H3-receptor antagonists: conformational analysis of thioperamide and x-ray crystal structure of the analog N-cyclohexyl-4-methylpiperidine-1-carbothioamide

Thioperamide (N-cyclohexyl-4-4(5)-imidazolyl]piperidine-1-carbothioamide) is a potent H3-receptor antagonist, the low conformational flexibility of which could be a favourable feature in the design of new H3-receptor antagonists using its structure as a template. Minimum-energy conformations of thioperamide were studied with the molecular mechanics approach, integrated by X-ray crystallography on an analogue, N-cyclohexyl-4-methylpiperidine-1-carbothioamide (1). Compound 1 was synthesized, and its structure has been solved by X-ray diffraction in order to verify the conformation of the piperidine-1-carbothioamide fragment, and to compare the crystallographic results with those of molecular mechanics. Conformational analysis on the free-rotating bonds of thioperamide was performed with different search methods in order to find the minimum-energy conformations and to estimate rotational barriers. For steric reasons, the rotation around the bond connecting the cyclohexane ring with the carbothioamide nitrogen is more hampered than that around the bond connecting imidazole with piperidine. The rotation around the first bond presents two symmetrical energy minima separated from a third minimum by an energy barrier of 40 KJ/mol. The spatial disposition of compound 1 in the crystal and the common part of thioperamide in one of its minimum-energy conformations are very similar. The minimum-energy conformations of thioperamide calculated by molecular mechanics are therefore reliable and they can be used for structural comparisons with other H3-receptor antagonists.