Thiourea Derivative Metal Complexes: Spectroscopic, Anti-Microbial Evaluation, ADMET, Toxicity, and Molecular Docking Studies

Round 1

Reviewer 1 Report

Yousef, Al-Janabi et al report the synthesis and characterization of a new series of M(II) complexes (M=Ni, Cu, Pd, Pt, Zn, Cd and Hg) having N-Phenylmorpholine-4-carbothioamide (HPMCT) as ligand. All compounds are full characterized, the manuscript is well presented and easy to read, therefore, in my opinion, the paper is suitable for publication on Inorganics in actual form.

Author Response

Reviewer #1:

Yousef, Al-Janabi et al report the synthesis and characterization of a new series of M(II) complexes (M=Ni, Cu, Pd, Pt, Zn, Cd and Hg) having N-Phenylmorpholine -4-carbothioamide (HPMCT) as ligand. All compounds are full characterized, the manuscript is well presented and easy to read, therefore, in my opinion, the paper is suitable for publication on Inorganics in actual form.

Response

Thank you very much for the evaluation of the manuscript, This is a testimony we are proud of by a scientific reviewer in your journal.

Reviewer 2 Report

The manuscript “Nano-thiourea derivative metal complexes 2 Spectroscopic, anti-microbial evaluation, ADMET, toxicity, and 3 molecular docking studies” of A. TF. Al-Halbosy et al. describes the synthesis of one ligand and their metal complexes in neutral and basic conditions forming complexes with 2:1 and 2:2 L:M stoichiometries. They characterise them by FT-IR, NMR and DFT as well as evaluate the biological effect in several bacteria and one cancer cell line. They complete their study with ADME and docking analysis. The study is interesting for a wide range of researchers, but it lacks for several items which are described hereafter:

(1) The text is highly misspelled in English and full of grammar errors which shall be corrected to have a minimum quality. I summarise some of them:

        Line 21 – has instead as

        Line 26 –“ screened for capability” is wrong. Screened for the antibacterial activity”

        Line 42 – “thiouredio moiety” what it means?

        Line 47 – “organo catalysts” instead of “Organo-catalists”

        Lines55-58 – The same sentence is written two times.

        Lines 87 – What is distal water?

(2) The text is full of format errors too. They shall be corrected. Some of them:

        Line 27 – numbering of complexes are not in bold, they shall be written in bold.

        Lines 29-30 – The number shall be written with significant numbers, 12.72 ± 0.376 is wrong, it shall be 12.7 ± 0.4

        Line 92 – “tested” instead “testes”

        In the actibacterial studies, the authors indicate five strains but in the paper there are only evaluated three strains.

        Lines 105 – Format of cis-platin is different from the whole text.

        Lines 133 – 136. The whole paragraph has not sense in English, it is without any connector.

        Lines 210-217 – The word ppm and Hz shall be separated from the numbers.

        Lines 227-229 – The format of the words are different from the text.

        Lines 244 – “was” shall be removed.

        Line 264 – Figure 4 has the names of complexes, they shall be numbers and s. aureus shall be S. aureus.

        Where is Figure 14?

        The section of Acknowledgement is wrong and they include the funding section details.

(3) The references and the text assigned to them shall be revised. For instance, lines 52-53 “and its X-ray structure was determined [17]. In the following year, Yuen et. al. has reported the synthesis of mixed ligand complexes of Ni derived from PMCH and dppe [18].” Reference 17 is a reference from 1980! But reference 18 is from 2020. “In the following year “ is not correct and in addition, in the same paragraph they stated, “in the last 10 years”, a reference from 1980 is far away from 10 years ago. Moreover, the authors have to include important review works dealing with urea/thiourea because they only have included some papers of them such as references 1-4.

(4) In the Experimental part, the authors shall be explained briefly the antibacterial and anticancer studies and no direct to some references that significantly does not detail these methods.

(5) The graphic of Figure 4 and the discussion has not indicated anything about the antibiotic tetracycline. The authors cannot state that the complexes have significant antibacterial activity without any reference. They shall re-analysis these results and include the antibiotic in the explanation.

(6) Why the authors evaluate the viability of 2 and 3 in cancer cells? Any explanation…

(7) The molecular docking studies do not finish with any discussion neither conclusion. The authors shall extract some discussions/conclusions which clearly the authors have not done.

(8) Idem that point 7 with the Molecular similarity. It added no information to the investigation. Moreover, in this section there is only explained the method!

(9) The same than in points 7 and 8 for the ADMET studies and toxic effect.

