Abstract
Applications of 9-aminoacridine (9aa) and its derivatives span fields such as chemistry, biology, and medicine, including anticancer and antimicrobial activities. Protonation of such molecules can alter their bioavailability as weakly basic drugs like aminoacridines exhibit reduced solubility at high pH levels potentially limiting their effectiveness in patients with elevated gastric pH. In this study, we analyse the influence of protonation on the electronic characteristics of the molecular organic crystals of 9-aminoacridine. The application of quantum crystallography, including aspherical atom refinement, has enriched the depiction of electron density in the studied systems and non-covalent interactions, providing more details than previous studies. Our experimental results, combined with a topological analysis of the electron density and its Laplacian, provided detailed descriptions of how protonation changes the electron density distribution around the amine group and water molecule, concurrently decreasing the electron density at bond critical points of N/O-H bonds. Protonation also alters the molecular architecture of the systems under investigation. This is reflected in different proportions of the N⋯H and O⋯H intermolecular contacts for the neutral and protonated forms. Periodic DFT calculations of the cohesive energies of the crystal lattice, as well as computed interaction energies between molecules in the crystal, confirm that protonation stabilises the crystal structure due to a positive synergy between strong halogen and hydrogen bonds. Our findings highlight the potential of quantum crystallography in predicting crystal structure properties and point to its possible applications in developing new formulations for poorly soluble drugs.
| Original language | English |
|---|---|
| Pages (from-to) | 5340-5350 |
| Number of pages | 11 |
| Journal | RSC Advances |
| Volume | 14 |
| Issue number | 8 |
| DOIs | |
| State | Published - Feb 12 2024 |
Funding
The authors would like to thank the Polish National Science Centre (NCN) for financial support within OPUS (grant no. 2018/31/B/ST4/02142). The research was carried out at the Biological and Chemical Research Centre, University of Warsaw, established within the project co-financed by European Union from the European Regional Development Fund under the Operational Programme Innovative Economy, 2007-2013. The X-ray diffraction data collection was accomplished at the Core Facility for Crystallographic and Biophysical research to support the development of medicinal products. The “Core Facility for Crystallographic and Biophysical research to support the development of medicinal products” project is carried out within the TEAM-TECH Core Facility programme of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund. This manuscript has been authored in part by UT-Battelle, LLC, under contract DE-AC05-00OR22725 with the US Department of Energy (DOE). The publisher acknowledges the US government license to provide public access under the DOE Public Access Plan (https://energy.gov/downloads/doe-public-access-plan). Theoretical calculations were performed using the resources of the Wroclaw Centre for Networking and Supercomputing (https://wcss.pl) (grant no. 115). The authors would like to thank the Polish National Science Centre (NCN) for financial support within OPUS (grant no. 2018/31/B/ST4/02142). The research was carried out at the Biological and Chemical Research Centre, University of Warsaw, established within the project co-financed by European Union from the European Regional Development Fund under the Operational Programme Innovative Economy, 2007–2013. The X-ray diffraction data collection was accomplished at the Core Facility for Crystallographic and Biophysical research to support the development of medicinal products. The “Core Facility for Crystallographic and Biophysical research to support the development of medicinal products” project is carried out within the TEAM-TECH Core Facility programme of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund. This manuscript has been authored in part by UT-Battelle, LLC, under contract DE-AC05-00OR22725 with the US Department of Energy (DOE). The publisher acknowledges the US government license to provide public access under the DOE Public Access Plan ( https://energy.gov/downloads/doe-public-access-plan ). Theoretical calculations were performed using the resources of the Wroclaw Centre for Networking and Supercomputing ( https://wcss.pl ) (grant no. 115).