Using 5-Nitroimidazole Derivatives against Neglected Tropical Protozoan Diseases: Systematic Review
, Edgar López-López 2,*, Catalina Soriano-Correa 3 and Carolina Barrientos-Salcedo 4,*
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe review by Vichi-Ramírez et al. entitled “5-Nitroimidazole Derivatives Against Neglected Tropical Protozoan Diseases: Systematic Review” brings an interesting contribution to the field of Medicinal Chemistry. However, the authors could consider some points to make the manuscript more appropriate for the proposed objective, as discussed below.
1. I recommend checking the sentence “Neglected tropical diseases (NTDs) are caused by protozoan parasites” (line 16) because not all NTDs are caused by protozoans. For instance, according to WHO, leprosy is an NTD, and a bacteria cause it. Dengue is also an NTD but is caused by a virus.
2. As the authors propose discussing 5-Nitroimidazole derivatives, it would be important to mention in the text whether papers discussed something specific about the nitro group. I suggest including more discussion about the possible toxic effects of the nitro group, perhaps including some schematic showing the formation of reactive species, among other aspects.
3. May the side effects caused by 5-Nitroimidazole (5-NI) derivatives be associated with the nitro group? Could the authors add some discussion about it in the introduction?
4. In line 156, please check if “nitrogen” should not be “nitro”.
5. In Figure 3, the authors should add other compounds from reference [16], including their IC50, or maybe mention that compounds 1 and 2 were more promising to explain why. Because just showing these two compounds and saying that there is an IC50 range is very vague and not very informative. The same applies to all other cases (Figure 4); either add all compounds with their respective IC50 or select some examples from each reference explaining why they are highlighted.
6. I suggest putting together Figure 4 and Table 1 or at least mentioning in Figure 4 what the “R” substituents mean. Similar to other cases (Figure 5/Table 2, Figure 9/table 6, Figure 11/table 7, Figure 13/table 9, Figure 17/ table 11 and so on).
7. Table 2 has some information missing. In all tables where any information is missing, especially IC50, the authors must either place a dash in the corresponding place or add a note justifying the absence of information, but it cannot be left blank.
8. In line 200, “of four 5-NI derivatives based on pyrazoline” the number of compounds “25-28” must be added.
9. Include a reference in lines 126-127 and 396-399
10. In lines 164-168, the authors mentioned the fexinidazole and its derivatives but did not number these compounds (51-53). The corresponding number must be associated whenever a compound is mentioned in the text. Please note this for the entire manuscript.
11. In Table 5, please check if “mg/kg -1” is correct. Is the number “-1” necessary? Because there is the symbol “/”.
12. In “2-(1-methyl-5-nitro-1H- imidazol-2-yl)” the “1H” should be in italics. The authors should check all these small details.
13. In Figures 10, 16, and 18, if the authors intend to show a chemical reaction, please add the complete reaction information: solvent, time, temperature, and reagents.
14. Paragraphs 311-314 and 319-324 must be together.
15. In line 338, “they synthesized six molecules”, but only three are described in the review. Please check this.
16. Please include some references in (lines 361-362) “Several research groups have directed their focus toward quinoline and metronidazole hybrids as a potential solution for VL”. Mainly because the authors said "several groups" but only discussed one of them. In this case, it would also be interesting to include a justification for why this specific example was selected.
17. In line 458, “They concluded that the substitution of the bromine atom at position 8 with aryl moieties”, it is not clear where the position 8 is. Furthermore, authors need to mention exactly what these compounds are.
18. “in silico” (line 576) must be in italics.
19. During the review, authors could present more discussions, make comparisons, and discuss other authors' conclusions, among other things. This way, the manuscript would be more interesting and critical.
Author Response
The review by Vichi-Ramírez et al. entitled “5-Nitroimidazole Derivatives Against Neglected Tropical Protozoan Diseases: Systematic Review” brings an interesting contribution to the field of Medicinal Chemistry. However, the authors could consider some points to make the manuscript more appropriate for the proposed objective, as discussed below.
Response: All the authors of this work thank you for your detailed and useful review. We have attended to each of your comments, which improved the quality of this work.
