Crystal and molecular structure of the antimalarial agent enpiroline

Abstract

To identify common spatial and structural features of amino alcohol antimalarial agents with the eventual goal of designing more effective drugs and a better understanding of the mechanism of action of this class of antimalarial agents, the three-dimensional crystal and molecular structure of enpiroline, a new antimalarial agent active against chloroquine-resistant Plasmodium falciparum, was determined by X-ray crystallography and compared with the crystal structures of the cinchona alkaloids and of the new antimalarial agent WR 194,965. The aromatic rings of the phenyl-pyridine ring system of enpiroline are twisted from each other by approximately 18 degrees. The intramolecular aliphatic N-O distance in enpiroline was 2.80 A (1 A = 0.1 nm), which is close to the N-O distance found in the antimalarial cinchona alkaloids. Enpiroline contains both an intramolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms and an intermolecular hydrogen bond between the aliphatic nitrogen and oxygen atoms of two neighboring molecules. One enantiomer of enpiroline superimposed best with quinine, and the other enantiomer of enpiroline superimposed best with quinidine, suggesting that both enantiomers of enpiroline possess antimalarial activity. Since a common feature of the crystal structures of the amino alcohol antimalarial agents is the formation of intermolecular hydrogen bonds, the common spatial direction of hydrogen bond formation indicates the potential ability of these antimalarial agents to bind to a common receptor site. The crystallographic parameters were as follows: C19H18F6N5O; Mr = 404.3; symmetry of unit cell, monoclinic; space group, P2(1)/a; parameters of unit cell---a = 9.454 +/- 0.004 A, b = 18.908 +/- 0.008 A, c = 10.300 +/- 0.004 A, and beta = 96.55 +/- 0.03 degrees: V (volume of unit cell) = 1829.2 A3; Z (number of molecules per unit cell) = 4; Dchi (calculated density) = 1.46 g cm-3; source of radiation, CuK alpha (lambda = 1.54178 A); mu (absorption coefficient) = 11.49 cm-1; F(000) (sum of atomic scattering factors at zero scattering angle) = 832; room temperature; final R = 8.7% for 1,798 reflections with [F0] > 3 sigma.