Design, Synthesis, Antiproliferative Actions, and DFT Studies of New Bis–Pyrazoline Derivatives as Dual EGFR/BRAF^V600E Inhibitors

Round 1

Reviewer 1 Report

Comments for author File: Comments.pdf

Author Response

Reviewer: 1

Comments to the Author

In this article B. G. M. Youssif, A. M. Hayallah et al. present their studies on bis-pyrazoline derivatives as dual EGFR/BRAFV600E inhibitors. The presented research is sound, clear and in my opinion, it meets the criteria to be published in IJMS after minor revision and answering some questions.

Thank you for taking the time to review our manuscript. We appreciate your constructive feedback and suggestions for improvement. We have carefully considered your comments and have addressed them point by point in this letter.

1) Some minor editorial mistakes should be carefully rechecked and corrected as for example: SN2 (subscript is missing); J is globally written without italics in the experimental part and in the article; number of digits in J values makes no physical sense (should be 3 only); and following the 1H NMR description style that the authors chose, the authors should refer multiplets from the most downfield part to the most upfield (7.60-7.55, instead of 7.55-7.60 that were used in the article).

Response:

We apologize for the minor editorial mistakes in our manuscript and thank you for bringing them to our attention. We have made the necessary corrections, including adding the subscript for S_N2, using italics for J, and formatting the ¹H NMR description style to refer to multiplets from the most downfield to the most upfield.

2- As a starting point for their studies the authors decided to synthesize bis-pyrazoline derivatives as possible molecular hybrids. However, to call it a molecular hybrid, it would be worth considering the values of IC₅₀ for compound I towards BRAF-V600E, and on the other hand IC₅₀ for compound II towards EGFR. Is the data available?

Response:

Thank you for your feedback on our manuscript. We have carefully considered your suggestion regarding the evaluation of IC₅₀ values for compound I towards BRAF-V600E and compound II towards EGFR. However, we regret to inform you that we do not have this data available currently.

We would like to inform you that we have replaced the two compounds mentioned in our study with other ones that have full data available. These new compounds were tested for their inhibitory activity towards both kinds of kinases, and the resulting data supports the notion that our compounds can be considered as molecular hybrids.

3- The authors suggested beneficial effect of methoxy group on the activity of their products. To explore the nature of its effect, have authors considered synthesis of compounds with hydroxy- or ethoxy- substituents?

 Response:

We appreciate your interest in exploring the effect of different substituents on the activity of our compounds. We have not yet considered the synthesis of compounds with hydroxy- or ethoxy-substituents, due to fund limitation, but we believe that this could be an interesting avenue for future research. We will keep this suggestion in mind for future studies.

Once again, we appreciate your valuable feedback and suggestions. We hope that the revisions we have made to our manuscript address your concerns and improve the clarity of our work.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

The main subject of the research is design, synthesis, and full physicochemical and biological description of new dual inhibitors of EGFR and BRAFV600E kinases involved in the proliferation of cancer. In this respect, it is a state-of-the-art technology to combine two anticancer drugs with a dual action against both kinases. The authors combined two pyrazoline moieties to create ten compact bis-pyrazoline hybrids bearing potentially high dual anti-proliferative activity of cancer progression providing minimal side effects and targeting on a specific active site of EGFR and BRAFV600E mutated proteins. The authors of the research make a valuable contribution to the field of anti-cancer drug discovery addressing a specific gap connected with finding the ways of decreasing toxicity of the chemotherapy. This research is totally relevant to the Special Issue “Recent Advances: Heterocycles in Drugs and Drug Discovery” of the Molecular Pharmacology section of IJMS and can be expected to present a highly useful information to those who are desperately doing everything they can to beat the cancer disease. In this way, I have no doubt that this research should be published in IJMS. As to specific improvements, I can only point at a few misprints and ask some minor questions that can be of interest to a common reader:

1.       L. 414: You have mistaken by a factor of two: σ = 1/(IP-IA) = 1/(2η). Also correct global softness in Table 5.

2.      Figure 8 presents the shapes of HOMO and LUMO. What does this visual information give to the reader if you are thinking in terms of energies (HOMO-LUMO energies)? Maybe, it is better not to include unimportant visual information for the sake of clarity of the presentation?

