Solid-state structures and conformational studies of four 1,2,3,4-tetrahydroacridine Alzheimer's disease therapeutics

The solid-state structures of four 1,2,3,4-tetrahydroacridines [taurine hydrochloride monohydrate (1), 7-methoxytacrine hydrochloride monohydrate (2), velnacrine hydrogenmaleate (3) and suronacrine hydrogenmaleate (4)] were determined from single-crystal X-ray diffraction analysis. (1): monoclinic, P2(1)/n, a = 8.778(1), b = 8.521(1), c = 17.603(2) angstrom, beta = 101.34(1)-degrees. (2): monoclinic, C2/c, a = 12.326(7), b = 18.050(9), c = 13.822(8) angstrom, beta = 113.70(4)-degrees. (3): triclinic, P1-, a = 7.349(2), b = 9.417(3), c = 12.557(4) angstrom, alpha = 109.62(2), beta = 98.12(2), gamma = 101.18(2)-degrees. (4): monoclinic, P2(1)/n, a = 8.513(6), b = 18.74(1), c = 13.401(6) angstrom, beta = 91.21(5)-degrees. Final R factors for compounds (1)-(4) are 0.047, 0.057, 0.057, 0.11, respectively. The overall arrangement of the common aminotetrahydroacridine skeleton looks similar in all derivatives. However, whereas enantiomerization of the unsubstituted cyclohexenyl rings occurs in (1) and (2), only quasi-axially hydroxyl substituted diastereomers are found for (3) and (4). This is presumably due to the different propensities for hydrogen bonding of axially vs. equatorially disposed hydroxyl groups with the hydrogenmaleate anions. Empirical and semiempirical calculations were performed to examine the conformational behavior of the four compounds, both in vacuo and in solution.