Lipophilicity as a Central Component of Drug-Like Properties of Chalchones and Flavonoid Derivatives
Round 1
Reviewer 1 Report
The paper titled „Lipophilicity as a central component of drug-like properties of chalchones and flavonoid derivatives“ authored by Teodora Constantinescu, Claudiu N Lungu, Ildiko Lung, presents the practical utilization of RP-TLC in lipophilicity determination of chalchones and flavonoid derivatives as well as computational approach in estimation of their drug-like properties. The paper may become suitable for publication after the point below are addressed.
1. The authors should use subscript and superscript in writing the following chromatographic parameters: RM0 instead of RMo, RM instead of RM, φ0 instead of φ0, C0 instead of Co. Also, the slope should be written in italic – b.
2. lines 39-41. “Some studies have removed significant relationships between the determination of lipophilic parameters and the chemical structure, bioactivity, and the pharmacokinetic properties of the biologically active compounds [5].” Some studies have removed? Are you sure that suitable verb is used here?
3. lines 42-43: “there are two classes of methods developed for log P determination: by calculation and experimental.” Instead of “by calculation” use “computational”.
4. lines 47-48: “RP-TLC method has numerous advantages over RP-HPLC, such as simplicity of the equipments, extremely low mobile phase usage, high transfer rate and low cost of analysis.” Comment: the RP-HPLC is more powerful chromatographic method in lipophilicity determination and it provides more reliable results than RP-TLC!
5. Figure 1 is presented in not so clear way. It must be improved. Also, there is no unit of RM0, it is a non-dimensional number!
6. Figure 2 is of very poor quality and must be improved. There is no need to put all the abbreviations in figure’s title. The separate subsection with all the abbreviations mentioned in the MS should be presented.
7. Figure 3 is not clear. It must be corrected.
8. Figure 4. Is not clear as well. Where the compounds are presented in the figure?
9. Figure 5 should be moved in the Supplementary data.
10. Line 202: What is MRo?
11. Regarding the MLR model: Was the Topliss-Costello rule respected during the formation of the model? Which type of cross-validations was used? The authors should repeat the MLR modeling so the external test set is formed and the external predictivity of the models must be proven!
12. Conclusions must be rewritten. The authors wrote some general things in the conclusion that are not related with the results presented in the manuscript. The conclusions should not contain general things. For example, the sentence: “Based on the results obtained, it can be stated that lipophilicity is influenced by the basic structure of the molecule and by the nature, position and number of functional groups on the basic structure.” It is generally known that chemical structure has an influence on the lipophilicity. Here, the particular molecular features that have the influence on the lipophilicity of the studied series of compounds must be emphasized.
13. Please consider having your paper reviewed by a native English speaker for language quality!
Author Response
Comment 1: The authors should use subscript and superscript in writing the following chromatographic parameters: RM0 instead of RMo, RM instead of RM, φ0 instead of φ0, C0 instead of Co. Also, the slope should be written in italic – b.
Response: We replaced RMo with RM0, RM with RM , φ0 with φ0 and Co with C0 . Also, b (slope) in written in italic – b.
Comment 2: lines 39-41. “Some studies have removed significant relationships between the determination of lipophilic parameters and the chemical structure, bioactivity, and the pharmacokinetic properties of the biologically active compounds [5].” Some studies have removed? Are you sure that suitable verb is used here?
Response: We replaced ,,removed,, with ,,described a,,
Comment 3: lines 42-43: “there are two classes of methods developed for log P determination: by calculation and experimental.” Instead of “by calculation” use “computational”.
Response: We replaced ,,by calculation,, with ,,computational,,
Comment 4: lines 47-48: “RP-TLC method has numerous advantages over RP-HPLC, such as simplicity of the equipments, extremely low mobile phase usage, high transfer rate and low cost of analysis.” Comment: the RP-HPLC is more powerful chromatographic method in lipophilicity determination and it provides more reliable results than RP-TLC!
Response : We replaced “RP-TLC method has numerous advantages over RP-HPLC, such as simplicity of the equipments, extremely low mobile phase usage, high transfer rate and low cost of analysis.” with Although RP-HPLC represents a very good method for lipophilicity determination because of its good accuracy, low sample comsuption, on-line detection and its ability to perform measurements even in a presence of a mixture, RP-TLC method has numerous advantages such as simplicity of the equipments, extremely low mobile phase usage, high transfer rate and low cost of analysis. We have also added a reference for RP-HPLC (Jevrić, L.; Karadžić, M.; Mandić, A.; Podunavac Kuzmanović,S.; Kovačević, S.; Nikolić, A.; Okljesa, A.; Sakač, M.; Gasi, K.; Stojanović, S. Lipophilicity estimation and characterization of selected steroid derivatives of biomedical importance applying RP HPLC. J Pharm Biomed Anal 2017, 134, 27-35.)
Comment 5: Figure 1 is presented in not so clear way. It must be improved. Also, there is no unit of RM0, it is a non-dimensional number!
Response: figure 1 was improved as suggested.
Comment 6: Figure 2 is of very poor quality and must be improved. There is no need to put all the abbreviations in figure’s title. The separate subsection with all the abbreviations mentioned in the MS should be presented.
Response: figure 2 was corrected as suggested. A separate subsection was introduced with all the abbreviations.
