N-Aryl Amino Acids as Potential Antibacterial Agents
Round 1
Reviewer 1 Report
Familoni et la reported the synthesis of N-aryl amino acids and evaluation their antibacterial activities. 10 kinds of N-aryl amino acids were synthesized. In the evaluation of the antibacterial activities, 3a was more potent than streptomycin against Escherichia coli.3a,3d, 3i, 3j were more potent than streptomycin against Streptococcus pneumoniae. This paper can be accepted if the authors address the following issues:
1. The author should introduce more about the significance of N-aryl amino acids, show some examples of core structure containing peptides and proteins.
2. In line 99, 2-90 should be 25-90
3. The aryl group in the obtained products are all containing electron withdrawing groups, but no electron donating groups, the author should talk more about the influence of the aryl group to the antibacterial activities.
4. The amino acid used in the reactions are all chiral, some of the structures in Table 2 are not correct.
In summary, this paper can be accepted after major revision.
Author Response
Reviewer # 1
Comment 1: The author should introduce more about the significance of N-aryl amino acids, show some examples of core structure containing peptides and proteins.
Response: More content on the significance of N-aryl amino acids has been included and some examples of core structures (figure 1) containing peptides and proteins are provided. This can be seen between lines 38 – 51.
Comment 2: In line 99, 2-90 should be 25-90
Response: Thank you, this error has been corrected and is reflected in lines 120 and 161
Comment 3: The aryl group in the obtained products are all containing electron-withdrawing groups, but no electron-donating groups, the author should talk more about the influence of the aryl group on the antibacterial activities.
Response: Discussion on the influence of the aryl group has been included, see lines 196 - 201
Comment 4: The amino acid used in the reactions are all chiral, some of the structures in Table 2 are not correct.
Response: Thank you for the observation, corrections have been made, see Figure 2
Reviewer 2 Report
The manuscript presented by Osinubi et al. has scientific impact but results are very bad presented and the English language is poor. I have the following general remarks:
1. Authors have to present the used synthetic methodology (lines 61, 113, 125). Readers cannot jump from journal to journal to search the methodologies used in the study.
2. In line 74-75 authors mentioned: Column chromatography was performed with silica gel (300–400 mesh) and solvents. What kind of solvents? How someone could repeat this step?
3. Why authors mentioned all details between lines 66-70? Nobody is interested in which institution different analysis are done. This information in my opinion has to be removed. In the same time authors do not mentioned producers of some of the used apparatus!
4. Why authors used big first letters for chemical names of the substances as well as to mention fungi? These are not own names of the person. If they use big first letter for the word Fungi, why they do not use big first letter for parasites (line 50 for example)?
5. Scheme 1 is a real disaster. Where is X in the scheme, because in the legend is written X = F, I. And if it is true where are the iodine containing derivatives in the table 1. Moreover how compound 3g enter in the general structure in scheme 1? For n=0 the scheme is also not appropriate. This scheme has to be re-written in the other manner. In addition, all presented structures in page 4 could not be a table. This is a figure! In addition, how the configuration of 3b is determined. All other compounds are L, and 3c is with D,L-configuration? What is the reason to obtain changing in the configuration?
6. Sometime litter is marked with L another with l, please unify (line 128 for example). The units CFU/mL are not well presented (line 116)
7. In table 1 two symbols are mentioned in line 2 and 7(9), which defined 24h and 48h. And the question which arise is “How many hours the other reactions are done?”
8. In table 3 what are the units of zones? Are they in mm?
9. At many places English language is very poor. There is no verb or construction of sentences is bad. The text is needed to be revised by English speaking person.
10. In the beginning of the introduction section more recent studies on bioconjugates have to be also included. For example see
- Amanda R. P. Silva, Marina S. Guimarães, Jheniffer Rabelo, Lisandra Herrera Belén, Caio José Perecin, Jorge G Farías, João H. P. M. Santos and Carlota O. Rangel-Yagui, Recent advances in the design of antimicrobial peptide conjugates, DOI: 10.1039/D1TB02757C (Review Article) J. Mater. Chem. B, 2022, 10, 3587-3600
- Sirine Jaber, Ivan Iliev, Tsvetelina Angelova, Veronica Nemska, Inna Sulikovska, Emilia Naydenova, Nelly Georgieva, Ivan Givechev, Ivo Grabchev, Dancho Danalev, Synthesis, Antitumor and Antibacterial Studies of New Shortened Analogues of (KLAKLAK)2-NH2 and Their Conjugates Containing Unnatural Amino Acids, Molecules 2021, 26, 898. https://doi.org/10.3390/molecules26040898
- Sadiq Noor Khan, Farzana Shaheen, Umair Aleem, Sumbla Sheikh, Alfred Ngenge Tamfu, Sajda Ashraf, Zaheer Ul-Haq, Saeed Ullah, Atia-tul- Wahab, M. Iqbal Choudhary, Humera Jahan, European Journal of Pharmaceutical Sciences, Volume 168, 1 January 2022, 106045, https://doi.org/10.1016/j.ejps.2021.106045
- Dancho Danalev, Ivan Iliev, Dessislava Borisova, Tatyana Dzimbova, Tamara Pajpanova, Zdravka Zaharieva, Veronika Karadjova, Tsvetelina Foteva, Emilia Naydenova, Synthesis, anticancer activity, docking calculations and hydrolytic stability studies of bioconjugates of monofluorenated analogue of BIM-23052, Protein&Peptide Letters, 29 (8), 2022, 721-731 DOI: 10.2174/0929866529666220530085836
and many others.
