Fluorine is a typical substituent to appear in a variety of FDA approved drugs and can provide drastic changes in the potency of compounds. Previously, we began optimization of a class of triazolopyridazines that were effective in a cell-based assay against Cryptosporidium parvum to give the compound SLU-2633 (EC50 = 0.17 μM). Further optimization of the aryl tail group led to the discovery of the more potent compound, SLU-10482 (EC50 = 0.07 μM). Along with this discovery, it was also observed that the addition of a fluorine substitution could lead to an efficacy increase of up to 34-fold, and the placement of fluorine at other positions of the aryl ring could lead to greater that 1000-fold shifts in potency. While SLU-10482 is a potent compound, the target and mechanism of action of this class of compounds is unknown. The work herein employs molecular modelling to help rationalize fluorine structure activity relationships and give insight to potential binding interactions present in the target. Three distinct types of interactions were modelled: Halogen bonding, hydrogen bonding, and π-π stacking interactions. Among them, the hydrogen bonding and π-π stacking models provided the most significant results that were consistent with the obtained SARs, with calculated binding energies of up to 8.35 and 6.84 kcal/mol respectively. From this, a fourth model was designed to measure both interactions simultaneously and analyze their individual contributions. This final model led to lower, but still significant, binding energies of 6.66 kcal/mol. With these computed binding energies, we believe that it is possible that these types of interactions are a reasonable cause for the dramatic effect of fluorine on the efficacy of this class of compounds.

Modelling potential causes of the effect of fluorine substitution in a class of compounds active against Cryptosporidium parvum

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