Solvates of New Arylpiperazine Salicylamide Derivative-a Multi-Technique Approach to the Description of 5 HTR Ligand Structure and Interactions.

Edyta Pindelska,Izabela D Madura,Jolanta Jaśkowska,Anna Marczewska-Rak

doi:10.3390/ijms22094992

Abstract

A new ligand for 5-HT1A and 5-HT7 receptors, an arylpiperazine salicylamide derivative with an inflexible spacer, is investigated to identify preferred fragments capable of creating essential intermolecular interactions in different solvates. To fully identify and characterize the obtained crystalline materials, various methods including powder and single-crystal X-ray diffraction, solid-state NMR, and thermal analysis were employed, supplemented by periodic ab initio calculations. The molecular conformation in different solvates, types, and hierarchy of intermolecular interactions as well as the crystal packing were investigated to provide data for future research focused on studying protein–ligand interactions. Based on various methods of crystal structure analysis, including the interaction energy calculation and programs using an artificial neural network, a salicylamide fragment was found to be crucial for intermolecular contacts, mostly of dispersion and electrostatic character. A supramolecular 2D kite-type layer of {4,4} topology was found to form in crystals. The closed voids between layers contain disordered solvents, very weakly interacting with the molecule and the layer. It has been postulated that the separation of the layers might be influenced by an increase in temperature or the size of the solvent; hence, only methanol and ethanol hemi-solvates could be obtained from a series of various alcohols.

Highlights

Synthesis of a new active pharmaceutical ingredient (API) is very often a challenge and many attempts are made to obtain pure, well-crystallized material with a defined structure
Obtaining new polymorphic forms or solvates is sometimes the desired effect, especially from an economic point of view related to the possibility of securing new patents, but new forms must be carefully tested for pharmaceutical properties, such as, e.g., solubility, hygroscopicity, or thermal stability [1,2]
We we found found out out that that in in calcucalculated structures, methanol and ethanol molecules are weakly bound via hydrolated structures, methanol and ethanol molecules are weakly bound via O-H

Summary

Introduction

Synthesis of a new active pharmaceutical ingredient (API) is very often a challenge and many attempts are made to obtain pure, well-crystallized material with a defined structure. Both the choice of the solvent and the process itself can affect the final product. Phenomena such as polymorphism or co-crystallization of the solvent molecules always have to be considered. The presence of a solvent molecule may sometimes influence a molecular structure of an API. As a rule, this does not much affect the therapeutic properties of the compound itself, but for research related to the modeling of ligand–protein interactions or chemical modifications of a given drug, the obtaining and characterizing of new solvates or polymorphs is extremely valuable. The broader the landscape of API conformations, the more precise are further studies using modern algorithms based on big data; for example, for ligand–protein interaction predictions [4], protein crystal structure refinement [5], or drug discovery [6]

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Results

Conclusion