Session: Physical Organic Chemistry: Calculations, Mechanisms, Photochemistry & High-Energy Species:

The insertion of a bicyclo[1.1.1] pentane (BCP) moiety into a bioactive molecule leads to a structure with relatively higher lipophilicity, which in turn results in modification of its therapeutic value. 3D geometry and non-covalent interactions (NCI) are the effective forces for the recognition between a drug molecule and its target. An understanding of the physical origin of NCIs is of fundamental interest for improving the current drug design and synthetic protocols. Recently, various synthetic methods have been invented to formulate BCP derivatives. However, the lack of reports on NCI of BCP derivatives is one of the reasons for disabling marketing of the potential bioisosteres. Crystal engineering is an important tool to understand how a modified drug interacts within the biological media. Hence, we carried out a systematic study on seven rationally designed BCP derivatives that exhibit specific and directional NCI. X-ray analysis revealed the three-dimensional structures and presence of, I…N, O…O, H…H, and π…π interactions. The BCP core generally shows a D_3h symmetry and forms very week H-interactions. Hirshfeld surfaces analysis was used to quantify the nature of NCI. Molecular electrostatic potentials (MEP) show the electron-rich and -poor regions on the molecules. Atoms-in-molecules (QTAIM) analysis supported the presence of halogen or hydrogen bond in co-crystals. In summary, these interaction profiles can serve as examples in designing BCP bioisosteres.

Molecular structure of BCP-DABCO co-crystal.

Molecular structure of BCP-DABCO co-crystal.

Dr Nitika Grover

Trinity College Dublin

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