Supervisors info:
Νικόλαος Λουγιάκης, Επίκουρος Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ (Επιβλέπων)
Νικολαΐς Πουλή, Καθηγήτρια, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Παναγιώτης Μαράκος, Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Summary:
Hepatitis C is a global health problem and is caused upon infection with the HCV virus. Unless
treated, it can lead to chronic liver inflammation, that may turn into liver fibrosis or cirrhosis, or
into hepatocellular carcinoma. HCV is a single-stranded positive RNA ((+)ssRNA) virus, member
of the Hepacivirus genus, that belongs to the Flaviviridae family. The genome of the HCV
encodes for a long polyprotein, that consists of approximately 3000 amino acids. This precursor
protein will be processed into the functional viral proteins: three structural proteins
(nucleocapside core C, envelope E1 and E2 glycoproteins), the viroprotein p7, and six nonstructural proteins (NS2, NS3, NS4Α, NS4Β, NS5Α και NS5Β).
For many years, treatment of hepatitis C included administration of interferon analogues,
usually in combination with the nucleoside analogue Ribavirin (RBV), although this therapeutic
scheme was found to exert severe adverse effects. During the last decade, drugs that directly
target the proteins of the HCV have been discovered (Direct Acting Antivirals, DAAs). Since
2013, several DAAs against HCV have been approved by the FDA, that can act as NS3 and NS4A
inhibitors, as NS5B polymerase inhibitors or as NS5A inhibitors. Remarkably, the combination of
DAAs targeting different viral proteins of HCV has reduced the therapy period significantly.
HCV can induce the formation of new membrane structures inside the infected cell, that are
called Membranous Web (MW) and facilitate its RNA replication. The non-structural protein
NS4B plays a crucial role in this procedure. Many recent studies have pointed out that NS4B can
be an attractive target for drug design towards HCV treatment, since its inhibition can stop viral
replication by acting at the initial stages of the HCV’s life cycle. Among the first compounds that
were reported to inhibit the NS4B and suppress HCV replication were the hydrochloric salt of
Clemizole, an H1 histamine receptor antagonist, and Anguizole, a substituted pyrazolo[1,5-
a]pyrimidine derivative. Additionally, several structurally related analogues of Anguizole,bearing the imidazo[1,2-a]pyridine, pyrazolo[1,5-a]pyridine or the indole scaffold, have been
reported to possess significant anti-HCV activity.
Based on the main structural features of Clemizole and Anguizole that seem to be essential for
NS4B inhibition, in this work we have decided to synthesize a series of novel compounds that
have the imidazo[4,5-c]pyridine scaffold, which has not been studied towards this target yet.
The new derivatives are substituted with a N-methylpiperazine side chain at position -2,
through a methylene group, and are simultaneously substituted with small sized moieties at
position -4 of this scaffold. In order to investigate the effect on the antiviral activity caused by
the incorporation of substituents on the nitrogen atoms of the imidazole ring, we have also
decided to synthesize selected derivatives that are N1 or N3 alkyl substituted, as well.
For the synthesis of all the target derivatives, commercially available 4-amino-2-chloropyridine
was used as the starting material, which was converted through a series of reactions into the
imidazo[4,5-c]pyridine compounds, substituted at position -4 of the scaffold. Then, on selected
derivatives, the alkyl substituents were introduced at position -1 or -3 of the imidazole ring.
Totally, in this work, 18 novel target compounds were synthesized, and their structure was fully
elucidated. The evaluation of their antiviral activity against HCV is currently ongoing.