3.      Why only the global descriptors of the reactivity? You could approximate the local intermolecular hardness and softness of the outer molecular regions using the electronic contribution to the molecular electrostatic potential, thus combining the sections 2.3.4 and 2.3.3 together.

4.      Please, look through the text and find misprints like that in Line 389 “basis set of 6-31G. (d,p)”, which is to be replaced with “6-31G (d,p)”.

5.      The figures are given in low resolution. Text symbols are hardly visible, especially on Fig. 4.

Author Response

Reviewer: 2

Comments to the Author

The main subject of the research is design, synthesis, and full physicochemical and biological description of new dual inhibitors of EGFR and BRAFV600E kinases involved in the proliferation of cancer. In this respect, it is a state-of-the-art technology to combine two anticancer drugs with a dual action against both kinases. The authors combined two pyrazoline moieties to create ten compact bis-pyrazoline hybrids bearing potentially high dual anti-proliferative activity of cancer progression providing minimal side effects and targeting on a specific active site of EGFR and BRAFV600E mutated proteins. The authors of the research make a valuable contribution to the field of anti-cancer drug discovery addressing a specific gap connected with finding the ways of decreasing toxicity of chemotherapy. This research is totally relevant to the Special Issue “Recent Advances: Heterocycles in Drugs and Drug Discovery” of the Molecular Pharmacology section of IJMS and can be expected to present a highly useful information to those who are desperately doing everything they can to beat the cancer disease. In this way, I have no doubt that this research should be published in IJMS. As to specific improvements, I can only point at a few misprints and ask some minor questions that can be of interest to a common reader:

Thank you for your constructive comments on our manuscript. We appreciate your valuable feedback, and we will address the issues you raised in your review.
1. L. 414: You have mistaken by a factor of two: σ = 1/(IP-IA) = 1/(2η). Also correct global softness in Table 5.

Response:

We apologize for the mistake in the equation and the global softness value in Table 5. We have corrected the equation and corrected the global softness value in Table 5.

2. Figure 8 presents the shapes of HOMO and LUMO. What does this visual information give to the reader if you are thinking in terms of energies (HOMO-LUMO energies)? Maybe, it is better not to include unimportant visual information for the sake of clarity of the presentation?

Response:

Thank you for your feedback on our manuscript. We appreciate your suggestion regarding Figure 8 and have revised it to remove the shapes of HOMO and LUMO to avoid any confusion for readers. However, we would also like to point out that the shapes of HOMO and LUMO can provide important visual information to the reader. In particular, compounds 12 and 15 have HOMO spatial distributions that are primarily distributed on their pyrazoline ring (A) and phenolate moieties (the electron transfer zones), while their LUMO spatial distributions are located on the other pyrazoline ring (B) and aniline moieties (the electron acceptor zones). This information can be useful for readers who are interested in the electronic properties of the compounds.
3.   Why only the global descriptors of the reactivity? You could approximate the local intermolecular hardness and softness of the outer molecular regions using the electronic contribution to the molecular electrostatic potential, thus combining the sections 2.3.4 and 2.3.3 together.

Response:

We thank you for the suggestion to approximate the local intermolecular hardness and softness of the outer molecular regions using the electronic contribution to the molecular electrostatic potential. We have included this analysis in our revised manuscript and we have combined sections 2.3.3 and 2.3.4 in one section.

4. Please, look through the text and find misprints like that in Line 389 “basis set of 6-31G. (d,p)”, which is to be replaced with “6-31G (d,p)”.

Response:

We have carefully reviewed the manuscript for misprints and have corrected the mistake in line 389 to read "6-31G (d,p)".

5. The figures are given in low resolution. Text symbols are hardly visible, especially on Fig. 4.

Response:

We have revised the figures and submitted high-resolution versions to improve the visibility of text symbols, particularly in Figure 4.

 

Author Response File: Author Response.pdf