Studies of molecular structure parameters of 20-piperidin-2-yl-5α-pregnan-3β,20-diol and its N-methyl derivative: two inhibitors of Δ24(25) sterol methyl transferase and Δ24(24′) sterol methyl reductase of Trypanosoma cruzi

Abstract

Molecular structural parameters of two potential drugs against Trypanosoma cruzi epimastigotes, 20-piperidin-2-yl-5α-pregnan-3β,20-diol (1) and 20-N-methylpiperidin-2-yl-5α-pregnan-3β, 20-diol (2) were studied using a combination of a stereoselective synthetic route, spectroscopic characterization and single-crystal X-ray analysis. Both compounds were synthesized with an R configuration at C20. This chirality is a consequence of the stereoselectivity observed during the formation of the intermediate 20-pyridin-2-yl-5α-pregnan-3β,20R-diol (4). NMR data indicated that the six-membered aza ring of (2) is conformationally more restrained, in CDCl3 solution, than (1). X-ray studies showed that maximum deviations among structural molecular parameters of (1) and (2) correspond to torsion angles along the C20—C22 bonds, leading to a different relative orientation of the N atom; a critical structural parameter for the binding properties of aza-sterols to Δ24(25) sterol methyl transferase. Cremer–Pople parameters of the five-membered rings of (1) and (2) lie in the observed range for a family of tetracyclic fused ring systems retrieved from the CSD. The φ2 parameter of (1) lies just on the mean of the family, while φ2 of (2) deviates significantly towards the lower limit.