Review Reports

Round 1

Reviewer 1 Report

The manuscript by Balewski and Kornicka presents the synthesis of the guanidine derivative N-{[(7-(4,5-dihydro-1H-imidazol-2-yl)-2-(p-tolyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)- ylidene)amino](phenylamino)methylene}benzamide. The manuscript is well written and the experiments have been carried out carefully and correctly analyzed.

The reviewer has few specific comments:

1. It is recommended that the authors reference in the Introduction, the introduction of guanidino groups into position 6 of the morphinan skeleton (doi: 10.2174/138161281942140105164804).
2. The Section “Conclusions” is omitted. In this section, it would be valuable for the reader to briefly state which future chemical/biological strategies are foreseen on the described guanidine derivative and additional analogues.  

Author Response

Dear Reviewer,

I appreciate valuable comments and remarks on the submitted manuscript entitled ‘Synthesis of the Guanidine Derivative: N-{[(7-(4,5-dihydro-1H-imidazol-2-yl)-2-(p-tolyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)amino](phenylamino)methylene}benzamide’. All changes in the original text were marked in red color.

Response to Reviewer 1 Comments

Point 1: It is recommended that the authors reference in the Introduction, the introduction of guanidino groups into position 6 of the morphinan skeleton (doi: 10.2174/138161281942140105164804).

Response 1: According to the Reviewer’s suggestion, in the introduction has been added appropriate reference (doi:10.2174/138161281942140105164804). I agree that will give valuable information to the text.

The following text has been added:

‘An important strategy in the development of preclinically and clinically valuable opioids is functionalization and modification of the highly versatile carbonyl group in position 6 of morphinan-6-one ring of well-known opioid agonists. The 6-guanidine analogs derived from 6-aminomorphinanes showed potent opioid receptor agonist activities and antinociceptive properties.’

Point 2: Section “Conclusions” is omitted. In this section, it would be valuable for the reader to briefly state which future chemical/biological strategies are foreseen on the described guanidine derivative and additional analogues.

Response 2: The ‘Conclusion’ section has been added which briefly summarizes the text giving a future chemical/biological strategies on the described guanidine derivative and additional analogues.

The following text has been added:

‘In conclusion, we synthesized a novel tri-substituted guanidine derivative 3 in the reaction of appropriate thiourea 2 with a primary aromatic amine in the presence of mercury(II) chloride and triethylamine. Optimization of the reaction was studied at different temperatures and various solvents. It was found that the higher conversion of starting thiourea 2 and better yield of desired product 3 could be achieved using dimethylformamide as a solvent at an ambient temperature.

The structural modifications of this class of compounds may be gained by the introduction of the different substituents at the phenyl rings using a series of aromatic amines or thiourea derivatives as starting materials. The guanidine represents an anchoring group that is a prominent scaffold for further functionalization. It will lead to a diversity of guanidine-analogs.

Having in mind that, the class of guanidines includes the well-known drugs and the field of potential applications for guanidines constantly extends, the obtained in this work guanidine derivative 3, and its possible analogs may exhibit promising biological activity with potential applications in medicinal chemistry. Therefore, the guanidine derivative 3 constitutes a platform for the development of a new class of compounds that would deserve further biological investigations to evaluate their potent cytotoxic activity against human tumor cell lines. This allows a better understanding of structure-activity relationships (SARs), determining further structural modifications of this class of guanidine-containing derivatives.’