Theoretical study of cimetidine and rigid analogues

R D ENRIZ; G.M.CIUFFO; E.A.JAUREGUI

JOURNAL OF MOLECULAR STRUCTURE THEOCHEM

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 1991 vol. 226 p. 327 - 338

0166-1280

An electronic and conformational study using semiempirical MNDO calculations on cimetidineand rigid analogues was carried out. Imidazolylthiophene and imidazolylfuran rigid analogues ofcimetidine were proposed and theoretical calculations were carried out on these molecules. Forthe molecules under study, all the possible configurational isomers with respect to the cyanoguanidinegroup were taken into account. Cimetidine showed a high molecular flexibility, the foldedand half-folded conformations being the preferred ones. Folded and half-folded conformations ofcimetidine were assumed to present the biologically advantageous spatial ordering. Imidazolylphenylenederivatives showed a different electronic behavior from that of cimetidine. This differencemay be the reason for the lower biological activity of the phenylene analogues. In contrast,the imidazolylthiophene and imidazolylfuran analogues showed molecular electrostatic potentialmaps closely similar to those of cimetidine. The presence of an electronegative structural element(S or 0) between the two electron systems (imidazole ring and cyanoguanidine group) appearsto yield critical electronic effects, which may be related to the antagonist activity on H,-histaminereceptors.