- I recommend checking the sentence “Neglected tropical diseases (NTDs) are caused by protozoan parasites” (line 16) because not all NTDs are caused by protozoans. For instance, according to WHO, leprosy is an NTD, and bacteria cause it. Dengue is also an NTD but is caused by a virus.
Response: We appreciate this observation. The abstract and main text were modified according to your suggestion.
- As the authors propose discussing 5-Nitroimidazole derivatives, it would be important to mention in the text whether papers discussed something specific about the nitro group. I suggest including more discussion about the possible toxic effects of the nitro group, including some schematic showing the formation of reactive species, among other aspects.
Response: According to your suggestion we improved the discussion around the impact of the nitro group, and we added Figure 1 to discuss it.
- May the side effects caused by 5-Nitroimidazole (5-NI) derivatives be associated with the nitro group? Could the authors add some discussion about it in the introduction?
Response: In agreement with your suggestion we improve the discussion around the side effects associated with the nitro group.
- In line 156, please check if “nitrogen” should not be “nitro”.
Response: The modification was done. The correction is shown on line 164 of the revised document.
- In Figure 3, the authors should add other compounds from reference [16], including their IC50, or maybe mention that compounds 1 and 2 were more promising to explain why. Because just showing these two compounds and saying that there is an IC50 range is very vague and not very informative. The same applies to all other cases (Figure 4); either add all compounds with their respective IC50 or select some examples from each reference explaining why they are highlighted.
Response: Following their suggestion, the current Figure 4 was modified to show the Quinoline-based 5-nitroimidazole derivatives with the best activity values.
- I suggest putting together Figure 4 and Table 1 or at least mentioning in Figure 4 what the “R” substituents mean. Similar to other cases (Figure 5/Table 2, Figure 9/table 6, Figure 11/table 7, Figure 13/table 9, Figure 17/ table 11 and so on).
Response: We have modified the current Figure 5 accordingly. Now this figure only has a single "R" group, which avoids possible confusion in the interpretation of Table 1. We appreciate this valuable suggestion.
- Table 2 has some information missing. In all tables where any information is missing, especially IC50, the authors must either place a dash in the corresponding place or add a note justifying the absence of information, but it cannot be left blank.
Response: Table 2 was corrected.
- In line 200, “of four 5-NI derivatives based on pyrazoline” the number of compounds “25-28” must be added.
Response: According to your suggestion. The compound numbers were added (Line 214).
- Include a reference in lines 226-227 and 396-399
Response: References 20 (line 240) and 35 (line 410) were added, respectively.
- In lines 264-268, the authors mentioned fexinidazole and its derivatives but did not number these compounds (51-53). The corresponding number must be associated whenever a compound is mentioned in the text. Please note this for the entire manuscript.
Response: Compounds 51-53 were mentioned explicitly in the main text. Line 280.
- In Table 5, please check if “mg/kg -1” is correct. Is the number “-1” necessary? Because there is the symbol “/”.
Response: Table 5 was corrected.
- In “2-(1-methyl-5-nitro-1H- imidazol-2-yl)” the “1H” should be in italics. The authors should check all these small details.
Response: Thanks a lot for this typography observation. The modification was done, and the main text was revised according to this suggestion.
- In Figures 10, 16, and 18, if the authors intend to show a chemical reaction, please add the complete reaction information: solvent, time, temperature, and reagents.
Response: Figures 11, 17, and 19 were modified to illustrate correctly the structures.
- Paragraphs 311-314 and 319-324 must be together.
Response: The paragraphs were put together. Line 323 - 331.
- In line 338, “they synthesized six molecules”, but only three are described in the review. Please check this.
Response: The sentence was corrected. Line 351.
- Please include some references in (lines 361-362) “Several research groups have directed their focus toward quinoline and metronidazole hybrids as a potential solution for VL”. Mainly because the authors said "several groups" but only discussed one of them. In this case, it would also be interesting to include a justification for why this specific example was selected.
Response: The sentence was corrected. Line 372.
- In line 458, “They concluded that the substitution of the bromine atom at position 8 with aryl moieties”, it is not clear where the position 8 is. Furthermore, the authors need to mention exactly what these compounds are.
Response: We modified the main text to mention explicitly that the aryl moiety addition in 66y improves the activity of all of their derivatives (67a - 67m). Line 470.
- “in silico” (line 576) must be in italics.
