Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro
, Mariscal Brice Tchatat Tali 1, Cyrille Armel Njanpa Ngansop 1, Rodrigue Keumoe 1, Eugenie Aimée Madiesse Kemgne 1,2, Lauve Rachel Tchokouaha Yamthe 1,3, Patrick Valere Tsouh Fokou 1,4, Boniface Pone Kamdem 1,*, Katsura Hata 5 and Fabrice Fekam Boyom 1,2,*Round 1
Reviewer 1 Report
Comments and Suggestions for Authors· Write potassium ion charge as superscript
· The selecting compounds X. Y and Z which database is used
· The inhibition activity should be presented with some photos and figures
· The scope of study is quite narrow at least the library of compounds should be prepared for insilico screening
Comments on the Quality of English LanguageQuality of english is ok
Author Response
Manuscript ID: futurepharmacol-2839853
Title: Target-based 6-5 fused ring heterocyclic scaffolds display broad antiparasitic potency in vitro.
Response to Reviewers’ comments
Reviewer 1
Suggestions for Authors
- Write potassium ion charge as superscript
Answer: Thank you for the remark. We have now used the superscript (+) throughout the text.
- The selecting compounds X. Y and Z which database is used
Answer: As acknowledged in the manuscript, Eisai Co., Ltd. supported this study by designing and generously supplying the 6-5 fused ring heterocyclic antifolates (Compound-X, Compound-Y and Compound-Z) and the potassium channel blocker (E4031).
- The inhibition activity should be presented with some photos and figures
Answer: We acknowledge that. However, all relevant information is already available in the text.
- The scope of study is quite narrow at least the library of compounds should be prepared for insilico screening
Answer: Thank you for the suggestions. Future studies will encompass a detailed investigation of a larger set of compounds.
Reviewer 2 Report
Comments and Suggestions for AuthorsIn this manuscript a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y and Z) and one K+ channel blocker (E4031) was screened for their inhibitory effect on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. Cytotoxicity of test compounds was evaluated on Vero, Raw 264.7 and HepG-2 cells. Pharmacokinetic properties were predicted using the online tool pkCSM. Results are interesting, however, major revisions are required.
1. Include docking and dynamics simulations results.
2. How authors justify the selectivity against different species?
3. Split introduction into few paragraphs of appropriate length instead of one-page summary in a single paragraph.
4. Same applies to discussion part.
5. Authors do not mention the source of compounds or their synthesis? Include appropriate details in either case.
6. Manuscript needs a thorough proofread.
7. Authors should justify the selection of four compounds? How they chose? Why only four? As limited number is not sufficient to draw appropriate conclusions.
Comments on the Quality of English LanguageMinor editing required.
Author Response
Manuscript ID: futurepharmacol-2839853
Title: Target-based 6-5 fused ring heterocyclic scaffolds display broad antiparasitic potency in vitro.
Reviewer 2
Comments and Suggestions for Authors
In this manuscript a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y and Z) and one K+ channel blocker (E4031) was screened for their inhibitory effect on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. Cytotoxicity of test compounds was evaluated on Vero, Raw 264.7 and HepG-2 cells. Pharmacokinetic properties were predicted using the online tool pkCSM. Results are interesting, however, major revisions are required.
- Include docking and dynamics simulations results.
Answer: Thank you for your suggestions. However, the target-based inhibitors were previously tested in vitro to confirm their activity against DHFR and K+ channel blocker enzymes (see Table 1, references [40, 41, 42]). Therefore, the need to include docking and dynamics simulations results is limited.
- How authors justify the selectivity against different species?
Answer: Thank you. “The different levels of selectivity of the inhibitors for the three parasites can be justified based on several factors, including target specificity, genetic variability, and structural differences in their essential biomolecules, such as enzymes or receptors, resistance profile to specific inhibitors due to variations in their resistance mechanisms. The rationale often lies in the unique biochemical, genetic, or structural features that distinguish one parasite from another”. We have now made this statement in the manuscript to justify the observed discrepancies in selectivity.
- Split introduction into few paragraphs of appropriate length instead of one-page summary in a single paragraph.
Answer: Thank you. We have now split the introduction into paragraphs of appropriate length.
- Same applies to discussion part.
- Answer: The change has been amended as suggested.
- Authors do not mention the source of compounds or their synthesis? Include appropriate details in either case.
Answer: Thank you. We have now mentioned in the manuscript that the compounds were provided by Eisai Co., Ltd.
- Manuscript needs a thorough proofread.
Answer: Thank you. We have now proofread the manuscript and performed English editing. The changes have been colored red with yellow stripes across the manuscript.
- Authors should justify the selection of four compounds? How they chose? Why only four? As limited number is not sufficient to draw appropriate conclusions.
Answer: Thank you for your query. The 4 compounds were duly selected and provided by Eisai Co., Ltd. within the scope of a project focusing on the antiprotozoal screening of target-based small molecules.
