Drug Candidates for the Treatment of Alzheimer’s Disease: New Findings from 2021 and 2022

Round 1

Reviewer 1 Report

In this manuscript, the authors review the development of acetylcholinesterase inhibitors over the past four years. The manuscript addresses an important health problem, Alzheimer's disease, which is expected to increase in importance in the coming years, making the development of new drugs for this disease crucial.

The manuscript should be grammatically checked, as a large number of errors were found.

“The active site of the enzyme comprises two regions: the anionic choline-binding site and the catalytic esteratic site and is located within the gorge [18,19]. X-Ray crystallographic structure of AChE from Torpedo californica (PDB ID: 1ACJ and 1ACL) revealed that the enzyme’s active site has two primary binding sites, that is the catalytic active site (CAS) and the gorge-connected peripheral anionic site (PAS)[20-23]. Amino acids such as Trp279, Tyr70, Tyr121, Asp72 and Phe290 forms the PAS whereas amino acids of the esteratic subsite gorge (Ser200, His440 and Glu327), anionic substrate (Trp84, Glu199 and Phe330),and acyl binding pocket (Phe288 and Phe299) together form the CAS [24-26].” Is the anionic choline binding site the same as PAS and the catalytic ester site the same as CAS? If so, please change this paragraph so that this is clearly understood. As it is currently written, this is not clear. I also suggest showing the binding of ACh to its binding sites and indicating all the pockets and amino acids discussed.

The mechanism of acetylcholine degradation according to Scheme 2 should be described in more detail in the text. Also, the amino acid residues in Scheme 2 should be labeled. Is estractic site the correct term?

The structure of galantamine in Scheme 3 is incorrect.

The manuscript was supposed to cover 4 years of AChE inhibitor development, but instead there are two chapters, one for the year 2022 (the title of this chapter should be changed because it says "current" year but describes the year 2022) and the year 2021, so it only covers 2 years, what about the remaining 2 years?

In reviewing the manuscript, I noticed that the authors sometimes use compounds numbering from original papers and sometimes use their own numbering. Please unify them so that only the authors' numbering is shown. Also, I noticed that authors do not use the correct sign when indicating the values of scoring functions or binding energies; in most cases these values should be negative, while in the manuscript they are almost always positive.

Lines 171-174: “The Ellman's assayresults disclosed that the derivatives 2and 3inhibit AChE activity and revealed that the greater inhibition percentageat thevaried concentrations of 10–4 and 10–10 M while low inhibition percentage was obtained at 10–12 and 10–4 M respectively.” In the original paper, low inhibition was observed only at 10–12 M, but not at 10–4 M.

Lines 224-225: “Finally, study has singled out compound 7 as the most assuring compoundfor the treatment of AD.” In the original paper, two compounds were identified as the most potential, compound 2 and 16 (numbering as in the original paper).

Lines 236-238: “All synthesized compounds 8-13 having better pharmacokinetic profile for potential to act as a cholinesterase inhibitor against Alzheimer’s disease.” Better than which compound?

Lines 281-283: “High anti-lipid peroxidation activities were presented by compound 16 whereas compound 17 give on to a new and promising class with antioxidant and anti-AChE activities.” Compound 16 is described in the previous paragraph and not in this one.

The structure of compounds 26, 27, 30 are incorrect.

Lines 499-501: “The multifunctional properties of chalcone 42, 43, and 44 were all advantages that demonstrate an excellent candidate for the development of an effective drug against AChE.” In the original paper only compound 15 (numbering as in the original paper) was disclosed as the most promising.

I noticed that many sentences are identical to those in the original papers. The text between lines 456-468 is copied from the abstract of the original paper.

 

