ANALYSIS OF ELECTRONIC-STRUCTURES OF PHYSOSTIGMINE ANALOGS

AIM: To elucidate the action mechanism and structural prerequisites of 21 physostigmine analogs as acetylcholinesterase inhibitors at the mo lecular level, and help the rational design of these dihydroindoline i nhibitors. METHODS: Initial structures of these compounds were built a nd minimized by SYBYL 6.2 molecular modeling software, Conformations o f those molecules with the highest predictive abilities in the Compara tive Molecular Field Analysis model were chosen to the semiempirical q uantum chemical calculations. RESULTS: (I) The highest occupied molecu lar orbital (HOMO) consisted mainly of the orbitals in phenyl group an d N-1 atom; the lowest unoccupied molecular orbital (LUMO) of the mole cules was contributed from phenyl group and C-11 atom, While the HOMO energies did not show any recognizable relationship with activity, the LUMO energies showed a decreased tendency with increasing activity. T he active compounds showed lower LUMO energies, (2) The carbon atom (C -11) had the most positive net atom charge. The most active compound h ad the most positive charge on this carbon, but had the lower charges on the carbonyl oxygen (O-12) which Tvas the most negative charge atom . (3) The bond order of carbon-oxygen bond (C-11 - O-10) was invariant across the series of the compounds. (4) Compounds with too high or to o low total dipole moment had lower activities, while the most active one had a lower molecular polarizability. CONCLUSION: A molecular mode l was suggested to explain the possible mode of action by which these compounds inhibit acetylcholinesterase.