A New Symmetrical Thiazolidinedione Derivative: In Silico Design, Synthesis, and In Vivo Evaluation on a Streptozotocin-Induced Rat Model of Diabetes

Round 1

Reviewer 1 Report

The article submitted by Mendieta-Wejebe and coworkers is a really interesting paper on in silico study for an array of 219 compounds against several targets involved into onset of diabetic and inflammatory diseases. The described compounds have been classified into 8 families according to their chemical features, among these compound 1G has been selected as the most active and thus it has been synthesized by a fast synthetic route. Moreover, many free online available programs have been used to predict the pharmacokinetic properties. All data fit with the already reported ones and with those experimentally measured. This study provides a versatile and efficient route to identify and then synthesize new entities endowed with antidiabetic properties, for example.

The study is well organized and written. It can be accepted for publication in Processes.

Minor comments:

Line 102 please add a bracket 5Z,5'Z)

Line 112 please replace “at” with “on” aliphatic chain

Table 1. please add thicker borders to separate the different parameters and/or to highlight the connected ones

Figure 3 needs to be converted into a Scheme. Moreover, higher resolution structures should be included.

(2.26 g, 1.0 191 mmol) (Sigma-Aldrich, MKBK3285VP) as the limiting reagent and 2,4-thiazolinedinedione (0.28 g, 2.4 mmol, 2.4 equivalents) (Sigma-Aldrich, BCBK1726V), in presence of piperidine (0.03 mL, 0.3 mmol, 30%) (Sigma-Aldrich, 05919ME) and benzoic acid (0.04 g, 0.3 mmol, 30%) (Chemical products Monterrey, Mexico, 0946). Are you sure of the added data (e.g. mmol, g etc)?? The final amount of compound 1G appears very low in comparison with the starting material.

Figures 3S and 4S please add full scale 1H and 13C spectra. What is the purity of synthesized compound 1G?

Line 222. Please provide HPLC conditions (column and mobile phase)

Lines 755-761 please use name’s abbreviation to specify the authors contribution

References: the list of the references needs to be adjusted according to MDPI rules.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

The manuscript -  Processes-1304313 -  Title: A New Symmetrical Thiazolidinedione Derivative: Design Inn silico, Synthesis, and In vivo Evaluation on a Streptozotocin-Induced Diabetic Rat  Model - is a research article focusing on the in silico analysis of many new derivates.

Authors, after the in silico analysis, selected the compounds (1G) as the best one on the basis of pharmacokinetic, pharmacodynamic, and toxicology parameters and for orientation of binding data  with PPAR- gamma.

 

Authors provided to synthetized and characterized only the one selected compound, 1G.

The in vivo therapeutical effect of 1G administration in rat animal models for diabetes was compared with different rat treatments.

 

The manuscript is professionally written, and the different experiment seem well conducted.

   

Lane 441 reports data of 1G on Caco2 cell, but in the text, there is no description of the method and of the conditions used to test 1G on Caco2.

 

 Lane 648 - to assess oxidative stress, ROS can be measured in the blood of diabetic rats using specific commercial assay kits.

 

Lane 696 -Authors refer to the advantages of the in silico study before synthesizing and testing the new derivative 1G in vivo.

To really validate their in silico method, the Authors would have had to use also compounds lacking some pharmacophore nuclei of 1G , in the in vivo model.

Even if it required the synthesis of another new derivatives, the in vivo use of a negative control would have been necessary to support the Author's deductions and the in silico data analysis.

This lack of experimental data should be noted in the manuscript.

Author Response

GIANCARLO CRAVOTTO, PROF., DR.

EDITOR-IN-CHIEF

PROCESSES

 

Enclosed please find the revised version of the manuscript (processes-1304313) entitled “A New Symmetrical Thiazolidinedione Derivative: In silico Design, Synthesis, and In vivo Evaluation on a Streptozotocin-Induced Rat Model of Diabetes”.

The authors greatly appreciate the comments and suggestions by the reviewers, which were very helpful in improving the manuscript. A point-by-point response to the reviewers’ recommendations has been included below. All changes in the manuscript are marked using the “Track Changes” function. We hope that you now find the new version of the manuscript suitable for publication in your prestigious journal.

We are grateful for your kind attention and look forward hearing from you.

Sincerely,

 

JESSICA ELENA MENDIETA-WEJEBE & DR. FELICIANO TAMAY CACH

CORRESPONDING AUTHORS

Sección de Estudios de Posgrado e Investigación

Escuela Superior de Medicina, Instituto Politécnico Nacional

Mexico City, Mexico

 

Point by point response to the reviewers´ comments

 

Reviewer #2

 

1. Lane 441 reports data of 1G on Caco2 cell, but in the text, there is no description of the method and of the conditions used to test 1G on Caco2.

Response: We thank the reviewer for this comment. We calculated pharmacokinetic parameters using different software. The word “prediction” was added. The pharmacokinetic prediction is mentioned on lines 478-480:  

“Compound 1G appears to have good intestinal absorption, according to the theoretical prediction, despite the TPSA value. Theoretical predictions are based on information from molecules with a similar structure in each database.”

 

2. Lane 648 - to assess oxidative stress, ROS can be measured in the blood of diabetic rats using specific commercial assay kits.

Response: We did not determine ROS since the focus of the study is on the 1G-induced effects on glucose and liver toxicity in a rat model of diabetes. A general overview of oxidative stress was made in accordance with an analysis of endogenous antioxidant molecules in the blood. In this sense, we discussed the present results based on previous reports of ROS generated by diabetes and also by the administration of PIO. Therefore, we added the appropriate references (used previously) at the end of the sentence on lines 739-743:

“With the administration of PIO, on the other hand, the significantly enhanced SOD activity and the tendency to an increment in CAT activity (Figure 10e) could be related to a rise in systemic oxidative stress or simply the oxidative damage that occurs in diabetic animals [2,31].”

 

3. Lane 696 -Authors refer to the advantages of the in silico study before synthesizing and testing the new derivative 1G in vivo.

To really validate their in silico method, the Authors would have had to use also compounds lacking some pharmacophore nuclei of 1G , in the in vivo model.

Even if it required the synthesis of another new derivatives, the in vivo use of a negative control would have been necessary to support the Author's deductions and the in silico data analysis.

This lack of experimental data should be noted in the manuscript.

Response: We agree with the reviewer’s comment. The study was based on theoretical results in order to conduct in vivo experiments in a complementary manner. The intention was to obtain theoretical information about a new molecule in order to establish the safety of using certain doses with animals.

In the present study, the negative control used was pioglitazone (PIO), which is the lead compound to produce the derivatives (the test compounds). The target of PIO and 1G is PPAR gamma. For this reason, we did not include compounds lacking the pharmacophore nuclei of 1G.

With regard to the last comment, the discussion and conclusions are structured according to the hypothesis indicated on lines 576-578:

“Compound 1G is analyzed under the hypothesis that it acts in a similar way as PIO due to the structural similarity, the docking results, and the generation of adipose tissue by both compounds.”

Finally, the use of the English language was checked, and modified where appropriate, throughout the manuscript.

Round 2

Reviewer 2 Report

  

This revised form of the manuscript has been greatly improved.

Authors took into account the Reviewers' comments.

The manuscript can be accepted in the present form.