Author Response

Reviewer Comment	Author’s reply
The manuscript should be grammatically checked, as a large number of errors were found.	Yes we agree with the reviewer’s comment and it has been grammatically checked throughout the manuscript.
The active site of the enzyme comprises two regions: the anionic choline-binding site and the catalytic esteratic site and is located within the gorge [18,19]. X-Ray crystallographic structure of AChE from Torpedo californica (PDB ID: 1ACJ and 1ACL) revealed that the enzyme’s active site has two primary binding sites, that is the catalytic active site (CAS) and the gorge-connected peripheral anionic site (PAS)[20-23]. Amino acids such as Trp279, Tyr70, Tyr121, Asp72 and Phe290 forms the PAS whereas amino acids of the esteratic subsite gorge (Ser200, His440 and Glu327), anionic substrate (Trp84, Glu199 and Phe330),and acyl binding pocket (Phe288 and Phe299) together form the CAS [24-26].” Is the anionic choline binding site the same as PAS and the catalytic ester site the same as CAS? If so, please change this paragraph so that this is clearly understood. As it is currently written, this is not clear. I also suggest showing the binding of ACh to its binding sites and indicating all the pockets and amino acids discussed.	Yes it have been checked and corrected according to the reviewer’s comments.
The mechanism of acetylcholine degradation according to Scheme 2 should be described in more detail in the text. Also, the amino acid residues in Scheme 2 should be labeled. Is estractic site the correct term?	Incorporated as per reviewer’s suggestion in the manuscript
The structure of galantamine in Scheme 3 is incorrect.	Yes I completely agree with the reviewer’s observation and the structure of galantamine is corrected in Scheme 3.
The manuscript was supposed to cover 4 years of AChE inhibitor development, but instead there are two chapters, one for the year 2022 (the title of this chapter should be changed because it says "current" year but describes the year 2022) and the year 2021, so it only covers 2 years, what about the remaining 2 years?	We the authors would like to thank the reviewer for their keen observation toward our manuscript and suggested us to correct mistakes in manuscript. And we have made correction according to reviewer comment.
In reviewing the manuscript, I noticed that the authors sometimes use compounds numbering from original papers and sometimes use their own numbering. Please unify them so that only the authors' numbering is shown. Also, I noticed that authors do not use the correct sign when indicating the values of scoring functions or binding energies; in most cases these values should be negative, while in the manuscript they are almost always positive.	Corrected as per reviewer’s suggestion in the manuscript
Lines 171-174: “The Ellman's assayresults disclosed that the derivatives 2and 3inhibit AChE activity and revealed that the greater inhibition percentageat thevaried concentrations of 10–4 and 10–10 M while low inhibition percentage was obtained at 10–12 and 10–4 M respectively.” In the original paper, low inhibition was observed only at 10–12 M, but not at 10–4 M.	Corrected as per reviewer’s suggestion in the manuscript
Lines 224-225: “Finally, study has singled out compound 7 as the most assuring compound for the treatment of AD.” In the original paper, two compounds were identified as the most potential, compound 2 and 16 (numbering as in the original paper).	Corrected as per reviewer’s suggestion in the manuscript
Lines 236-238: “All synthesized compounds 8-13 having better pharmacokinetic profile for potential to act as a cholinesterase inhibitor against Alzheimer’s disease.” Better than which compound?	Corrected as per reviewer’s suggestion in the manuscript
Lines 281-283: “High anti-lipid peroxidation activities were presented by compound 16 whereas compound 17 give on to a new and promising class with antioxidant and anti-AChE activities.” Compound 16 is described in the previous paragraph and not in this one.	Corrected as per reviewer’s suggestion in the manuscript.
The structure of compounds 26, 27, 30 are incorrect.	Yes, the structure of the compounds 26, 27 and 30 were wrong and the structures were corrected by referring the original article.
Lines 499-501: “The multifunctional properties of chalcone 42, 43, and 44 were all advantages that demonstrate an excellent candidate for the development of an effective drug against AChE.” In the original paper only compound 15 (numbering as in the original paper) was disclosed as the most promising.	Corrected as per reviewer’s suggestion in the manuscript.
I noticed that many sentences are identical to those in the original papers. The text between lines 456-468 is copied from the abstract of the original paper.	Yes I completely agree with the reviewer’s comment and sentences has been rewritten.

 

Reviewer 2 Report

The presented paper is a “current” review on design, synthesis and molecular docking studies on acetylcholinesterase inhibitors. Despite the amount of the collected information, “.. review encapsulates the ongoing therapeutic strategies for the development of these AChEIs in the last four years.” The first arised question is why the authors have decided to consider four, but not five years? But most important is the fact, that the presented manuscript sounds just like a chronic of the development of acetylcholinesterase inhibitors, but far from a real review. Тхус, the paper needs some additional efforts before to be considered for publishing in such an esteemed journal as Drug and Drug Candidates.

1.      First of all, the manuscript needs serious efforts toward English, both as grammar and style, starting with the very first sentence of the abstract.…

2.      There are many glued words in the manuscript, e.g. “derivatives 2and 3inhibit AChE activity” (row 172), “weillustrated” (row180), “it’sin vivo ability to lowerAChE” (row 189), “observedincompound”(row 217), and many others.

3.      There are many abbreviations, introduced more than ones, e.g. (AD) – 4 times, (ACh) – 6 times, etc. Meanwhile, there are some abbreviations without explanations, e.g. NMDARs.

