SAMOP 2021 – scientific programme
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MO: Fachverband Molekülphysik
MO 3: Chirality
MO 3.6: Talk
Tuesday, September 21, 2021, 12:15–12:30, H3
Signatures for chiral enantiomers of a dual p38α MAPK/PDE-4 inhibitor CBS3595 using DFT calculations — •Madeline Van Dongen1, Feng Wang1, Andrew Clayton1, and Zongli Xie2 — 1Swinburne University of Technology, Melbourne, Victoria 3122, Australia — 2CSIRO Manufacturing, Private bag 10, Clayton South, Victoria 3169, Australia
Most biological molecules are naturally present in only one of their chiral forms, hence the binding affinity for a chiral drug can differ for diastereomers and between enantiomers. In clinical environments enantiomers of drugs may have reduced, no, or even deleterious effects. This underscores the need to avoid unknown chiral mixtures and focus on chiral synthesis. Hence, the United States Food and Drug Administration (FDA) issued guidelines and policies in 1992 requiring that absolute stereochemistry be known early in drug development. The less experimental effort spent on unsuccessful compounds, the greater the reduction of time and cost. Instead, a computer based rational approach can justify the selection of a chiral entity. In the present study, we use density functional theory (DFT) to explore measurable properties of chiral CBS3595 (N-{4-[5-(4-Fluorophenyl)-3-methyl-2-methylsulfanyl-3H-imidazol-4-yl]-pyridin-2-yl}-acetamide), a potent dual inhibitor of mitogen activated protein kinase (MAPK) p38α and phosphodiesterase-4 (PDE-4) with promisingly low toxicity, in order to differentiate the enantiomers. Preliminary spectroscopic properties of the enantiomers such as IR, VCD, NMR are presented.