Studies of molecular structure parameters of 20-piperidin-2-yl-5 alpha-pregnan-3 beta,20-diol and its N-methyl derivative: two inhibitors of Delta(24(25)) sterol methyl transferase and Delta(24(24 ')) sterol methyl reductaseof Trypanosoma cruzi

Molecular structural parameters of two potential drugs against Trypanosoma cruzi epimastigotes, 20-piperidin-2-yl-5 alpha -pregnan-3 beta ,20-diol (1) and 20-N-methylpiperidin-2-yl-5 alpha -pregnan-3 beta, 20-diol (2) were st udied using a combination of a stereoselective synthetic route, spectroscop ic 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-5 alpha -pregnan-3 beta ,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 a mong structural molecular parameters of (1) and (2) correspond to torsion a ngles along the C20-C22 bonds, leading to a different relative orientation of the N atom; a critical structural parameter for the binding properties o f azasterols to Delta (24(25)) sterol methyl transferase. Cremer-Pople para meters 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 phi2 parameter of (1) lies just on the mean of the family, while phi2 of (2 ) deviates significantly towards the lower limit.