Unit:
Κατεύθυνση Φαρμακευτική Ανάλυση - Έλεγχος ποιότηταςLibrary of the School of Science
Author:
Παπαδήμα Κωνσταντίνα
Supervisors info:
Α. Τσαντίλη-Κακουλίδου Καθηγήτρια (Επιβλέπουσα), Ε. Παντέρη Αναπλ. Καθηγήτρια, Ε. Γκίκας Επίκ. Καθηγητής
Original Title:
Φυσικοχημικό προφίλ παραγώγων πυρρολύλο-μόνο και δίφθορο-φαινόλης,αναστολέων αναγωγάσης αλδόζης
Translated title:
Physicochemical profile of pyrrolyl-acetic acid derivatives, carrying the group of the mono- or difluoro-phenol, inhibitors of aldose reductase.
Summary:
The investigation of the physicochemical profile of new drug molecules is
particularly important for understanding both biological activity and
pharmacokinetic behavior. Especially in the case of new chemotypes,
experimental data are particularly important because it can contribute to the
updating of existing algorithms. This thesis is a continuation of attempts to
identify the physico-chemical profile of new chemotypes, inhibitors of
aldosereductase,andevaluationofcomputersystems.
The study involves four substituted of pyrrolyl-acetic acid derivatives
(inhibitors of aldose reductase), carrying the group of the mono- or
difluoro-fluoro-phenol. For this purpose, we investigated the profile of
lipophilic logD in capable pH range and the profile logD / pH used for the
extraction of logP and pKa values. In the first section the lipophilicity was
assessed by direct partitioning experiments in the n-octanol-water system at pH
5,0-11,0 and compared with values obtained using various computer systems.
The experimental difficulties can lead to profile logD / pH deviating from the
theoretically expected, mainly on the slope of the linear portion. It suggested
the difference in inclination to take into account the non-linear adjustment to
the export of logP and pKa values. Therefore, the consistency of the
predictions was evaluated, as well as the reliability between experimental and
predicted logP or logD values and pka.The second part of the thesis focuses on
biomimetic chromatography using stationary phases IAM. Furthermore, Immobilized
Artificial membrane Chromatography IAM was used for the investigation of
lipophilicity for all compounds. It is considered that IAM chromatography
simulates better the distribution in biological membranes than the
octanol-water system. The results of previous studies on related compounds
combined with IAM results associated with the distribution in octanol-water
system.It was evaluated-updated the model equation for the IAM / logD
relationship imparted by structurally diverse compounds, which reflects the
retaining mechanism ionized molecules. Comparison logkwIAM values showed
significantly higher retention of the mono-fluoro derivatives, which was
attributed to the reduced ionization, while no difference in retention IAM
isomers of compounds 3 and 4 was observed, which was attributed to the effect
of the configuration.In combination with results of similar compounds enhance
the view on the contribution of electrostatic interactions in the containment,
which partly offset the effect of ionization, leading logkwIAM values
correlate better with logP values instead of logD7,4 values. The derivatives
of mono- and diafthoras- fluoro-phenol pyrrole show no further specificities
regarding the retention mechanism which fits the general equation-model
extracted based structurally different compounds. These data provide useful
information for further research similar chemotypes, combined with the
inhibitory effect on aldose reductase.
Keywords:
Inhibitors of aldose reductase, Profile logD / pH, Immobilized Artificial membrane Chromatography (IAM), LogP and pKa values
Number of references:
141
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