Conformational studies on timolol: A β-blocker by PCILO and NMR methods

Abstract

Conformational features of timolol, a non-selective β-blocker have been investigated by quantum mechanical perturbative configuration interaction using localized orbitals (PCILO) method and by one-dimensional and two-dimensional NMR techniques. PCILO predicts two different intramolecularly hydrogen-bonded conformations. The first conformation, which is energetically more stable by about 3 kcal mol −, involves N 10 and 015 atoms, whereas in the second conformation, the atoms involved are 012 and NIT However, when the aqueous solution is mimicked by disallowing the above intramolecular hydrogen bondings, PCILO predicts essentially an extended backbone conformation for the “free base”. The NMR results on timolol maleate indicate that there is no intramolecular hydrogen bonding and the backbone conformation of timolol is predominantly an extended one. This agrees excellently with the PCILO prediction for the “free base”. The biologically active conformation of timolol is discussed in the light of the above results and earlier reports for other β-blockers.