Crystal structure and conformation of Tilorone monohydrate [2,7-{bis1-oxo-4-(1-piperidinyl)butyl}-9H-fluoren-9-one] monohydrate: an antiviral agent and an interferon inducer

Abstract

Tilorone is an orally active pharmacological agent that protects mice against infections with RNA and DNA viruses. It is also the only known small molecule that is an interferon inducer. It has anti-tumor and anti-inflammatory properties and was shown to interact and influence the immune mechanisms in human and animals. Structure-function studies of Tilorone and its several analogs have been undertaken in our laboratories with an objective to correlate the structural features with the immuno-suppressive activity. Crystals of the title compound are triclinic, space group $P\bar 1$, with the following crystallographic parameters: a = 7.068(2), b = 9.030(3), c = 23.635(3) Å, α = 103.91(2), β = 108.49(2), γ = 93.84(4)°, V = 1371.9 ų, ρ_obs = 1.17 Mg/m³, ρ_calc = 1.168 Mg/m³ and Z = 2. The structure was solved with CAD-4 data, using SHELX-86 program and refined to a final R value of 0.063. The oxobutyl groups are in an extended zig-zag conformation and are co-planar with the central fluorenone chromophore. The two terminal piperidine rings are in the preferred chair conformation. The crystal structure lends support to the intercalative mechanism of action for Tilorone. We hypothesize that the stereochemistry and molecular geometry of these drugs and/or their active metabolites affect both the receptor interaction and the mode of immunomodulation. Comparison of the biological effects of the various tilorone analogs should allow us to obtain some more insight into their structure-function correlations.