PONE-D-20-15280

One-Pot Three Component Synthesis of Substituted Dihydropyrimidinones Using Fruit Juices as Biocatalyst and their Biological Studies

PLOS ONE

Dear Dr. Gulati,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The manuscript was reviewed by three experts who have differing opinions, including one who recommended rejection. The revised manuscript should address all the comments and feedback provided by the reviewers. To summarise, here are the key points:

• Simplify the abstract
• Cite appropriate scientific literature including the examples recommended by the reviewers
• Correct solvent free to ‘under aqueous conditions’
• Carry out quantitative measurement of natural acids and proteins as requested by reviewer 1
• Discuss the nature of the catalyst- ascorbic acid, other acids, metal ions etc.
• Follow the literature precedents for discussion on the mechanism
• Write clear experimental procedures to enable reproducibility by others
• Provide detailed characterization of compounds including copies of NMR spectra to confirm compound purity

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Kind regards,

A Ganesan

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: N/A

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Substituted Dihydropyrimidinones are very well known from high biological activity. Common synthetic method leading to target product is based on one-pot three - components reaction. Several aspects of this reaction were already discussed within literature. The authors used as a solvent for reaction fruit juices viz. Cocos nucifera L., Solanum lycopersicum L., Citrus limetta. Model experiments on 4-hydroxy-3-methoxybenzaldehyde, methyl acetoacetate and urea were performed in Cocos nucifera L. juice. The juices were used as prepared and not characterized. The protein contents, the amounts of natural acids was not determined what makes this procedure completely unrepeatable. Although the authors claims in graphical abstract that natural acids participate in reaction that was not validated.

The results of model experiments showed in Table 1 and 2 are confusing to readers since respective experimental procedures are entirely different. It seems to reader that the amount of juice was changed from 1 to 2.5 mL (Table 1) and rom 4 to 10 ml (Table 2). This is just the dilution effect on the reaction course not catalytic effect. The product which should be obtained in reaction is missed in experimental part. The synthetic procedures are full of mistakes and misunderstandings. In method B on page 33 reaction mixture was stirred at room temperature and then cooled to room temperature. Compounds provided in Table 3 were characterized by melting points and 1H NMR what is far away from Journal requirements. The purity of all substances was not determined what do not fulfill requirements of the Journal. The catalytic effect of juices was only postulated and was not verified. The contents of Table 4 is difficult to understand since the experimental procedure is not included in manuscript body. The possible mechanism of reaction discussed in Scheme 2 should be based on sole literature data not speculations. Biological dates were collected for compounds of undefined purity.

Reviewer #2: Authors have described a new and facile one-pot three component synthetic protocol for substituted dihydropyrimidinones derivatives via reaction of equimolar substituted aldehydes, methyl acetoacetate and urea in presence of nature derived catalyst viz. Cocos nucifera L. juice, Solanum lycopersicum L. juice and Citrus limetta juice, commonly known as coconut juice, tomato juice and musambi juice, respectively, at room temperature.

This reviewer doesn’t have much in terms of criticism for the described work which has been very well explored in the literature before; one of the most explored reaction under dozens of reaction conditions.

The major comment at the outset is to decrease the verbose descriptions in the abstract; it reads more like an introduction and experimental presently; no need to mention TLC, or characterization details, mmol scale and in fact with proper referencing, they can avoid lots of duplication of data on known compounds. Secondly, authors have described properly in conclusion but to say that it is a solvent-free reaction is not correct as juices are mostly water. So, aqueous media is the correct description.

I that context, I think it would be prudent to have some quality references while describing the reaction as most of the citations are poor quality and not from original works. As an example, this reviewer could easily find 2 examples for solvent-free and aqueous medium reaction, respectively on the title compounds, as shown below:

Microwave-Assisted High-Speed Parallel Synthesis of 4-Aryl-Dihydro-pyrimidin-2(1H)-ones using a Solventless Biginelli Condensation Protocol. Synthesis, 1799-1803 (1999)

and

Biginelli Reaction in Aqueous Medium: A Greener and Sustainable Approach to Substituted 3,4-Dihydropyrimidin-2(1H)-ones. Tetrahedron Lett., 48, 7343 (2007). Similar types of citations should be offered in the introduction section and like most of the paper, description need to be curtailed enormously. Authors have not cited a relevant paper that describes the utility of juices, “Exploring the utility of fruit juices as green medium for Biginelli reaction”, December 2013, Research Journal of Pharmaceutical, Biological and Chemical Sciences 5(5) :444-449 and related papers by TANAY PRAMANIK, SIMARJIT KAUR PADAN on this topic.

Reviewer #3: The authors here display an important study that used some natural juices as catalysts to attain Bignilli Reaction

and study the Herbicidal activity and antibacterial activity of the obtained compounds

The results show that Cocos nucifera L. juice is the best catalyst for the used time 10 min.

But I am surprising that author put in graphical abstract some acid that may be mean the component of juices

this is not logic if the catalytic activity of Cocos nucifera L. juice due to Ascorbic acid, therefor the results of ascorbic acid should be put in table 2 which present in the following ref.

Ascorbic acid-Catalyzed One-Pot Three-Component Biginelli Reaction: A Practical and Green Approach towards Synthesis of 3,4-dihydropyrimidin- 2(1H)-ones/thiones

Journal Name: Letters in Organic Chemistry

Volume 10 , Issue 7 , 2013

But Cocos nucifera L. juice contain many sugers, many vitamins includs Vit. C (Ascorbic acid) and many metal ion that may be make a synergistic action that give this catalytic activity.

Therefore authors should remove the acids that present in Graphical Abstract.

also, authors should submit NMR Charts for the synthesized compounds to ensure the purity.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Tamer S. Saleh

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PONE-D-20-15280R1

One-Pot Three Component Synthesis of Substituted Dihydropyrimidinones Using Fruit Juices as Biocatalyst and their Biological Studies

PLOS ONE

Dear Dr. Gulati

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

One reviewer has commented on the revised manuscript, and has suggested some additional changes with regards to the references. These recommendations should be followed.

==============================

Please submit your revised manuscript by 15 August 2020. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

A Ganesan

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Although it has improved fair bit but the suggested quality and original references in the introduction section have not been incorporated and the last three references now added are of poor quality. I reproduce what I suggested originally, again:

As an example, this reviewer could easily find 2 examples for solvent-free and aqueous medium reaction, respectively on the title compounds, as shown below:

Microwave-Assisted High-Speed Parallel Synthesis of 4-Aryl-Dihydro-pyrimidin-2(1H)-ones using a Solventless Biginelli Condensation Protocol. Synthesis, 1799-1803 (1999)

and

Biginelli Reaction in Aqueous Medium: A Greener and Sustainable Approach to Substituted 3,4-Dihydropyrimidin-2(1H)-ones. Tetrahedron Lett., 48, 7343 (2007). Similar types of citations should be offered in the introduction section and like most of the paper, description need to be curtailed enormously. Authors have not cited a relevant paper either that describes the utility of juices, “Exploring the utility of fruit juices as green medium for Biginelli reaction”, December 2013, Research Journal of Pharmaceutical, Biological and Chemical Sciences 5(5) :444-449 and related papers by TANAY PRAMANIK, SIMARJIT KAUR PADAN on this topic.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

One-Pot Three Component Synthesis of Substituted Dihydropyrimidinones Using Fruit Juices as Biocatalyst and their Biological Studies

PONE-D-20-15280R2

Dear Dr. Gulati,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

A Ganesan

Academic Editor

PLOS ONE

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