FDA approved.
Crisaborole – 2016 FDA approved
Ixazomib – 2015 FDA approved
Vaborbactam – 2017 FDA approved
That is, bortezomib was approved a very long time ago and is not a new boron-based drug.
It is necessary to reformulate the proposal without removing the drug Bortezomib. The change is not significant, but the article will be better.
Classic article sections mdpi:
1) Introduction
2) Materials and Methods
3) Results and Discussion
4) Conclusion
or
1) Introduction
2) Materials and Methods
3) Results
4) Discussion
5) Conclusion
In both cases there should be a section «Materials and Methods»
The entire article is dedicated to the synthesis of new hybrids of benzo[ c][1,2,5]oxadiazoles/thiadiazoles and boronic acid pinacol esters by molecular hybridization via amine and ether linkage. However, the authors hid all the nuances of the synthesis in the supplementary and inaccurately indicate the synthesis conditions.
For example:
Synthethic Scheme 1. General synthetic scheme of boron-based compounds. Reagents and 3 conditions: (i) DMF, 95 °C (ii) tBuONa, DMF, room temperature; (iii) Et3N, ACN, room temperature (iv) KHF2, MeOH.
Or
«Scheme 2. Synthesis of boronic acid derivative (23). Reagents and conditions: (v) SiO2, EtOAc, H2O.1-2h room temperature»
What room temperature: 22 or 25C?
You need to remove the Supplementary. Transfer data from the Supplementary to the appropriate sections: 2) Materials and Methods 3) Results 4) Discussion
Also, everywhere for reactions, indicate more precisely the reaction conditions, the ratio of reagents, conversion, yield of target products, indicate by-products (they can be brought into supplementary).
Author Response
Reviewer 2:
Query: Indeed, boron-based hetereocycles are being established as vital templates in the field of medicinal chemistry after the FDA approval ofnew boron-based drugs (e.g. Vaborbactam, Ixazomib, crisaborole, tavaborole and bortezomib). Tavaborole –2014 FDA approved,Bortezomib – 2003-2006 FDA approved. Crisaborole – 2016 FDA approved, Ixazomib – 2015 FDA approved, Vaborbactam – 2017 FDA approved. That is, bortezomib was approved a very long time ago and is not a new boron-based drug. It is necessary to reformulate the proposal without removing the drug Bortezomib. The change is not significant, but the article will be better.
Response: The proposed changed has been incorporated in the revised manuscript (Page # 2, paragraph 1) as suggested by the reviewer.
Query: Classic article sections mdpi:
1) Introduction
2) Materials and Methods
3) Results and Discussion
4) Conclusion
or
1) Introduction
2) Materials and Methods
3) Results
4) Discussion
5) Conclusion
In both cases there should be a section «Materials and Methods»
Response: Materials and Methods chapter has been removed from Supplementary Material and included in the revised manuscript (page 6-14) as the format of the journal as suggested by reviewer.
Query: The entire article is dedicated to the synthesis of new hybrids of benzo[ c][1,2,5]oxadiazoles/thiadiazoles and boronic acid pinacol esters by molecular hybridization via amine and ether linkage. However, the authors hid all the nuances of the synthesis in the supplementary and inaccurately indicate the synthesis conditions.
For example:
Synthethic Scheme 1. General synthetic scheme of boron-based compounds. Reagents and 3 conditions: (i) DMF, 95 °C (ii) tBuONa, DMF, room temperature; (iii) Et3N, ACN, room temperature (iv) KHF2, MeOH.
Or
«Scheme 2. Synthesis of boronic acid derivative (23). Reagents and conditions: (v) SiO2, EtOAc, H2O.1-2h room temperature»
What room temperature: 22 or 25C?
Response: Materials and Methods section has been incorporated in the revised manuscript (page 6-14). The reaction conditions and specific room temperature has been indicated in the revised manuscript (page 4 and 5) as suggested by reviewer.
Query: You need to remove the Supplementary. Transfer data from the Supplementary to the appropriate sections: 2) Materials and Methods 3) Results 4) Discussion
Response: Materials and Methods chapter has been removed from Supplementary Material and included in the revised manuscript (page 6-14) as suggested by reviewer.
Query: Also, everywhere for reactions, indicate more precisely the reaction conditions, the ratio of reagents, conversion, yield of target products, indicate by-products (they can be brought into supplementary).
Response: The above mentioned changes are now incorporated in Materials and Methods section of the revised manuscript (page 4 and 5; pages 6-14) as suggested by reviewer.
Author Response File: Author Response.pdf
Reviewer 3 Report
The presented manuscript “Design and synthesis of new boron-based benzo[c][1,2,5]oxadiazoles and benzo[c][1,2,5]thiadiazoles as Potential Hypoxia inhibitors” deals with synthesis of series benzo[c][1,2,5]oxadiazoles and benzo[c][1,2,5]thiadiazoles linked via amine or oxygen bridge with p-boron-substituted phenyl group.
The results obtained are reliable and do not cause any complaints.
