Synthesis and In Silico Study of Some New bis-[1,3,4]thiadiazolimines and bis-Thiazolimines as Potential Inhibitors for SARS-CoV-2 Main Protease
, Sayed M. Riyadh 2,3, Magda H. Abdellattif 4, Tariq Z. Abolibda 1, Hassan M. Abdel-aziz 5, AbdElAziz. A. Nayl 6, Alaa M. Elgohary 7 and Abdo A. Elfiky 7,*Round 1
Reviewer 1 Report
In the present manuscript, the authors describe the synthesis and the in silico study of new bis-[1,3,4]thiadiazolimines and bis-thiazolimines as potential SARS-CoV-2 main protease inhibitors.
The manuscript needs a careful revision by a native English speaker, as there are grammatical and syntax errors. Some corrections and suggestions have been included in the annotated pdf file.
The synthesis of the new compounds is simple and clear. The spectroscopic characterization is adequate. The results of the in silico study indicate that the majority of the new compounds present improved, but not impressively improved, binding energy values compared to that of the know inhibitor N3.
An issue that must be addressed by the authors is related with the binding mode of their compounds and the known inhibitors O6K and N3. To my opinion, a figure that shows the arrangement of the known inhibitors O6K and N3 inside the binding pocket of the enzyme in comparison to that of compound 5h must be added and commented by the authors.
Did the authors try to test in vitro their compounds or at least compound 5h and check if they act as SARS-CoV-2 main protease inhibitors? I believe that such a study would strengthen the quality and significance of the manuscript and would be in accordance with the scope of the Journal.
On this basis, I recommend publication of the present manuscript after minor revision.
Comments for author File: 
Comments.pdf
Author Response
Dear reviewer! Many thanks for your time spending and efforts to review the manuscript.
The manuscript needs a careful revision by a native English speaker, as there are grammatical and syntax errors. Some corrections and suggestions have been included in the annotated pdf file.
Response: The suggested corrections are made in the revised version and the whole manuscript is revised against any syntax errors.
- The synthesis of the new compounds is simple and clear. The spectroscopic characterization is adequate. The results of the in silico study indicate that the majority of the new compounds present improved, but not impressively improved, binding energy values compared to that of the know inhibitor N3.
Response: We agree with the reviewer in that most of the compounds are not impressively improved but have compounds that posses comparable binding affinity against Mpro active site (compared to positive controls) is a good start for designing potential inhibitors based on the binding affinity and binding mode, especially compound 5h. This is reported in the conclusion of the revised manuscript (lines: 412-414)
- An issue that must be addressed by the authors is related with the binding mode of their compounds and the known inhibitors O6K and N3. To my opinion, a figure that shows the arrangement of the known inhibitors O6K and N3 inside the binding pocket of the enzyme in comparison to that of compound 5h must be added and commented by the authors.
Response: Done
- Did the authors try to test in vitro their compounds or at least compound 5h and check if they act as SARS-CoV-2 main protease inhibitors? I believe that such a study would strengthen the quality and significance of the manuscript and would be in accordance with the scope of the Journal.
Response: We agree with the reviewer for the need to perform antiviral and cytotoxicity assays to test the best compound and we suggest that as future work (lines: 412-414).
Reviewer 2 Report
The paper entitled “Synthesis and in silico study of some new bis-[1,3,4]thiadiazolimines and bis-thiazolimines as potential inhibitors for SARS-CoV-2 main protease” by Gomha et al. describes novel series of heteroarylimines, containing a thiadiazol or a thiazol ring, as potential drugs against SARS-CoV-2 targeting the Mpro.
The authors synthesize and characterize 15 new compounds using a straightforward synthetic methodology, in which they have previous experience, and analyse their binding affinity in silico by Mpro of SARS-CoV-2 to predict their therapeutic potential against the virus.
Although no experimental biological data are provided, I consider the content relevant and suitable for publication in the journal “Current Issues in Molecular Biology” after minor revision.
Please, consider the following suggestions that can contribute to clarify and improve the manuscript.
1. Paxlovid is not a drug, is a medicine which consists of two drugs, nirmatrelvir (protease inhibitor) and ritonavir (nirmatrelvir bioavailability enhancer). Please revise and clarify this.
2. Check and correct Scheme 2, please. Delete the number 2 (above arrows) for haloalkyl compounds 6a-e and 9a-b and include the structural features for compounds 9 and 11 in a table, as was done for compounds 6 and 8.
3. Include in the computational analysis information about the crystal used in these studies, also identifying the ligand. Please, clarify the reason why compound N3 was selected as positive control.
4. A drug likeness prediction study would be interesting to get information about the potential bioavailability of proposed compounds.
In addition, authors should check the entire manuscript to correct some grammar mistakes and typos. As an example, replace “bis-thiadiazoles core” by “bis-thiadiazole core”, “with alkyl linker” by “with an alkyl linker”, “Bis-1,3-thiazole derivatives was examined” by “Bis-1,3-thiazole derivatives were examined; line 204, replace “α-haloketones 6a-e or 10a-b” by “α-haloketones 6a-e or 9a-b”…
Author Response
Dear reviewer! Many thanks for your time spending and efforts to review the manuscript.
Paxlovid is not a drug, is a medicine which consists of two drugs, nirmatrelvir (protease inhibitor) and ritonavir (nirmatrelvir bioavailability enhancer). Please revise and clarify this.
Response: Done (lines: 54-55)
- Check and correct Scheme 2, please. Delete the number 2 (above arrows) for haloalkyl compounds 6a-e and 9a-b and include the structural features for compounds 9 and 11 in a table, as was done for compounds 6 and 8.
Response: Done
Include in the computational analysis information about the crystal used in these studies, also identifying the ligand. Please, clarify the reason why compound N3 was selected as positive control.
Response: Done (lines: 91-100)
- A drug likeness prediction study would be interesting to get information about the potential bioavailability of proposed compounds.
Response: Done (lines: 174-177)
- In addition, authors should check the entire manuscript to correct some grammar mistakes and typos. As an example, replace “bis-thiadiazoles core” by “bis-thiadiazole core”, “with alkyl linker” by “with an alkyl linker”, “Bis-1,3-thiazole derivatives was examined” by “Bis-1,3-thiazole derivatives were examined; line 204, replace “α-haloketones 6a-e or 10a-b” by “α-haloketones 6a-e or 9a-b”…
Response: All corrections were done
