Structural and Biological Properties of Heteroligand Copper Complexes with Diethylnicotinamide and Various Fenamates: Preparation, Structure, Spectral Properties and Hirshfeld Surface Analysis

Round 1

Reviewer 1 Report

In this paper, the authors has reported that the synthesis, structural and spectroscopic characterization and biological activity of five copper(II) complexes with fenamate ligand and N,N-diethylnicotinaide. The characterization of these compounds have been carried out in detail, and there is no problem with the results. I don't think it's necessary to modify the content, but it would be better if the content could be summarized a little more compactly.

Author Response

In this paper, the authors has reported that the synthesis, structural and spectroscopic characterization and biological activity of five copper(II) complexes with fenamate ligand and N,N-diethylnicotinamide. The characterization of these compounds have been carried out in detail, and there is no problem with the results. I don't think it's necessary to modify the content, but it would be better if the content could be summarized a little more compactly.

 

Re:

We have simplified the results in conclusion. Thank you for your comments.

Reviewer 2 Report

In this paper the five copper (II) complexes were synthesized and characterized. Then the biological activity of the compounds was carried out. The studied complexes are monomeric, forming a distorted tetragonal bipyramidal stereochemistry around the central copper ion. The crystal structures of all five complexes were determined and refined with an aspheric model using the Hirshfeld atom refinement (HAR) method. Hirshfeld surface analysis and fingerprint plots were used to investigate the intermolecular interactions in the crystalline state. The redox properties of the complexes were studied and evaluated by cyclic voltammetry. The complexes exhibit good superoxide scavenging activity as determined by NBT assay along with a copper based redox-cycling mechanism resulting in the formation of ROS which in turn predispose the studied complexes for their anticancer activity. The ability of complexes to interact with calf thymus DNA was investigated using absorption titrations, viscosity measurements and ethidium bromide displacement fluorescence-based method suggesting mainly intercalative binding of the complexes to DNA. The affinity of complexes 1-4 for bovine serum albumin was determined by fluorescence emission spectroscopy and quantitatively characterized by corresponding binding constants. The cytotoxic properties of complexes 1-4 have been studied using the cancer cell lines A549, MCF-7 and U-118MG.

The paper can be accepted after some additions and corrections.

1-    The H-NMR Spectra of flufenamate (fluf), niflumate (nifl), 19 tolfenamate (tolf), clonixinate (clon), mefenamate (mef) and N,N-diethylnicotinamide (dena) should be given in Suppl. info.

2-    The C-NMR Spectra of flufenamate (fluf), niflumate (nifl), 19 tolfenamate (tolf), clonixinate (clon), mefenamate (mef) and N,N-diethylnicotinamide (dena) should be given in Suppl. info.

3-    In Figure 5., the figures should be given in same scale.

4-    Figure 6 is very blurry. It given should be given a better form.

5-    Figure 9 is very blurry. It given should be given a better form.

6-    Some references can be added about complex compounds and application such as Complexation properties and synthesis of a novel Schiff base with triphenylene nucleus, Journal of hazardous materials 183 (1-3), 334-340. Synthesis and photophysical properties of modifiable single, dual, and triple-boron dipyrromethene (Bodipy) complexes, Tetrahedron Letters 56 (14), 1873-1877

 

 

Best Regards

 

 

Author Response

 

1-The H-NMR Spectra of flufenamate (fluf), niflumate (nifl), 19 tolfenamate (tolf), clonixinate (clon), mefenamate (mef) and N,N-diethylnicotinamide (dena) should be given in Suppl. info.

 

Re:

All ligands were obtained from commercial sources (Sigma,Merck) and used as received. The purity of the ligands was confirmed by X-ray data as well as spectral data from IR and elemental analysis.

 

2- The C-NMR Spectra of flufenamate (fluf), niflumate (nifl), 19 tolfenamate (tolf), clonixinate (clon), mefenamate (mef) and N,N-diethylnicotinamide (dena) should be given in Suppl. info.