4.      Pharmaceutical drug brand names, where used, should be written with a capital letter.

5.      I would suggest either presenting the compounds as figures, or their collecting in a Table, in both ways with relevant references. Some of structures are unnecessarily large in size (e.g., compound 19). Moreover, most of the compounds might be presented as parent structure with deviations…

6.      I have no see a need “Design and Synthesis of New AChE Inhibitors” to be presented  by years… I would highly appreciate any kind of classification either by chemical structures, or by biological activity…

Author Response

Reviewer Comment	Author’s reply
.      First of all, the manuscript needs serious efforts toward English, both as grammar and style, starting with the very first sentence of the abstract.…	Yes we agree with the reviewer’s comment and it has been grammatically checked throughout the manuscript.
There are many glued words in the manuscript, e.g. “derivatives 2and 3inhibit AChE activity” (row 172), “we illustrated” (row180), “it’sin vivo ability to lowerAChE” (row 189), “observed in compound” (row 217), and many others.	Yes, I agree with the reviewer comments and glued words were there in the manuscript and corrected through the manuscript.
There are many abbreviations, introduced more than ones, e.g. (AD) – 4 times, (ACh) – 6 times, etc. Meanwhile, there are some abbreviations without explanations, e.g. NMDARs.	Corrected as per reviewer’s suggestion in the manuscript.
Pharmaceutical drug brand names, where used, should be written with a capital letter.	Corrected as per reviewer’s suggestion in the manuscript
.      I would suggest either presenting the compounds as figures, or their collecting in a Table, in both ways with relevant references. Some of structures are unnecessarily large in size (e.g., compound 19). Moreover, most of the compounds might be presented as parent structure with deviations…	Corrected as per reviewer’s suggestion in the manuscript
.      I have no see a need “Design and Synthesis of New AChE Inhibitors” to be presented  by years… I would highly appreciate any kind of classification either by chemical structures, or by biological activity…	As we the authors highlighted only on synthesis, biological evaluation and molecular docking studies. So in this manuscript we couldn’t incorporate the classification. But in future we will work on suggestion made by you.

 

Reviewer 3 Report

In the manuscript, the authors reviewed the last five years development on the design, synthesis, molecular docking studies for acetylcholinesterase inhibitors against Alzheimer's disease that is common neurodegenerative disorder among old age people worldwide. The authors also concluded that the most treatment strategies for the enhancement of ACh would be considered an effective method to compensate for the deficiency of acetylcholine are focused on enhancing cholinergic neurotransmission. The information presented could be useful and provided insights for the researcher in the field. Furthermore, the manuscript is well-organized and presented. It could be suitable for publishing in Drugs Drug Candidates.

Some suggestions for the manuscript could be further improved by the authors in order to increase the readiness and attractiveness of the work.

1. Line 31 and 139: “metals (Cu2+, Zn2+, or Fe2+)” could be presented as “metal ions (Cu(II), Zn(II), or Fe(II)). Or the “2+” is in superscript format.

2. In Scheme 2, arrows of the reactions could be replaced with sold arrows. It now looks the symbol of retrosynthesis.

3. Scheme 3, the structure of Rivastigmine is not chiral. The dash bond of methyl group could be replaced with a solid bond.

4. Page 7, the first structure, the OH group should be chiral. Please use dash or wedge bond for the presentation if it is known. In addition, the drawing for 7 R1 seems not correct. Please double check all the structures for their accuracy.

5. Line 540: “some” could be deleted. “30” could be written as “thirty”.

6. For the compounds reviewed, Line 540-547, the authors are strong recommended to make a table listed these compounds (number 1-44) to summarize their inhibitory activity against the target of AChE and/or BChE, and other useful information, the reference number, etc.. This summary may be useful for readers to do comparison among the compounds.

