Controlled Crystallization, Structure, and Molecular Properties of Iodoacetylamphotericin B

A new crystallization method of N-iodoacetylamphotericin
B derivative is reported. The crystallization process in the presence
of different quantities of amphotericin B additives was extensively
studied and its mechanism was proposed. It also resulted in good quality
single crystals suitable for X-ray structure determination (100 K).
The structural information obtained allowed for periodic and dimer
single point computational studies at the B3LYP/6-31G** level of theory.
These confirmed the proposed controlled crystallization mechanism
and the stabilization of crystals formed by the iodoacetyl derivative
and parent amphotericin B. The calculation results indicate the strength
of different intermolecular interactions and reveal the great contribution
of the solvent molecules to the crystal lattice formation, with the
total energy gain of about 335 kJ·mol–1, which
almost doubles the cohesive energy value. Hirshfeld surface analysis
shows the more efficient crystal packing of N-iodoacetylamphotericin
versus amphotericin B and the effect of the iodoacetyl group on the
intermolecular contacts. The generated electrostatic potential maps
reveal the impact of the iodoacetyl substituent on the nitrogen atom
basicity and thus confirm the stronger hydrogen bonding created via
nitrogen atom in the case of N-iodoacetyl amphotericin
B, and higher drug activity of amphotericin B related to the ability
of the zwitterion formation.