Comment 7 : Figure 3 is not clear. It must be corrected.
Response: figure 3 was corrected as suggested
Comment 8: Figure 4. Is not clear as well. Where the compounds are presented in the figure?
Response : Figure was adjusted. Cluster of retention factor are represented here. The following comment was added in the text: ,,One main cluster is observed consecutively with three minor ones,,
Comment 9: Figure 5 should be moved in the Supplementary data.
Response: We moved Figure 5 in the Supplementary data
Comment 10: Line 202: What is MRo?
Response: We replaced Mro with Rmo (relative lipophily)
Comment 11: Regarding the MLR model: Was the Topliss-Costello rule respected during the formation of the model? Which type of cross-validations was used? The authors should repeat the MLR modeling so the external test set is formed and the external predictivity of the models must be proven!
Response: Yes - Topoliss –Costello rule was respected with a ratio of 5:1 (descriptors per dependent variable), N fold cross validation was used .The external validation was included in model algorithm and was already performed, however as suggested the step was repeat and retrieved the same outcome. In text the following was added: Line 150 ,, with Topoliss –Costello rule. Data was spleet randomly equally in a training and a data set. Model was internal and external validated,,
Comment 12: Conclusions must be rewritten. The authors wrote some general things in the conclusion that are not related with the results presented in the manuscript. The conclusions should not contain general things. For example, the sentence: “Based on the results obtained, it can be stated that lipophilicity is influenced by the basic structure of the molecule and by the nature, position and number of functional groups on the basic structure.” It is generally known that chemical structure has an influence on the lipophilicity. Here, the particular molecular features that have the influence on the lipophilicity of the studied series of compounds must be emphasized.
Response: We excluded “Based on the results obtained, it can be stated that lipophilicity is influenced by the basic structure of the molecule and by the nature, position and number of functional groups on the basic structure.” We added 3-Hydroxyflavones have a lower retention capacity compared to flavones. Acetylated derivatives has a decrease in retention capacity compared to hydroxyl-chalcones and 3-hydroxyflavones from which the compounds have been obtained.
Comment 13: Please consider having your paper reviewed by a native English speaker for language quality!
Response: some language corrections were performed.
Supplementary materials were uploaded, as they were missing.
All text modifications were made in red.
Reviewer 2 Report
The paper by Constantinescu et al. reports about the relevance of lipophilicity to assess drug-like properties of chalchones and flavonoid derivatives. Overall the paper is of poor quality. The evidence that lipophilicity affects not only antitumoral activity but also ADME properties of compounds is expected to be a crucial point of the paper but it is not discussed in the Introduction. The aim is not clearly described. The computational part is meaningless in the present format. For instance, the authors switch from a QSPR model to a pharmacophore model without any explanation (no details in the Experimental Section too). The most important references about the relevance of lipophilicity in drug discovery are missing. I do not suggest the publication of this paper in Molecules.
Author Response
Comment 1: The evidence that lipophilicity affects not only antitumoral activity but also ADME properties of compounds is expected to be a crucial point of the paper but it is not discussed in the Introduction.
Response: We added “Lipophilicity of a drug molecule is of particular importance due to its impact on the metabolism, pharmacokinetics, pharmacodynamics and molecular toxicity of molecules. It correlates with the absorption, distribution, metabolism, excretion and molecule toxicology (ADMET) processes”[11-16].
Comment 2: The aim is not clearly described.
Response: Te new aim is “Since flavonoids and thiazole compounds exhibit nomerous biological activities and lipophilia is an essential parameter for pharmacokinetics, pharmacodynamics and molecular toxicology, the aim of the current study was to determinate the lipophilicity of 44 compounds (thiazole chalcones, flavanones, flavones, 3-hydroxyflavones and their acetylated derivatives) previously synthesized by us using experimental and computational methods in order to evaluate this central component of drug-like properties. Keeping in mind the antitumoral activity of the synthetised compounds, lipofilicity is an important parameter to indicate whether these compounds may constitute a starting point for the development of novel antitumoral agents.”
Comment 3: The computational part is meaningless in the present format. For instance, the authors switch from a QSPR model to a pharmacophore model without any explanation (no details in the Experimental Section too).
Response: The manuscript was rearranged and changes were shown in red
Comment 4: The most important references about the relevance of lipophilicity in drug discovery are missing.
Response: We added 11 articles with the relevance of lipophilicity in drug dicovery
Reviewer 3 Report
The topic of the influence of functional groups on retention capacity and lipophilic and also hydrophilic properties is presented in a very interesting way. All results obtained are comprehensively discussed and described statistically. Editorial errors (RM instead of RM and so on, many spaces between words are missing) and some gramma errors (especially in "Abstract") do not affect the substantive value of the work.
Author Response
Comment 1 : Editorial errors (RM instead of RM and so on, many spaces between words are missing) and some gramma errors (especially in "Abstract") ….
Response : editorial and grammar errors were corrected as suggested.
Round 2
Reviewer 1 Report
The authors have corrected the manuscript according to the suggestions. I recommend the publication of the manuscript.
Reviewer 2 Report
I appreciate that the authors made an effort to improve the quality manuscript but it remains a study of overall poor quality (and not so much work) which in my opinion cannot be published in a journal with IF about 3.