 

Re:

All ligands were obtained from commercial sources (Sigma,Merck) and used as received. The purity of the ligands was confirmed by X-ray data as well as spectral data from IR and elemental analysis.

 

 

3-In Figure 5., the figures should be given in same scale.

 

Re:

We have corrected the figure 5. Thanks for comment

 

4- Figure 6 is very blurry. It given should be given a better form.

Re:

We have corrected the figure 6.

 

 

5-Figure 9 is very blurry. It given should be given a better form.

 

Re:

We have enlarged the figure 9.We should note that the presented figures are in good quality (png format) but maybe the problem is that they were reduced in size to fit the format.

 

6-Some references can be added about complex compounds and application such as Complexation properties and synthesis of a novel Schiff base with triphenylene nucleus, Journal of hazardous materials 183 (1-3), 334-340. Synthesis and photophysical properties of modifiable single, dual, and triple-boron dipyrromethene (Bodipy) complexes, Tetrahedron Letters 56 (14), 1873-1877

 

Re:

We tried to find a connection of mentioned papers with our results but we have failed to do so.

Reviewer 3 Report

Reviewer’s Report

The paper under review is devoted to the preparation of Cu(II) heteroligand complexes with various derivatives of 2-(phenylamino)benzoic acid and N,N-diethylnicotinamide and their comprehensive study using various physicochemical methods. As a result of the study, the stoichiometric composition of each of the five compounds obtained was established, and their anticancer activity was revealed (although I can’t judge how great it is, because I have no right to consider myself a specialist in the field of pharmacology and medicine).

The material presented in the given paper is of a certain academic and practical interest, and its content is presented in general in good language and style (although I do not presume to judge the quality of the English used in it, since I do not consider myself competent in this matter). Therefore, I have no objection to its publication in Inorganics, and I think this article will be a good contribution to the Special Issue of the given Journal in which it is presented. However, while reading this paper, I had some questions and comments that should be answered before its publication.

1. The title of the paper contains the phrase “copper fenamates with diethylnicotinamide”, which is incorrect from the point of view of the IUPAC nomenclature for coordination compounds, since the ligands included in their composition should be listed with the conjunction AND, and not with the preposition WITH, as was done by the authors of the paper. Considering that the authors actually deal with heteroligand complexes, the title of the paper should sound like “Structural and biological properties of heteroligand copper(II) complexes with diethylnicotinamide and various fenamates: Preparation, structure, spectral properties and Hirshfeld surface analysis”. Such a change is necessary already because the paper is submitted to the Special Issue “Recent Progress in Coordination Chemistry”, and therefore, the objects studied in it must be correctly named. Similar corrections regarding the names of the complexes should, of course, be made in the text of the paper, too.

2. Lines 140-143. The authors write: “The complexes under study were obtained in a moderate yields (57 - 75%) using complexation reaction between corresponding fenamic acid and NaOH with copper acetate dihydrate and N, N-diethylnicotinamide (in molar ratio 2:2:1:2 ) in ethanol/methanol according to the Scheme 2.” Probably, it is necessary to explain why exactly the indicated ratios of the reagents were chosen and how, in the opinion of the authors, the result of the synthesis would change with other ratios of the starting substances.

3. According to the XRD analysis data presented in the paper, the copper(II) complexes (1–5) obtained by the authors have an unusual structure: either 4-membered chelate cycles (CuOCO) are realized in them with bidentate coordination of the phenamate ligand to Cu(II) (in complexes 2 and 4), or monodentate coordination of the ligand to a given complexing agent (in complexes 1, 3, and 5). However, bidentate coordination of ligands to Cu(II) through donor nitrogen and oxygen atoms is quite acceptable here (and even seems more probable) with the formation of 6-membered chelate cycles (CuNCCCO), which, according to the Chugaev’s cycle rule, should be more stable than 4-membered ones. On the other hand, the coordination number 6 is realized in these complexes, which is also not very typical for Cu(II), whereas the above bidentate coordination of the ligand would result in the coordination number 4, which is most typical for this complexator. So that, the above fact should be explained, and this should be done in the text of the paper.

