ΠΜΣ με ειδίκευση ΣΥΝΘΕΤΙΚΗ ΦΑΡΜΑΚΕΥΤΙΚΗ ΧΗΜΕΙΑ
Library of the School of Science

2016-09-30

2016

Γιαννακοπούλου Ερωφίλη

Ζωίδης Γρηγόρης Επίκ. Καθηγητής

Νέα ετεροκυκλικά δικετοπιπεραζινικά ανάλογα με ανασταλτική δράση έναντι της PA ενδονουκλεάσης του ιού της Influenza

Greek

Novel heterocyclic diketopiperazine analogues with inhibitory activity against Influenza virus PA endonuclease

Influenza viruses cause seasonal epidemics as well as pandemic outbreaks and
are related with huge economic costs and significant morbidity and mortality.
The widely recommended Influenza vaccines require annual updates and provide
inadequate protection. Additionally, vaccination cannot counteract the threat
of a sudden Influenza pandemic. As a result, antiviral drugs are an
indispensable component of the broad approach for the treatment and prevention
of Influenza infections, including for pandemic preparedness planning and
response.
TheInfluenzapolymeraseiswidely recognized as akeydrugtargetforthedevelopment of
new classes of antiviral drugs due to its critical role in virus replication
and high degree of conservation among Influenza A and B viruses.
ItsΡΑsubunitperformsa"cap-snatching" endonuclease reaction in which
cellularpre-mRNAsare cleaved, yielding capped primers for transcription of
viral RNAtomRNA. TheinhibitionofPAendonucleasebyΡΑinhibitorsto halt virus
replication represent the target of this thesis project.
In this thesis,the design,the synthesis and the in vitro evaluation of the PA
inhibitory activity of novel heterocyclic diketopiperazine hydroxyimides and
acetohydroxamic analogues are described. Inspiration for the design of the new
compounds were several molecules that bear a N-hydroxyimidic group and
especially the structurally related natural compound Flutimide, the first
identified natural product that is found to inhibit selectively the “cap-
snatching” endonuclease reaction in Influenza A and B viruses.
More specifically, the pharmacophore of Flutimide was integrated in an indole
nucleus, which is considered as one of the most flexible structural patterns in
drug development research.
Thedesignoftheanaloguescomprisedstructuralmodificationoftheindolemoietyaswellasi
nsertionoftheacetohydroxamicgroupontheimidicnitrogenofthediketopiperazinescaffol
d,
offeringthepossibilitytoinvestigatevariouschemicalmodificationsthatmightenhancet
hebindingaffinitywiththemetalionspresent in PA’s catalytic moiety. Moreover,
the results of in vitro evaluation will be helpful in the clarification of the
role of several structural characteristics in the Structure-Activity
Relationships of the compounds with the active center of the enzyme that may
help in an ameliorated future design of potent PA inhibitors.

Influenza, Endonuclease, Indole analogues, Flutimide, N-hydroxy-imides

Yes

2

Yes

180

130

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https://pergamos.lib.uoa.gr/uoa/dl/object/1319141