Synthesis, Crystal Structure and Anti-Leukemic Activity of 1,3-Dihydro-1-{1-[4-(4-phenylpyrrolo[1,2-a]quinoxalin-3-yl)benzyl]piperidin-4-yl}-2H-benzimidazol-2-one

Round 1

Reviewer 1 Report

Guillon et al. designed and synthesized a new pyrrolo[1,2-a]quinoxaline inhibitor 9 and then evaluated its antileukemic activity on several human leukemic cell lines. This inhibitor 9 exhibiting good antileukemia properties may become a potential candidate for further pharmacomodulations and pharmacological investigations. 

Overall, the results are well and this reviewer recommends to publish above results in Molbank.

Author Response

To: Mrs. Claire Gao,

Assignated Editor, MDPI

Paper ref. No. molbank-1589390 - Minor Revisions

Dear Mrs. Claire Gao,

            Thank you for your letter of february 2 and the review of our above-mentioned manuscript. In the enclosed version (the revised manuscript), we have addressed the reviewer's request for major revisions.

            Please note the changes that have been made in this amended version:

Reviewer #1:

• No change requested.

 

Reviewer #2:

-      As requested, we have introduced a new sentence with the appropriate references to explain the characterization of described compounds 3-7, as following : “The characterization of compounds 3-6 [8,9] and 7 [20] were in accordance with those previously described in the literature.”

• In the introduction part, we have specified the proper literature citations indicating more precisely the reference for each biological activity mentioned, as following “Such nitrogen-containing valuable heterocyclic compounds have been previously described as antipsychotic agents [3], antiviral agents [4], adenosine receptor modulators [5], antituberculosis agents [6,7], antiprotozoal agents [8-14] and anticancer agents [15–19].”
• As requested, in Scheme 1, the NMR position numbering of the compounds 8 and 9 have been assigned for an easier tracking of the NMR peaks.
• The vibrational wave numbers of compound 8 has been attributed to the corresponding functional group and incorporate them in the spectral characterization of the compounds in Materials and method.

 

Reviewer #3:

• As requested, in Scheme 1, the NMR position numbering of the compounds 8 and 9 has been assigned to improve the clarity of the work.

We thank you again for your consideration and the reviewer for their careful reading, and hope that you will now find this manuscript in order for publication.

            Looking forward to hearing from you.

Sincerely yours,

                                                                                   Pr. Jean GUILLON

Reviewer 2 Report

The authors present the synthesis of 1,3-dihydro-1-{1-[4-(4-phenylpyrrolo[1,2-a]quinoxalin-3-yl)ben-zyl]piperidin-4-yl}-2H-benzimidazol-2-one and its anti-leukemic activity on tree types of human leukemic cell lines U937, K562, and HL60.

Concerning the descriptive aspect of the investigated problem the paper fulfills the goals proposed by the authors. Nevertheless, there are some questions which should be clarified.

• Even that the authors stated that the title compound “has been synthesized through a multi-step pathway starting from commercially available 2-nitroaniline” (see Abstract and first sentence from Results and discussion), in fact at least the first 4 steps (until the synthesis of the compound 5) were previously reported by the same author on the synthesis of the anti-leukemic pyrroloquinoxaline derivative JG576. The novelty of the synthesis described in the present manuscript reside from the fact that the author changed the order of the boronic acid used in Suzuki–Miyaura cross-coupling reaction switching this way the substituents from the 3 and 4 position of the pyrrolo[1,2-a]quinoxaline skeleton. Also, on Materials and methods, the authors present the general procedure and spectral characterization of the compounds 8 and 9 The authors must clarify this aspect.
• In introduction part “Such nitrogen-containing valuable heterocyclic compounds have been previously described as antipsychotic agents, antiviral agents, adenosine receptor modulators, anticancer agents and antiprotozoal agents [3–19].” require proper literature citations indicating more precisely the reference for each biological activity mentioned.
• Regarding the NMR spectra of the compounds, please include in Scheme 1 the NMR position numbering of the compounds for an easier tracking of the NMR peaks.
• Please attribute the vibrational wave numbers to the corresponding functional group and incorporate them in the spectral characterization of the compounds in Materials and method.