Reviewer 3 Report
Comments and Suggestions for AuthorsDear Editor,
Please find herein the comments about the manuscript Future Pharmacol.
The authors present an article dealing with the screening activity of 4 known molecules against 3 parasites. The cytotoxicity were also evaluated with 4 cell lines.
The rationale for using the tested compounds was explained, by repositioning DHFR inhibitors (3 compounds) and potassium channel blocker (compound E4031).
The search for new antiparasitic derivatives is always of great interest.
The introduction part is too long considering that the part in Results and discussion (lines 244 to 275) must be in the introduction part. On an other hand, there is no detail given about the molecules tested: origins, applications, if any, …
- Lines 279 and 280 : please revise and remove the “S” after IC50.
- “Highly active for IC50 < 10 µM” should be turned into “promising activity…”
I have a concern about the activity reported for the amphotericin B against L. donovani promastigote or amastigote. I think that the value must be in the nM range (cf. here : https://www.ebi.ac.uk/chembl/web_components/explore/activities/STATE_ID:WPJXrv14AM49eIKkqiRmvA== )
All the “discussion” about the predicted physicochemical and ADME properties should by considerably reduced, including the table 3. For this latter, it could be inserted in supplementary data.
The title of the article may need to be adapted as it not reflect the 2 chemical series nor the 2 pharmacological targets.
To conclude, some improvements must be made in order to consider this article for publication in Future pharmocol.
Author Response
Manuscript ID: futurepharmacol-2839853
Title: Target-based 6-5 fused ring heterocyclic scaffolds display broad antiparasitic potency in vitro.
Reviewer 3
Comments and Suggestions for Authors
Dear Editor,
Please find herein the comments about the manuscript Future Pharmacol.
The authors present an article dealing with the screening activity of 4 known molecules against 3 parasites. The cytotoxicity were also evaluated with 4 cell lines.
The rationale for using the tested compounds was explained, by repositioning DHFR inhibitors (3 compounds) and potassium channel blocker (compound E4031).
The search for new antiparasitic derivatives is always of great interest.
The introduction part is too long considering that the part in Results and discussion (lines 244 to 275) must be in the introduction part.
Answer: We agree with the reviewer’s inquisitiveness. Lines 244-275 of the results and Discussion section have now been summarized and incorporated in the introduction section. We have now reduced the introduction part. However, we will be ready to accept any other changes if required.
On an other hand, there is no detail given about the molecules tested: origins, applications, if any, …
Answer: We have now clearly stated in the manuscript that the 3 heterocyclic potential DHFR inhibitors (compounds X, Y and Z) (Figure 1) and 1 potassium channel blocker (E4031) were originally designed for anticancer research and were provided by Eisai Co., Ltd. The changes have been colored red with yellow stripes.
- Lines 279 and 280 : please revise and remove the “S” after IC50.
Answer: Thank you. We have now removed the “S” after IC50.
- “Highly active for IC50 < 10 µM” should be turned into “promising activity…”
Answer: Thank you. We have now changed “Highly active to “promising”.
I have a concern about the activity reported for the amphotericin B against L. donovani promastigote or amastigote. I think that the value must be in the nM range (cf. here : https://www.ebi.ac.uk/chembl/web_components/explore/activities/STATE_ID:WPJXrv14AM49eIKkqiRmvA== )
Answer: Thank you for this critical remark. We are sorry for the mistake and have now corrected it in Table 2 (IC50 0.020 µM and 0.248 µM for promastigote and amastigote respectively).
All the “discussion” about the predicted physicochemical and ADME properties should by considerably reduced, including the table 3. For this latter, it could be inserted in supplementary data.
Answer: We agree with the reviewer’s suggestion. Discussion regarding the predicted physicochemical and ADME properties has been reduced to a minimum. The changes have been colored red with yellow stripes.
The title of the article may need to be adapted as it not reflect the 2 chemical series nor the 2 pharmacological targets.
Answer: Compounds X and Y (6-5 fused ring heterocyclic series) were found to be the most promising compounds (IC50 values< 6.49 µM) that exhibited broad antiparasitic activity, compared to the K+ channel blocker (E4031) that displayed poor activity (IC50 values> 10.0 µM) against the tested parasites. That is the reason why the title of the manuscript was indicated as “Target-based 6-5 fused ring heterocyclic scaffolds display broad antiparasitic potency in vitro” to emphasize the most promising hits.
To conclude, some improvements must be made in order to consider this article for publication in Future pharmocol.
Answer: We are very thankful for your valuable comments that have considerably improved the scientific quality of our manuscript.
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsAuthors have improved the manuscript. It could be considered in the present form.
Comments on the Quality of English LanguageMinor editing can improve the quality of manuscript.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe authors have made substantial improvements and responded to all comments.
The article can be published in its current form.