To summarize, this manuscript cannot be published in the present form.

(1) The text is highly misspelled in English and full of grammar errors which shall be corrected to have a minimum quality. I summarise some of them:

        Line 21 – has instead as

        Line 26 –“ screened for capability” is wrong. Screened for the antibacterial activity”

        Line 42 – “thiouredio moiety” what it means?

        Line 47 – “organo catalysts” instead of “Organo-catalists”

        Lines55-58 – The same sentence is written two times.

        Lines 87 – What is distal water?

Author Response

Response to Reviewer #2:

Comments and Suggestions for Authors

The manuscript “Nano-thiourea derivative metal complexes 2 Spectroscopic, anti-microbial evaluation, ADMET, toxicity, and 3 molecular docking studies” of A. TF. Al-Halbosy et al. describes the synthesis of one ligand and their metal complexes in neutral and basic conditions forming complexes with 2:1 and 2:2 L:M stoichiometry. They characterize them by FT-IR, NMR and DFT as well as evaluate the biological effect in several bacteria and one cancer cell line. They complete their study with ADME and docking analysis. The study is interesting for a wide range of researchers, but it lacks for several items which are described hereafter:

(1) The text is highly misspelled in English and full of grammar errors which shall be corrected to have a minimum quality. I summaries some of them:

        Line 21 – has instead as

Response: Done

        Line 26 –“ screened for capability” is wrong. Screened for the antibacterial activity”

Response: Done

        Line 42 – “thiouredio moiety” what it means?

Response:  Thiouredio is a term describes the –NH-CS-NH- group [1] in thiourea. Sometimes this expression is used to discuss the changes on this group only.

[1] W. Henderson, R.D.W. Kemmitt, S. Mason, M.R. Moore, J. Fawcett, D.R. Russell, Thiadiazatrimethylenemethane and N,N',P-Triphenylphospphonothioic Diamide complexes of Platinum(II). J. CHEM. SOC. DALTON TRANS. 1992

        Line 47 – “organo catalysts” instead of “Organo-catalists”

Response: Done

        Lines55-58 – The same sentence is written two times.

Response: No repetition was found

        Lines 87 – What is distal water?

Response:  Misspelled word, it is corrected to be distilled water

 (2) The text is full of format errors too. They shall be corrected. Some of them:

        Line 27 – numbering of complexes are not in bold, they shall be written in bold.

Response: Done

        Lines 29-30 – The number shall be written with significant numbers, 12.72 ± 0.376 is wrong, it shall be 12.7 ± 0.4

Response: Done

        Line 92 – “tested” instead “testes”

Response: Done

        In the antibacterial studies, the authors indicate five strains but in the paper there are only evaluated three strains.

Response: We apologize for the confusion. This is typos error and we corrected.

        Lines 105 – Format of cis-platin is different from the whole text.

Response: We apologize for the confusion. We checked and corrected in all manuscript.

        Lines 133 – 136. The whole paragraph has not sense in English, it is without any connector.

Response: Done

        Lines 210-217 – The word ppm and Hz shall be separated from the numbers.

Response: Done

        Lines 227-229 – The format of the words are different from the text.

Response: Done

        Lines 244 – “was” shall be removed.

Response: The word ''was'' was not found.

        Line 264 – Figure 4 has the names of complexes, they shall be numbers and s. aureus shall be S. aureus.

Response: In accordance with the referees’ wishes, We update it and corrected

        Where is Figure 14?

Response:  Please see page 21 below the Figure 13

        The section of Acknowledgement is wrong and they include the funding section details.

Response: Acknowledgement was written according to funding institute instructions.

(3) The references and the text assigned to them shall be revised. For instance, lines 52-53 “and its X-ray structure was determined [17]. In the following year, Yuen et. al. has reported the synthesis of mixed ligand complexes of Ni derived from PMCH and dppe [18].” Reference 17 is a reference from 1980! But reference 18 is from 2020. “In the following year “ is not correct and in addition, in the same paragraph they stated, “in the last 10 years”, a reference from 1980 is far away from 10 years ago. Moreover, the authors have to include important review works dealing with urea/thiourea because they only have included some papers of them such as references 1-4.

Response: Done

 (4) In the Experimental part, the authors shall be explained briefly the antibacterial and anticancer studies and no direct to some references that significantly does not detail these methods.

Response: In accordance with the referees’ wishes, We update it

(5) The graphic of Figure 4 and the discussion has not indicated anything about the antibiotic tetracycline. The authors cannot state that the complexes have significant antibacterial activity without any reference. They shall re-analysis these results and include the antibiotic in the explanation.