Response: Todo el texto principal fue revisado de acuerdo con esta sugerencia.
- During the review, authors could present more discussions, make comparisons, and discuss other authors' conclusions, among other things. This way, the manuscript would be more interesting and critical.
Response: The discussion section was updated according to these suggestions.
Reviewer 2 Report
Comments and Suggestions for AuthorsDear Editor,
The manuscript by Vichi-Ramírez et al., 5-Nitroimidazole Derivatives Against Neglected Tropical Protozoan Diseases: Systematic Review describes a systematic review of 5-nitroimidazole derivatives that have been successfully used against neglected tropical diseases (NTDs), including a review of three of them: malaria, leishmaniasis, and human trypanosomiasis. The results show that 5-nitroimidazoles offer a broader spectrum of activity against a variety of protozoal pathogens.
I have carefully read through the manuscript and have these comments to make to improve on understanding and add clarity.
1. In the Abstract, the authors fail to provide any background but dive directly into the aim of the study. This background is needed to provide proper context.
2. The authors describe NTDs in the abstract as caused by protozoan parasites, this is quite misleading. Meanwhile, I am not sure if the authors wanted to talk about repurposing of drug instead of repositioning (line 22)
3. Also, the authors fail to give any strong implications, impact, or potential exploitation of their results in the Abstract.
4. The manuscript should be thoroughly corrected for spelling and grammar as lots of errors are found therein. I will advise that they get a proofreading service.
5. Some tables have missing results (e.g., Table 2 has some of the IC50 values blank). Not sure about the reason for this.
6. The tables in the Results section should be created to fit on a single page and not have more than a single.
8. In the last part of the Results where the authors talk about any adverse events reported in the trials for the drugs tested, they should include the number of participants who manifested any of these.
9. In the Discussion, the authors should begin by clearly stating the problem before proceeding to the rest of the things.
Comments on the Quality of English LanguageNeeds lots of improvement
Author Response
The manuscript by Vichi-Ramírez et al., 5-Nitroimidazole Derivatives Against Neglected Tropical Protozoan Diseases: Systematic Review describes a systematic review of 5-nitroimidazole derivatives that have been successfully used against neglected tropical diseases (NTDs), including a review of three of them: malaria, leishmaniasis, and human trypanosomiasis. The results show that 5-nitroimidazoles offer a broader spectrum of activity against a variety of protozoal pathogens.
I have carefully read through the manuscript and have these comments to make to improve on understanding and add clarity.
All authors appreciate your valuable time and constructive comments. We have responded to each of your suggestions, which improved the quality of this work.
1. In the Abstract, the authors fail to provide any background but dive directly into the aim of the study. This background is needed to provide proper context.
Response: Thanks a lot for this suggestion. We modify the abstract to expand the background that remarks the importance of this review.
2. The authors describe NTDs in the abstract as caused by protozoan parasites, this is quite misleading. Meanwhile, I am not sure if the authors wanted to talk about repurposing of drug instead of repositioning (line 22)
Response: The abstract was modified to clarify that some of the NTDs are caused by protozoan and that some 5-nitroimidazole derivatives have been repurposed to combat NTPDs.
3. Also, the authors fail to give any strong implications, impact, or potential exploitation of their results in the Abstract.
Response: We modify the abstract section to remark on this review's implications and main utility.
4. The manuscript should be thoroughly corrected for spelling and grammar as lots of errors are found therein. I will advise that they get a proofreading service.
Response: We greatly appreciate this suggestion. The authors decided to use the grammar correction service provided by this editorial. The receipt is attached.
5. Some tables have missing results (e.g., Table 2 has some of the IC50 values blank). Still trying to figure out the reason for this.
Response: Table 2 was corrected.
6. The tables in the Results section should be created to fit on a single page and not have more than a single.
Response: We appreciate the suggestion. However, and respectfully, the authors consider that the distribution of the tables is correct.
7. In the last part of the Results where the authors talk about any adverse events reported in the trials for the drugs tested, they should include the number of participants who manifested any of these.
Response: The main text was updated according to this valuable suggestion. Line 692- 706.
8. In the Discussion, the authors should begin by clearly stating the problem before proceeding to the rest of the things.
Response: We improved the discussion section according to your suggestion. Line 665 - 670.
