Crystal Structure, Hirshfeld Surface Analysis, In-Silico and Antimycotic Investigations of Methyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate

Round 1

Reviewer 1 Report

In the submitted manuscript the Authors present a crystal structure of a single compound, supported by some physiochemical and computational analysis. This work needs a major revision, details can be found below.

Lines 68-69, „interestingly, due to the presence of non-covalent interactions in the molecular structure, only one tautomer is detectable in solution.” – what do you mean by that? Is it a general feature of all dihydropyrimidines? I don’t think so. As always, in the case of tautomers, there must be some equilibrium. Variables such as solvent, temperature etc. would surely affect the equilibrium constant.

Lines 80-82, why the antifungal activity has been evaluated? Precisely, what was the reason behind choosing this particular pharmacological property and not, i.e., antibacterial?

Line 178, the basis set is quite small, it should be at least 6-311. After all, the studied molecules are not large for the DFT calculations.

Line 178, have you used Gaussian or other software?

Line 179, was the water used as a solvent? Or DMSO? It is not stated clearly and you have used several solvents in your experimental part-this is why I’m asking.

Lines 180-181, since the NMR spectra were recorded using DMSO, it would be advisable to use DMSO as a solvent in PCM model while calculating chemical shielding constants.

Lines 180-181, have you used any scaling factors for the IR calculations?

Lines 180-181, I guess there were no imaginary frequencies found?

Lines 184-185, molecular docking procedure must be described here in details (software, forcefield, method of pointing the binding site etc.)

Table 7, those values must be compared with the experimental ones. Please also add the experimental values to this table.

In the manuscript, it should be mentioned that the structure of “1” has been already solved previously, CSD refcode ABOVUM. Please compare the crystal structure of “1” and “2” in details.

In silico analysis, since the Authors had an access to the crystal structure of “1” (ABOVUM) and “2” (this work), why haven’t you performed periodic DFT calculations, i.e. in CRYSTAL or CASTEP? By doing this the Authors would receive more accurate results as this approach enables to take the periodicity of the system and intermolecular interactions into account.

Figure 7, what are the relative energies of 2(I) and 2(II)? Is 2(I) energetically more favorable, as this is the tautomer that exists in the solid state (according to the SCXRD results).

Lines 346-347, how can the NMR calculations prove that the structures are stable?

Lines 384-390, this should be moved to the Materials & Methods section.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

A.    Huseynzada and et al’s manuscript entitled, “Crystal structure, Hirshfeld surface analysis, in-silico and anti- mycotic investigations of methyl 6-methyl-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylate,” discuss the synthesis, crystal structure and antimycotic activity, which is further correlated with computational study. It is well addressed the objective of the reported work; however, it is required to address few comments for the improvement in the current version of manuscript for consideration towards acceptance of publication.

1)      Figure 1 & 3: There is no difference, only required to define R= NO2 group during elaboration. Therefore Figure 3 can be deleted.

2)      Page 5: NMR investigation of compound 2 revealed the absence of signal splitting, suggesting that 2 exists as a single tautomer in solution, Please clarify which form I or II ?

3)      Some of latest biological activity study may require to include in introduction for such heterocyclic scaffolds such as, for anti-diabetic study: Medicinal Chemistry 2020, 16, 996, Journal of Molecular Structure 1227 (2021) 129412,

            Larvicidal study: Chem Biol Drug Des. 2018 Dec;92(6):1924-1932.

4)      Page 7: Table 2: What is G and Ohm symbol stands for and their significance?

5)      Page 15: Table 8 Compound code C1 and C2 given, instead of 1 and 2 resp. Please check

6)      It is mentioned that “Data reported in Figure 11 and Table 8 evidenced that the studied compounds have a good binding affinity for the target protein”, as per the claim, it should be included the binding affinity of reference sample, Fluconazole?

7)      As per previous reported literature/cited 47, it is already established the preference of tautomeric form I or II, so what is unique in this study?

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The Authors have revised and improved the manuscript since the original submission. This version can be accepted for publication.

Reviewer 2 Report

The authors have addressed the raised comments, which are satisfactory for accepting the revised version of this article.