Recent Advances on Quinazoline Derivatives: A Potential Bioactive Scaffold in Medicinal Chemistry

Round 1

Reviewer 1 Report

This review is focused on the potential biological activity of quinazoline derivatives in order to provide information regarding latest developments on quinazoline analogs having completely different pharmacological activity. This study could provide useful information for the researchers to design future new drugs having quinazoline for the treatment of diseases. In my opinion, this article is appropriate for publication in ChemEngineering Journal and I propose this manuscript to be accepted in present form.

Author Response

Authors are thankful for such positive and motivating comments.
We have taken necessary cognizance in bringing the manuscript to its best form.
We have incorporated all the suggested corrections.
We now believe that updated manuscript will meet the standard of journal.

Thanks and Regards

Reviewer 2 Report

In this review article the Authors present the main results of a selection of articles, on the medicinal activity, such as antifungal, antiviral, antidiabetic, anticancer, anti-inflammatory, antibacterial, antioxidant etc., of molecules with quinazoline moiety. The manuscript is organized by paragraphs based on the type of medical activity, in addition, in some paragraphs there is a summary table.

In my opinion this review article is not within the scope of the Journal, furthermore it is weak in both drafting and content. The manuscript can be read easily, despite the 34 pages of the file, about 8/9 pages are those actually used for the text, the remaining pages are devoted mainly to the tables. “Engineering” is missing but the name of the Journal is “ChemEngineering”, there are some English and typing errors, the text is essentially a technical report, with no critical in-depth analysis and there is a complete lack of future perspectives. A completely different style was used for the bibliography than the one suggested by the journal, there are also articles published many years ago.

I think that as it was conceived, this review article is not adequate, I suggest rethinking the manuscript layout and rewrite it, focusing on the topics envisaged by this Journal, on the impact in the scientific field of the results of the articles reviewed, and on future prospects.

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

This review is a compendium of the use of several quinazoline-based drugs. The manuscript is robust and fit in to the scopes of the Journal. Therefore, this referee believes that it deserves to be published in ChemEngineering, pending the following minor points:

While the biological part is adequately addressed, the chemical part lacks from a proper discussion:

-Authors must include a section describing the general synthetic strategies to obtain quinazoline scaffold.

 -Toxicity of some relevant examples could be described.

-A section of quinazolines as antiparasitic drugs must be included. See the following references:

Mendoza-Martínez et al. Antileishmanial activity of quinazoline derivatives: synthesis, docking screens, molecular dynamic simulations and electrochemical studies. Eur J Med Chem. 2015, 92:314-31. doi: 10.1016/j.ejmech.2014.12.051.

Santos-Cruz et al. Genotoxicity assessment of four novel quinazoline-derived trypanocidal agents in the Drosophila wing somatic mutation and recombination test. Mutagenesis. 2020, 35(4):299-310. doi: 10.1093/mutage/gez042

Amrane et al. Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines. Molecules. 2020, 25(17):3929. doi: 10.3390/molecules25173929.

Author Response

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Author Response File: Author Response.docx

Reviewer 4 Report

Journal: ChemEngineering (ISSN 2305-7084)

Manuscript ID: ChemEngineering-1298982

Type: Review

Title: Recent advances on quinazoline derivatives: A potential bioactive scaffold

The submitted manuscript is a review of heterocyclic compounds being quinoline derivatives that exhibit the antifungal, antitumor, anti-inflammatory, antibacterial and antioxidant properties. The authors focus on reviewing the literature in terms of their structure and pharmaceutical performance based mainly on the IC index, but without going into the details of their synthesis and the mechanism of action. Despite the fact that the work does not take into consideration mentioned aspects (the method of synthesis and the mechanism of action), the way of compiling the information (in the form of tables and figures with structural formulas) systemize the knowledge of quinoline derivatives. The authors refer to the most recent information, which gives an insight into the latest progress in the field discussed in the work. Nevertheless, before the publication the paper needs to be improved in some points. Below, there are some comments and suggestions:

1) In agreement with the first part of the manuscript title, the paper actually considers recent advances, as evidenced by the quoted literature references from recent years. Nevertheless, the second part of the title may be misleading. In the submitted review, authors focus only on the use of quinoline derivatives in the field of medical chemistry to treat various diseases. The use of the word "bioactive" in the title may suggest that the manuscript describes a broader spectrum of applications for quinoline derivatives, while in the paper there is no information on the potential uses of quinazoline derivatives in other than medicine fields, such as: food industry, where the compounds with antibacterial and antifungal properties are widely used in the preservation of raw materials and food products. Therefore, it is advisable to narrow the title to medicinal use, for example: "Recent advances in the field of quinazoline derivatives: a potential bioactive scaffold in medical chemistry".