Response: In accordance with the referees’ wishes, We update it and the standard antibiotic in the Figure 4 and in anti-bacterial activity discussion.  

 (6) Why the authors evaluate the viability of 2 and 3 in cancer cells? Any explanation…

Response: In As it is known from previous literature, Pd(II) and Pt(II) complexes have excellent activities as anti-cancer agents. Accordingly, complexes 2 and 3 were chosen in the study of this part of the biological study.

 (7) The molecular docking studies do not finish with any discussion neither conclusion. The authors shall extract some discussions/conclusions which clearly the authors have not done.

Response: In accordance with the referees’ wishes, We update it

 (8) Idem that point 7 with the Molecular similarity. It added no information to the investigation. Moreover, in this section there is only explained the method!

Response: In accordance with the referees’ wishes, We update it

(9) The same than in points 7 and 8 for the ADMET studies and toxic effect.

Response: In accordance with the referees’ wishes, We update it

To summarize, this manuscript cannot be published in the present form.

Comments on the Quality of English Language

Response: We apologize for the confusion. In accordance with the referees’ wishes, the typos and grammar errors were all checked and corrected.

(1) The text is highly misspelled in English and full of grammar errors which shall be corrected to have a minimum quality. I summarise some of them:

        Line 21 – has instead as

Response: Done

        Line 26 –“ screened for capability” is wrong. Screened for the antibacterial activity”

Response: Done

        Line 42 – “thiouredio moiety” what it means?

Response:  Thiouredio is a term describes the –NH-CS-NH- group [1] in thiourea. Sometimes this expression is used to discuss the changes on this group only.

[1] W. Henderson, R.D.W. Kemmitt, S. Mason, M.R. Moore, J. Fawcett, D.R. Russell, Thiadiazatrimethylenemethane and N,N',P-Triphenylphospphonothioic Diamide complexes of Platinum(II). J. CHEM. SOC. DALTON TRANS. 1992

        Line 47 – “organo catalysts” instead of “Organo-catalists”

Response: Done

        Lines55-58 – The same sentence is written two times.

Response: No repetition was found

        Lines 87 – What is distal water?

Response:  Misspelled word, it is corrected to be distilled water

Reviewer 3 Report

Authors report on the synthesis, characterization, bioevaluation and molecular docking studies on metal complexes with N-Phenylmorpholine-4-carbothioamide. While chemical part can be regarded as interesting there are serious concerns regarding English language. Extended polishing is needed in order this contribution would become readable. But not just grammar, also chemical terminology needs much polishing. Synthetic protocols are not written according scientific standards, sometimes data on solvent is missing or awkward sentences are used. Some interpretation of for example PXRD “a wide peaks and non-regular spectra, indicated these complexes are presents in fine structure.” is incorrect. Wide peaks indicate low crystallinity and the presence of amorphous phase. It is a pitty that authors don’t report any SC XRD structure, much information is thus not delivered by the authors due to this fact.

Also, the word “nano” in the title is not really justified since this is more or less classical coordination chemistry. Furthermore, all bioassay was performed in solution thus no nano material was present at this bioevaluation step.

To my opinion, this contribution needs thorough polishing and only after a major revision or even resubmission as a new contribution might become suitable for publication.

Extended polishing is needed in order this contribution would become readable. But not just grammar, also chemical terminology needs much polishing.

Author Response

Reviewer #3:

Authors report on the synthesis, characterization, bioevaluation and molecular docking studies on metal complexes with N-Phenylmorpholine-4-carbothioamide. While chemical part can be regarded as interesting there are serious concerns regarding English language. Extended polishing is needed in order this contribution would become readable. (Response : Thank you very much for the evaluation of the manuscript, and the typos and grammar errors were all checked and corrected), But not just grammar, also chemical terminology needs much polishing. Synthetic protocols are not written according scientific standards, sometimes data on solvent is missing or awkward sentences are used (Response : We checked and  rewrite many paragraphs in the experimental part),. Some interpretation of for example PXRD “a wide peaks and non-regular spectra, indicated these complexes are presents in fine structure.” is incorrect. Wide peaks indicate low crystallinity and the presence of amorphous phase(Response : We checked and  corrected it),.. It is a pitty that authors don’t report any SC XRD structure, much information is thus not delivered by the authors due to this fact(Response : We thank the reviewer for raising this point and we fully agree that it is better to have X-ray single crystal structure of these complexes; however, our attempts to grow X-ray quality single crystals of these complexes by dissolving them in many solvents were failed. Unfortunately, all our trials were unsuccessful and no crystals suitable for X-ray diffraction studies were obtained. ),..

