Tuning Potency of Bioactive Molecules via Polymorphic Modifications: A Case Study

Polymorphism
in drugs and bioactive molecules is not uncommon,
and it has remained as one of the critical issues in drug development
processes. While improving physicochemical properties of bioactive
molecules has been a prime focus of the pharmaceutical chemists, not
much efforts have been put toward the improvement of their potency
via polymorphic modifications. Here, we consider five cases of 5-arylidene-2-aminothiazolidinones
derivatives, the known anticancer agents, and discover eights polymorphs
in three out of the five cases. We perform systematic crystallization
experiments and detailed crystal structure analysis of the eight polymorphs
and two compounds, estimate both their energetic and thermal stabilities,
and compare their solid state properties. We also compare in-solution
properties, e.g., equilibrium solubility, intrinsic dissolution rate,
and phase stability, of three polymorphs of one of the cases. Further,
we study the extent of inhibition imposed by those eight polymorphs
and seven bulk and crystal forms of the compounds on the proliferation
of MCF7 breast cancer cells and also the extent of their binding to
the isozyme γ-enolase. Furthermore, we perform MD simulations
on the eight polymorphs and one compound to estimate and compare their
binding affinity with γ-enolase. Our experimental and MD simulation
analyses in general emphasize the importance of polymorphism in improving
the biological potency of individual molecules.