Structural characterization of LASSBio-1289: a new vasoactive N-methyl-N-acylhydrazone derivative

Abstract

LASSBio-1289 compound has been found to promote intense vasodilation and antihypertensive activity. It is an innovative compound, without structural similarities to the three main classes of calcium antagonists (1,4-dihydropyridines, benzothiazepines and phenylalkylamines) commonly used. A complete knowledge of the structure, including stereochemistry, is essential to lead optimization in drug discovery. For this reason, in this work we determined the crystal structure of this novel vasoactive N-methyl-N-acylhydrazone derivative by means of X-ray powder diffraction data and an ab initio simulating annealing approach, allowing us to observe the relative configuration E of the imine double bond and its conformation as well as its most relevant intermolecular interactions. These findings were also checked by a FTIR analysis and confirmed in solution by NMR. The compound crystallized under a monoclinic crystal system with space group P2₁/c and unit cell parameters a = 14.5118(3) Å, b = 12.1374(2) Å, c = 7.5498(1) Å, β = 91.113(1)°, V = 1329.53(4) ų, Z = 4, Z′ = 1 and ρ_calc = 1.44042(4) g cm⁻³. Moreover, a crystal morphology prediction, experimentally compared with SEM inferred images, allowed a direct comparison of the microcrystalline habit and quality, allowing a study of the potential solvent effect on the crystal growth.