Also, the word “nano” in the title is not really justified since this is more or less classical coordination chemistry. Furthermore, all bioassay was performed in solution thus no nano material was present at this bioevaluation step.

Response: In accordance with the referees’ wishes, We update the manuscript title as following " Thiourea derivative metal complexes, Spectroscopic, anti-microbial evaluation, ADMET, toxicity, and molecular docking studies"

Round 2

Reviewer 3 Report

1.) Abstract: What is meant by “to give four coordination rings.”? Do the authors have in mind a chelate rings? Please correct accordingly. According to the Scheme 3 only two chelate rings are present.

2.) Synthetic protocols still need revision:

Current text, like: »An ethanolic solution of N-Phenylmorpholine-4-carbothioamide (HPMCT) (0.500g, 2.200 mmol) in (20ml) …«

Should be changed as »An ethanolic solution (20 mL) of N-Phenylmorpholine-4-carbothioamide (HPMCT) (0.500 g, 2.200 mmol) …«

or as »Solution of N-Phenylmorpholine-4-carbothioamide (HPMCT) (0.500 g, 2.200 mmol) in ethanol (20 mL) …«

Authors should report the volume of the solvent close to the solvent name or description, also authors should insert a space between a number and unit.

English polishing is still needed. Here are some exaples regarding the Abstract. Often a present tense form would be much better then the past tense.

“Further, reaction two equivalents of HPMCT” should be “Furthermore, reaction of two equivalents of HPMCT”

“and one equivalent bivalent metal ions” should be “and one equivalent of bivalent metal ions”

“Results suggested that (HPMCT)” should be “Results suggest that HPMCT”

“was bonded as mono-dentate via S atom” should be “is bonded as mono-dentate ligand via S atom” or as “is bonded monodentatelly via S atom”

“linkage as bi-dentate chelating style via S and N atoms” Should be “linkage as bi-dentate chelating ligand via S and N atoms” Or as “linkage bidentatelly via S and N”

“which displayed that the very best anti-bacterial activity was the complexes” should be “which display that the very best anti-bacterial activities have the complexes”

“were screened breast cancer cell lines” should be “were screened on breast cancer cell lines”

Rephrase the text: “that the most promising activity compound” this is unusual phrasing.

 “6-311++G(d,p) biases set” should be “6-311++G(d,p) basis set”

Author Response

Comments and Suggestions for Authors

1.) Abstract: What is meant by “to give four coordination rings.”? Do the authors have in mind a chelate rings? Please correct accordingly. According to the Scheme 3 only two chelate rings are present.

Done

2.) Synthetic protocols still need revision:

Current text, like: »An ethanolic solution of N-Phenylmorpholine-4-carbothioamide (HPMCT) (0.500g, 2.200 mmol) in (20ml) …«

Done

Should be changed as »An ethanolic solution (20 mL) of N-Phenylmorpholine-4-carbothioamide (HPMCT) (0.500 g, 2.200 mmol) …«

Done

or as »Solution of N-Phenylmorpholine-4-carbothioamide (HPMCT) (0.500 g, 2.200 mmol) in ethanol (20 mL) …«

Done

Authors should report the volume of the solvent close to the solvent name or description, also authors should insert a space between a number and unit.

Done

Comments on the Quality of English Language

English polishing is still needed. Here are some exaples regarding the Abstract. Often a present tense form would be much better then the past tense.

“Further, reaction two equivalents of HPMCT” should be “Furthermore, reaction of two equivalents of HPMCT”

Done

“and one equivalent bivalent metal ions” should be “and one equivalent of bivalent metal ions”

Done

“Results suggested that (HPMCT)” should be “Results suggest that HPMCT”

Done

“was bonded as mono-dentate via S atom” should be “is bonded as mono-dentate ligand via S atom” or as “is bonded monodentatelly via S atom”

Done

“linkage as bi-dentate chelating style via S and N atoms” Should be “linkage as bi-dentate chelating ligand via S and N atoms” Or as “linkage bidentatelly via S and N”

Done

“which displayed that the very best anti-bacterial activity was the complexes” should be “which display that the very best anti-bacterial activities have the complexes”

Done

 “were screened breast cancer cell lines” should be “were screened on breast cancer cell lines”

Done

Re phrase the text: “that the most promising activity compound” this is unusual phrasing.

Done

 “6-311++G(d,p) biases set” should be “6-311++G(d,p) basis set”

Done

Author Response File: Author Response.docx