My final opinion is that this article is not suitable for publication in the journal Reactions in the current form. The manuscript has to be improved at some places and pass cycle of second review.
At many places English language is very poor. There is no verb or construction of sentences is bad. The text is needed to be revised by English speaking person.
Author Response
Comment 1: Authors have to present the used synthetic methodology (lines 61, 113, 125). Readers cannot jump from journal to journal to search for the methodologies used in the study.
Response: All methodologies were presented in detail, please see lines 110 – 120 for synthetic methodology.
Line 136 – 144 for the sensitivity test and lines 146 – 157 for minimum inhibitory concentration/
Comment 2: In line 74-75 authors mentioned: Column chromatography was performed with silica gel (300–400 mesh) and solvents. What kind of solvents? How someone could repeat this step?
Response. Solvents have now been indicated, line 96
Comment 3: Why authors mentioned all details between lines 66-70? Nobody is interested in which institution different analysis are done. This information in my opinion has to be removed. In the same time authors do not mentioned producers of some of the used apparatus!
Response: The Institution of analysis has been removed and the producers of instruments details have already been indicated in lines 89 - 100
Comment 4. Why authors used big first letters for chemical names of the substances as well as to mention fungi? These are not own names of the person. If they use big first letter for the word Fungi, why they do not use big first letter for parasites (line 50 for example)?
Response: That was an oversight and has been corrected, see line 66
Comment 5: Scheme 1 is a real disaster. Where is X in the scheme, because in the legend is written X = F, I. And if it is true where are the iodine containing derivatives in the table 1. Moreover how compound 3g enter in the general structure in scheme 1? For n=0 the scheme is also not appropriate. This scheme has to be re-written in the other manner. In addition, all presented structures in page 4 could not be a table. This is a figure! In addition, how the configuration of 3b is determined. All other compounds are L, and 3c is with D,L-configuration? What is the reason to obtain changing in the configuration?
Response: Scheme 1 has been redrawn and 3g has been represented accordingly,
For n = 0 we mean to indicate an acyclic amino acid,
Table 4 has been corrected to Figure 2,
The DL pipecolinic acid is a commercially available amino acid and this was purchased and used for the synthesis of N-arylamino acid 3b.
Comment 6: Sometimes litter is marked with L another with l, please unify (line 128 for example). The units CFU/mL are not well presented (line 116)
Response: All observations on this have been corrected, see lines 138, 139, 142 etc
Comment 7: In Table 1 two symbols are mentioned in lines 2 and 7(9), which defined 24h and 48h. And the question which arises is “How many hours the other reactions are done?”
Response: The general reaction time is 3 h and was indicated in the general reaction scheme. This has now also been indicated at the base of Table 1, line 165.
Comment 8: In Table 3 what are the units of zones? Are they in mm?
Response: They are in mm, see line 187
Comment 9: At many places English language is very poor. There is no verb or construction of sentences is bad. The text is needed to be revised by English speaking person.
Response: The whole manuscript has been revised
Comment 10: At the beginning of the introduction section more recent studies on bioconjugates have to be also included.
Response: Studies have been included, see lines 38 -51
Reviewer 3 Report
The manuscript submitted by Familoni et al. presents the antibacterial activities of a series of N-Aryl amino acids, the synthesis of which was previously published by the same group. The antibacterial activities of all ten synthesized compounds against eight bacteria strains were tested by Agar well diffusion and a minimum inhibitory concentration of eight compounds was obtained.
1. Scheme 1 is not correct and needs to be fixed. There is no X in the structures. The position of R2 is not correct.
2. Line 99, yield of 3a-j should be 25-90%
3. Table 1, the yield of entry 8 is not correct based on the previously published synthetic paper.
4. In figure 1 and the paragraph in front of figure 1, the -OH from a carboxyl group could not be considered the same as a free hydroxyl (alcohol) group since the chemical environments are completely different.
Author Response
Comment 1: Scheme 1 is not correct and needs to be fixed. There is no X in the structures. The position of R2 is not correct.
Response: Scheme 1 has been redrawn and R2 has been represented accordingly.
Comment 2: Line 99, the yield of 3a-j should be 25-90%
Response: Thank you, this error has been corrected and is reflected in lines 120 and 161
Comment 3: In Table 1, the yield of entry 8 is not correct based on the previously published synthetic paper.
Response: Thank you for the observation, the correct yield has been indicated.
Comment 4: In Figure 1 and the paragraph in front of Figure 1, the -OH from a carboxyl group could not be considered the same as a free hydroxyl (alcohol) group since the chemical environments are completely different.
Response: This point is well noted and has been corrected, see line 203.
Round 2
Reviewer 1 Report
The revised manuscript has addressed my specific comments for revisions. As presented now, the experimental work is suitable for acceptance.
Author Response
Ther is no comment to respond to.
Reviewer 2 Report
Please see attachment.
Comments for author File: 
Comments.pdf
none
Author Response
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Author Response File: Author Response.pdf
