Crystal and Molecular Structure of the Antimalarial Agent 4-(tert-Butyl- 2-(tert-Butylaminomethyl)-6-(4-Chlorophenyl)Phenol Dihydrogen Phosphate (WR 194, 965 Phosphate)
WALTER REED ARMY INST OF RESEARCH WASHINGTON DC DIV OF EXPERIMENTAL THERAPEUTICS
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WR 194,965 phosphate, a new antimalarial agent containing a biphenyl ring structure active against chloroquine--resistant Plasmodium falciparum, crystallized in ionic form with a positive charge on the quaternary nitrogen atom. The oxygen and nitrogen atoms of WR 194,965 were hydrogen bonded to the same phosphate group. The nitrogen atom was also hydrogen bonded to a second phosphate group. The phosphate ions formed discrete clusters of four phosphate moieties. The phosphate clusters contained fourfold inversion symmetry. The intramolecular N-O distances in the active cinchona alkaloids and may be important for activity. A comparison of the crystalline structure of WR 194,965 with those of mefloquine and quinidine sulfate demonstrated that the regions of the three molecules in the vicinity of the aliphatic nitrogen atom and the oxygen atom superimpose. Much of the remainder of the WR 194,965 molecule spatially overlapped with the combined three-dimensional space defined by quinidine and mefloquine. Keywords Antimalarials, Reprints.