Conformational studies of a family of related antimalarial phenanthrene amino alcohols

Abstract

A conformational study utilizing quantum chemical methods was performed on a family of antimalarial alpha-(piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanols whose structures differ by the placement of the substituent on either the 2,3, or 4 position of the piperidyl ring. The antimalarial activity of these 3-substituted compounds has been shown experimentally to be highly stereospecific while the 2-substituted compounds are not and the 4-substituted compounds are inactive. In this study, such observed differences in behavior are correlated with conformational results and a pharmacophore is postulated. The identity of the active racemate of the 3-piperidyl compound is predicted.

10-Hydroxy-10-methyl-10,11-dihydroquinine, C21H28N2O3, a new derivative of quinine

“…No intramolecular hydrogen bond is observed, contrary to the suggestion of Cheng (1971) and Loew & Sahakian (1977) that such a bond should be present between O(12) and N(1) in the antimalarial compounds of this type (aminoalcohols). Symmetry code: (i) 1 -x, 0.5 + y, 0.5 -z; (ii) 1 -x, y -0-5, 0.5 -z~ (iii) 2-x, 0.5+y, 0.5-z;(iv)2-x,y-0.5,0-5-z.…”

Characterization of Pharmacologically Important Prototropic Species Derived from a Pyridinemethanol Antimalarial by Electronic Absorption and Fluorescence Spectroscopy

“…A more recent and specific study (29) dealt with the conformation of a family (VIla-VIIc) of related antimalarial phenanthrene amino alcohols that have a methanolpiperidine substituent capable of forming an intramolecular hydrogen bond like the one observed in I and IV. The study proposed a model pharmacophore for the singly charged cation, which includes an intramolecular hydrogen bond between a hydrogen at om on the protonated piperidyl nitrogen in VIIa and V l l b and the carbinol oxygen atom.…”