Author Response

Reviewer Comment	Author’s reply
Line 31 and 139: “metals (Cu2+, Zn2+, or Fe2+)” could be presented as “metal ions (Cu(II), Zn(II), or Fe(II)). Or the “2+” is in superscript format.	Corrected as per reviewer’s suggestion in the manuscript
In Scheme 2, arrows of the reactions could be replaced with sold arrows. It now looks the symbol of retrosynthesis.	Corrected as per reviewer’s suggestion in the manuscript
Scheme 3, the structure of Rivastigmine is not chiral. The dash bond of methyl group could be replaced with a solid bond.	Corrected as per reviewer’s suggestion in the manuscript
Page 7, the first structure, the OH group should be chiral. Please use dash or wedge bond for the presentation if it is known. In addition, the drawing for 7 R1 seems not correct. Please double check all the structures for their accuracy.	Corrected as per reviewer’s suggestion in the manuscript
. Line 540: “some” could be deleted. “30” could be written as “thirty”.	Corrected as per reviewer’s suggestion in the manuscript
For the compounds reviewed, Line 540-547, the authors are strong recommended to make a table listed these compounds (number 1-44) to summarize their inhibitory activity against the target of AChE and/or BChE, and other useful information, the reference number, etc.. This summary may be useful for readers to do comparison among the compounds.	As we the authors highlighted only on synthesis, biological evaluation and molecular docking studies. So in this manuscript we couldn’t incorporate the comparison of the study. But in future we will work on suggestion made by you.

 

Round 2

Reviewer 1 Report

The authors successfully resolved all issues raised by this reviewer. Consequently, the manuscript has been significantly improved and can be in its current version recommended for publication in DDC.

Author Response

Editor Comment	Author’s reply
The English language MUST be thoroughly revised by the authors or a fee should be added if the task is done in house	Yes it have been checked and corrected according to the editor’s suggestion.
Title should be changed into “Drug candidates for the treatment of Alzheimer’s disease: a review covering 2021 and 2022”	Yes it have been checked and corrected according to the editor’s suggestion.
The abstract must be shortened and concentrates on the subject of the review, namely drug candidates, but not on the disease itself.	Yes it have been checked and corrected according to the editor’s comment.
The present review outlines the current therapeutic strategies in the advancement of these AChEIs…” is a false statement: the review does not describe therapeutic strategies but rather drug candidates.	Yes it have been checked and corrected according to the editor’s comment.
Line 227: check: 0.0144–38.0·106	Yes it has been corrected according to the editor’s suggestion.
IC50: 50 in subscript	Yes it has been corrected according to the editor’s suggestion.
Statements must be precise: “N-benzyl-4-chloroaniline (19) showed the good inhibition effect on AChE”: values must be given. True for each compound, not that one only. Here another example (and not the only one): “Hydrazone derivatives containing piperazine 20 (compounds having higher binding energy).”	Yes it have been checked and corrected according to the editor’s suggestion.
Use the same nomenclature to describe amino acids; do not mix PHE and Phe Schemes illustrating the syntheses should be added as well as some figures describing bindings.	Yes it have been checked and corrected according to the editor’s suggestion.
All schemes and figures need a number and a caption Year 2021 should precede year 2022	Yes it have been checked and corrected according to the editor’s suggestion.
Compounds 6 and 7 should be drawn in full.	Yes it has been corrected according to the editor’s suggestion.

Reviewer 2 Report

The revised version has addressed just the technical points of my review, like abbreviations, glued words, etc. From the other side, it seems that serious efforts have been made toward language, although it is hard to be followed in the track changes mode… I would suggest authors to give a version of the paper with accepting the changes as well, and they will see that there are still grammatical errors to be fixed…

 

Meanwhile, the most important questions set in the first paragraph of the first stage review are left even without any comment:

 

1.      I have asked the authors why they have decided to consider four, but not five years? With a big surprise, I see that in the revised version not four, but even two-year period is considered? Meanwhile no references have been removed, which confuses me...

2.      The authors have not even considered my main concern, that the presented manuscript sounds just like a chronic of the development of acetylcholinesterase inhibitors, but it is too far from a real review.

3.      The authors have considered my suggestion for any kind of classification as future work, which comes to confirm my previous comment, that presented in such manner the paper is not a real review…

In such a way the authors do not convince me that this “review” worth to be published….

Author Response

Please see attached document

Author Response File: Author Response.pdf

Round 3

Reviewer 2 Report

As can be seen from the authors’ replies to my comments at the second round of revision, they have stood up for the structure, organization and presentation of their article… They still insist that this is a review, while my opinion differs quite much from their… The only one way for me to give a chance their work to be published is if the authors agree to change the title from “Drug candidates for the treatment of Alzheimer's Disease: A review covering 2021and 2022” to “Drug candidates for the treatment of Alzheimer's Disease: New findings from 2021 and 2022” and the paper to not be considered as a review as an article type…

Author Response

We the authors with whole hearted welcome and accepted to change the title as per the reviewer suggestions... We the authors tried to shorten the review type by elaborating  research work carried out by researchers.... Anyway we are glad enough for your precious time and patience towards our manuscript

Thanking you