 

Having in view this consideration I recommended the publication of this article in Molbank after minor revision.

Comments for author File: Comments.pdf

Author Response

To: Mrs. Claire Gao,

Assignated Editor, MDPI

Paper ref. No. molbank-1589390 - Minor Revisions

Dear Mrs. Claire Gao,

 

            Thank you for your letter of february 2 and the review of our above-mentioned manuscript. In the enclosed version (the revised manuscript), we have addressed the reviewer's request for major revisions.

            Please note the changes that have been made in this amended version:

 

Reviewer #1:

• No change requested.

Reviewer #2:

-      As requested, we have introduced a new sentence with the appropriate references to explain the characterization of described compounds 3-7, as following : “The characterization of compounds 3-6 [8,9] and 7 [20] were in accordance with those previously described in the literature.”

• In the introduction part, we have specified the proper literature citations indicating more precisely the reference for each biological activity mentioned, as following “Such nitrogen-containing valuable heterocyclic compounds have been previously described as antipsychotic agents [3], antiviral agents [4], adenosine receptor modulators [5], antituberculosis agents [6,7], antiprotozoal agents [8-14] and anticancer agents [15–19].”
• As requested, in Scheme 1, the NMR position numbering of the compounds 8 and 9 have been assigned for an easier tracking of the NMR peaks.
• The vibrational wave numbers of compound 8 has been attributed to the corresponding functional group and incorporate them in the spectral characterization of the compounds in Materials and method.

Reviewer #3:

• As requested, in Scheme 1, the NMR position numbering of the compounds 8 and 9 has been assigned to improve the clarity of the work.

We thank you again for your consideration and the reviewer for their careful reading, and hope that you will now find this manuscript in order for publication.

            Looking forward to hearing from you.

Sincerely yours,

                                                                                   Pr. Jean GUILLON

Reviewer 3 Report

The manuscript of Guillon et al. deals with the synthesis and biological activity (in vitro) of a new heterocyclic compound containing the quinoxaline skeleton.

The work is correctly written and presented. Although it is a single compound, the protocol to obtain it involves several steps including two Suzuki-Miyaura cross coupling reactions. The structural characterization is correct. Additionally, the resolution of the structure is obtained by X-ray electron diffraction using the single crystal methodology.

My only suggestion to improve the clarity of the work is to include the numbering followed for the assignment of signals in NMR on the structure of compound 9 (scheme 1). For example, reading the assignment described in section 3.2. it is difficult to determine to which position the nuclei C-2', C-2'' and C-2''' correspond.

Author Response

To: Mrs. Claire Gao,

Assignated Editor, MDPI

Paper ref. No. molbank-1589390 - Minor Revisions

Dear Mrs. Claire Gao,

            Thank you for your letter of february 2 and the review of our above-mentioned manuscript. In the enclosed version (the revised manuscript), we have addressed the reviewer's request for major revisions.

            Please note the changes that have been made in this amended version:

 

Reviewer #1:

• No change requested.

Reviewer #2:

-      As requested, we have introduced a new sentence with the appropriate references to explain the characterization of described compounds 3-7, as following : “The characterization of compounds 3-6 [8,9] and 7 [20] were in accordance with those previously described in the literature.”

• In the introduction part, we have specified the proper literature citations indicating more precisely the reference for each biological activity mentioned, as following “Such nitrogen-containing valuable heterocyclic compounds have been previously described as antipsychotic agents [3], antiviral agents [4], adenosine receptor modulators [5], antituberculosis agents [6,7], antiprotozoal agents [8-14] and anticancer agents [15–19].”
• As requested, in Scheme 1, the NMR position numbering of the compounds 8 and 9 have been assigned for an easier tracking of the NMR peaks.
• The vibrational wave numbers of compound 8 has been attributed to the corresponding functional group and incorporate them in the spectral characterization of the compounds in Materials and method.

Reviewer #3:

• As requested, in Scheme 1, the NMR position numbering of the compounds 8 and 9 has been assigned to improve the clarity of the work.

 

We thank you again for your consideration and the reviewer for their careful reading, and hope that you will now find this manuscript in order for publication.

            Looking forward to hearing from you.

Sincerely yours,

                                                                                   Pr. Jean GUILLON