Caxambu,
18 a 21 Novembro de 2001
XI
Simpósio Brasileiro de Química Teórica
Caxambu,
18 a 21 Novembro de 2001
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Omeprazole is a substituted benzimidazole which suppresses
the acid-gastric
secretion by H+,
K+-ATPase enzyme inhibition. It presents
and optically active center
located on the sulfur atom
from the sulfoxide group. Omeprazole is a pro-drug
and
thus it is not
exactly the active nhibitor of the enyme,
which produces the acid-
gastric secretion.
It is easily converted in its respective sulfenamide,
which has no
optical activity
at low pH.1 Figure
1 shows the decomposition
reaction from
omeprazole (1)
to sulfenamide (4). Besides,
omeprazole has some rotational
freedom.
Figure 1. Omeprazole decomposition reaction in acid medium.
The main goal of this work is to study the behavior of omeprazole
based on its
characteristics
discussed above. By
observing the molecular flexibility,
a
conformational analysis
was performed to find the
minimum energy structures.
Quantum chemistry coupled
to chemometric methods were used.2
The racemization
barrier for every minimum
energy structures was determined using the semi-empirical
PM3 method.
The total energy involved in the decomposition
reaction was also
calculated by ab-initio
method at Hartree-Fock level using a 6-31G** basis set. From
the conformational study,
three minimum energy structures were found with energy
around -35 kcal mol-1.
For racemizations barriers, the value found was around
43
kcal mol-1
whereas for the decomposition reaction the total energy found was -266.78
kcal mol-1.
1 A) M. Tanaka, H.
Yamazaki, H. Hakusui, N. Nakamichi, H. Sekino, Chirality,
9,
17
(1997). B)
B. D. Landes, J. D. Petite, B. Flouvat, Clin. Pharmacokinet.,
28,
1158
(1995). C)
P. Lindberg, P. Nordberg, T. Alminger, A. Brändströn,
B. Wallmark, J.
Med. Chem.,
29,
1329 (1986).
2 A. T. Bruni, V. B. P.
Leite, M. M. C. Ferreira, J. Comp. Chem., accepted.
CNPq, CENAPAD-SP,
FAPESP