Author Response

The title of the paper contains the phrase “copper fenamates with diethylnicotinamide”, which is incorrect from the point of view of the IUPAC nomenclature for coordination compounds, since the ligands included in their composition should be listed with the conjunction AND, and not with the preposition WITH, as was done by the authors of the paper. Considering that the authors actually deal with heteroligand complexes, the title of the paper should sound like “Structural and biological properties of heteroligand copper(II) complexes with diethylnicotinamide and various fenamates: Preparation, structure, spectral properties and Hirshfeld surface analysis”. Such a change is necessary already because the paper is submitted to the Special Issue “Recent Progress in Coordination Chemistry”, and therefore, the objects studied in it must be correctly named. Similar corrections regarding the names of the complexes should, of course, be made in the text of the paper, too.

 

Re:

We agree with the referee's comment and have changed the title according to the referee's recommendation. We have also corrected the text according to this recommendation in three places in the text (in the abstract and in the introduction).

 

2. Lines 140-143. The authors write: “The complexes under study were obtained in a moderate yields (57 - 75%) using complexation reaction between corresponding fenamic acid and NaOH with copper acetate dihydrate and N, N-diethylnicotinamide (in molar ratio 2:2:1:2 ) in ethanol/methanol according to the Scheme 2.” Probably, it is necessary to explain why exactly the indicated ratios of the reagents were chosen and how, in the opinion of the authors, the result of the synthesis would change with other ratios of the starting substances.

 

Re:

We agree with the opponent's comment and have aligned the yield data with Scheme 2 and in the Experimental section. The reactant ratios were chosen because of the preparation of the monomeric complexes.

 

3. According to the XRD analysis data presented in the paper, the copper(II) complexes (1–5) obtained by the authors have an unusual structure: either 4-membered chelate cycles (CuOCO) are realized in them with bidentate coordination of the phenamate ligand to Cu(II) (in complexes 2 and 4), or monodentate coordination of the ligand to a given complexing agent (in complexes 1, 3, and 5). However, bidentate coordination of ligands to Cu(II) through donor nitrogen and oxygen atoms is quite acceptable here (and even seems more probable) with the formation of 6-membered chelate cycles (CuNCCCO), which, according to the Chugaev’s cycle rule, should be more stable than 4-membered ones. On the other hand, the coordination number 6 is realized in these complexes, which is also not very typical for Cu(II), whereas the above bidentate coordination of the ligand would result in the coordination number 4, which is most typical for this complexator. So that, the above fact should be explained, and this should be done in the text of the paper.

 

Re:

Within the copper(II) complexes the bidentate coordination of carboxylate groups forming 4-membered rings (CuOCO) can be found, which is the case for complexes 2 and 4. Apart from that, 4+2 coordination is often found in copper(II) complexes, where four equatorial bond lengths are significantly shorter (about 2 angstroms), but the other two axial distances vary from 2.2-2.9 A between coordination to semi-coordination. In general, the axial position is usually occupied by solvent molecules such as water molecules as reported for complexes 1, 3, 5. Often the analogous square bipyramidal copper(II) complexes (4-2) form isostructural complexes with nearly octahedral zinc(II) ,Mn(II) or Co(II) and Ni(II) complexes. Otherwise, there is another possibility that the carboxylate group is coordinated bidentate, either in a symmetric bidentate manner or in an asymmetric bidentate manner according to the respective observed distances, as reported e.g. by Moncol et al. in J. Coord. Chem. 2004 57(12), 1065-1078. According to our experience and the reviewed literature data, we could not find any mention of the coordination mode (6-membered chelate cycles (CuNCCCO)) either for nicotinate anions (niflumates or clonixinate) or for the Dena ligand.