It is a good organic (!) synthetic work. And it is very strange to find manuscript in Inorganics. I think that journal profile is inorganic chemistry but the presented manuscript described only organic transformations of compounds. Because of it I take “Reject” to this manusctipt in Inorganics.
I think that the Authors need to send its manuscript to the other journal with the subject of organic chemistry.
Also I have some minor points.
i) The authors named their products “hybrids” but it’s a simple product of alkylation of primary amine to secondary (or ethers). "Entities should not be multiplied beyond necessity" said Occam's razor.
ii) Unfortunately the 11B and 19F NMR spectra of corresponding products are absent. These spectra provide control of purity of compounds.
Author Response
Reviewer 3:
The presented manuscript “Design and synthesis of new boron-based benzo[c][1,2,5]oxadiazoles and benzo[c][1,2,5]thiadiazoles as Potential Hypoxia inhibitors” deals with synthesis of series benzo[c][1,2,5]oxadiazoles and benzo[c][1,2,5]thiadiazoles linked via amine or oxygen bridge with p-boron-substituted phenyl group.
The results obtained are reliable and do not cause any complaints.
It is a good organic (!) synthetic work. And it is very strange to find manuscript in Inorganics. I think that journal profile is inorganic chemistry but the presented manuscript described only organic transformations of compounds. Because of it I take “Reject” to this manusctipt in Inorganics.
I think that the Authors need to send its manuscript to the other journal with the subject of organic chemistry.
Also I have some minor points.
Query: i) The authors named their products “hybrids” but it’s a simple product of alkylation of primary amine to secondary (or ethers). "Entities should not be multiplied beyond necessity" said Occam's razor.
Response: The above mentioned changes are now incorporated and the word ‘hybrids’ have been replaced in the revised version of the manuscript (page 4; second paragraph) as suggested by reviewer.
Query: ii) Unfortunately the 11B and 19F NMR spectra of corresponding products are absent. These spectra provide control of purity of compounds.
Response: 19F NMR of compounds 15, 16, 20 and 21 have been incorporated in the revised manuscript (page 11,12 and 13) in both the material and methods section and supplementary information (page 20,21, 26 and 28) as suggested by reviewer. 11B NMR some are reported.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
I appreciated the increase in the scientific level of the article by Das and col.
I understood the impossibility of the authors researching the biological effects of the synthesized compounds.
The authors should also pay attention to the following aspects:
Discussion of NMR spectral aspects. What are the most important signals that prove the structure of the synthesized compounds?
The presentation of the compounds in the text must be done uniformly, with the number written in bold; often they are written between parentheses or without using bold characters.
The name of the companies producing the substances must be written in capital letters (Fischer, Sigma-Aldrich).
The manufacturing companies of the equipment used for spectral characterization should be added.
Revised, I believe the article can reach a form in which it can be published.
Author Response
Reviewer 1:
We heartily thankful to reviewer 1 for the appreciation “I appreciated the increase in the scientific level of the article by Das and col”.
Query: I understood the impossibility of the authors researching the biological effects of the synthesized compounds.
Response: We thank the reviewer for his useful suggestions and for understanding the scope of our paper.
The authors should also pay attention to the following aspects:
Query: Discussion of NMR spectral aspects. What are the most important signals that prove the structure of the synthesized compounds?
Response: Discussion of NMR spectral aspects including the most important signals that prove the structure of the synthesized compound has been included in the results and discussion section of revised manuscript (page 5) as suggested by reviewer.
Query: The presentation of the compounds in the text must be done uniformly, with the number written in bold; often they are written between parentheses or without using bold characters.
Response: The comment has been and addressed and uniform presentation of the compounds in the text are incorporated in the revised manuscript.
Query: The name of the companies producing the substances must be written in capital letters (Fischer, Sigma-Aldrich).
Response: The above changes have now been incorporated in the material and methods section of revised manuscript (page 7).
Query: The manufacturing companies of the equipment used for spectral characterization should be added.
Response: The above changes have now been incorporated in the material and methods section of revised manuscript (page 7).
Reviewer 3 Report
The authors was carefully corrected all the points I wrote. I think it improved the manuscript.
I'm not afraid to repeat myself, but in my opinion, it is better to redirect the manuscript to another journal, such as Molecules.
If the Editor considers that the manuscript matches the profile of Inorganics, I believe that the article may be published in present form without further corrections.
Author Response
Reviewer 3:
Reviewer 3: The authors was carefully corrected all the points I wrote. I think it improved the manuscript.
Thank you reviewer 2 for your positive feedback. We tried our best to add all experiments, detail analysis of newly synthesized compounds.
Query: I'm not afraid to repeat myself, but in my opinion, it is better to redirect the manuscript to another journal, such as Molecules. If the Editor considers that the manuscript matches the profile of Inorganics, I believe that the article may be published in present form without further corrections.
Response: We thank and appreciate the reviewer for his constructive suggestions. However, our lab is focused on synthesizing new boron based compounds and as the special issue (Fifth Element: The Current State of Boron Chemistry) deals with the boron element, we believe that it is the right journal to publish our current findings for diversity audience to read our paper.