2) Introduction, paragraph 1: It seems that in the sentence “Synthesis of quinazoline, firstly reported through decarboxylation of 2-carboxy derivative by August Bischler and Lang in 1985 (Connolly et al. 2005).” is a mistake in a year. Shouldn’t it be 1895? Moreover, it is also worth to mention here about the Niementowski quinazoline synthesis in the chemical reaction of anthranilic acids with amides to form 4-oxo-3,4-dihydroquinazolines that was published in a similar period (1894).

3) Although the authors emphasize the antifungal properties of quinoline derivatives (the term “antifungal” appears in keywords and an abstract), this thread is not developed in the text of the manuscript. The only exceptions are “Albaconazole“ that is listened in table 1 point 13 as an example of quinoline derivatives exhibiting antifungal activity and the general statement in section 4, paragraph 2, i.e.:

“Based on pharmacophore hybrid approach, quinazoline derivatives were synthesized having 1, 2, 4-triazole thioether moiety and tested for their antibacterial and antifungal activities activity”.

Taking above into account, the manuscript needs to be expanded in information on the antifungal activity of the discussed compounds. Moreover, it seems that in the quoted sentence the last word “activity” should be delated.

4) Section 4 “Quinazoline as anti-viral“, paragraph 2: the text: “Based on pharmacophore hybrid approach, … agrobactericide Bismerthiazol (56.9 μg/mL)(Fan, Shi, and Bao 2018).” considers antibacterial not antiviral activity of quinoline derivatives, therefore it should to be moved to the next section of “Quinazoline as Anti-Bacterial“

5) Section 4, below paragraph 2: The sentence: “Quinazoline artemisinin hybrids were synthesized and evaluated for their in vitro biological” seems to be unfinished Probably the sentence has been moved and the "activity" from comment 3 should be at the end of this sentence.

6) Tables 3 and 4 are quite long and both include examples belonging to different groups (i.e. antiviral and antibacterial activity of Quinazoline derivatives (in Table 3); antitubercular and antioxidant activity of quinazoline derivative (in Table 4)), so it is worth breaking each of them down into two tables presenting each activity separately (the more so that the authors used such a division into sections in the text).

Table 5 contains single examples of compounds with different properties, therefore this table can remain in the present (aggregated) form.

7) The text of the manuscript requires many editorial corrections, i.e.:

• Are species names written in agreement with the journal requirements? Usually, latin names of species should be written in italics: “Xanthomonas axonopodis”, “S. aureus and E. coli.” etc. Moreover, when mentioning the name of a species, the name should be full for the first time, then the abbreviation of the genus is used.
• Full stop appears in the middle of the sentence (following ml) “with EC50=248.6 μg/mL. and potato virus”.
• Sometimes the full stop seems to be in the wrong place “New derivatives of 2-Ethylthio-4- methylaminoquinazoline were designed and assessed against Mycobacterium tuberculosis (M. tb). (Lupien et al. 2020)It was concluded that quinazoline based derivatives are potent moiety for the tuberculosis drug targeting (figure 3, table 4).”
• There are words in the sentences that are written without reason with a capital letter, i.e. “A new class of compounds were Synthesized…” This applies to the entire manuscript.
• On the other hand, there are sentences that start without using capital letter: “Quinazoline and its numerous derivatives can be extracted from plants. substituted quinazoline has been widely used as an anti-tumor agent due to its structure-activity relationship”.
• The same names are written for an unknown reason, once in uppercase and once in lowercase letters: “Quinazolinone is one of the derivatives of Quinazoline which is active as like quinazoline “.
• In the caption of Table 3 “Antiviral and antibacterial and activity of Quinazoline derivatives”, the crossed-out “and” is redundant.
• The IC index is used one time as the IC50 and another time with a footnote IC₅₀ - the notation should be unified.

Author Response

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Reviewer 5 Report

Minor remarks

Some references are not complete and they should be checked.

English should be improved by a native speaker.

Also, there are a lot of technical errors that should be removed.

All other minor remarks are given in the manuscript.

Comments for author File: Comments.pdf

Author Response

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Round 2

Reviewer 2 Report

Compared to the previous version, the style of the bibliography has been improved, and the bibliographic references have been better arranged. On the other hand the critical issues were not addressed, the manuscript was not sufficiently improved, a critical in-depth analysis is missing and lacks of future prospectives. 

Author Response

Dear Sir/ Madam
Authors are thankful for your suggestions. 
We have comprised future prospective in the conclusion part of this manuscript. We have also incorporated all the suggestions to bring this manuscript in its best form. 
As per your advice we are working on the second part of this manuscript which will be including the extended information of quinazoline moiety-based drugs.
Please consider this manuscript for the publication.

Thanks and regards

Author Response File: Author Response.docx