Unit:
Κατεύθυνση Σχεδιασμός και Ανάπτυξη νέων Φαρμακευτικών Ενώσεων - Φαρμακευτική ΧημείαLibrary of the School of Science
Author:
Papadakis Georgios
Supervisors info:
Πουλή Νικολαΐς, Καθηγήτρια, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Μαράκος Παναγιώτης, Καθηγητής, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Τσοτίνης Ανδρέας, Καθηγητής, Τμήμα Φαρμακευτικής, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Original Title:
Νέα Νουκλεοζιτικά Παράγωγα Ιμιδαζοπυριδίνης με Πιθανή Δράση Έναντι του Ανθρώπινου Κυτταρομεγαλοϊού
Translated title:
New Imidazopyridine Nucleoside Derivatives with Potential Anti-HCMV Activity
Summary:
Human cytomegalovirus (HCMV) is the most common sight- and life-threatening opportunistic pathogen in immunocompromised individuals. Therapeutic approaches for treatment or prophylaxis of HCMV infectious manifestations rely on a handful of approved drugs. Ganciclovir and its orally bioavailable prodrug, Valganciclovir, are still the gold standards for the treatment of HCMV diseases, while Cidofovir and Foscarnet serve as second-line therapies. However, the clinical effectiveness of these compounds, all of which are targeted at the viral DNA polymerase, is limited due to severe side effects, poor pharmacokinetic properties and the development of resistant strains. The recent approval of the terminase inhibitor Letermovir with fast-track procedures highlights the urgent need to overcome these handicaps by developing anti-HCMV agents with novel modes of action and improved clinical safety. In this scope, research efforts led to the development of a number of polyhalogenated benzimidazole nucleosides, exemplified by 2,5,6-trichloro-1-(β-D-ribofuranosyl)benzimidazole (TCRB) and its 2-bromo analogue (BDCRB), that were found to strongly inhibit viral replication. In terms of improving the metabolic stability of these compounds, the 2-halo substituent was replaced by small aliphatic amines in both the β-D- as well as the β-L-ribose derivatives. The 2-isopropylamine substituted derivative of the β-L-series Maribavir proved to be more potent than BDCRB, reducing HCMV DNA synthesis via the inhibition of the viral pUL97 kinase and has entered clinical trials. In order to expand the structure-activity relationships of the benzimidazole series to the less-studied and more “purine-like” imidazo[4,5-b]pyridine scaffold, we have designed a number of novel imidazopyridine nucleoside derivatives, which can be considered as 4-aza-D-isosters of Maribavir. We aim to explore the spatial limitations of the target enzymes and gain insight on the network of the developed interactions. Within this context, we disclose herein the preparation and pharmacological evaluation of the 1- and 3-regioisomeric β-D-ribosides of 5,6-dichloroimidazo[4,5-b]pyridine, introducing various aminosubstituents at the vacant position of the imidazole ring.
Main subject category:
Health Sciences
Other subject categories:
Pharmacy
Keywords:
Bbenzimidazole nucleosides, Maribavir, pUL97 kinase, 5,6-dichloroimidazo[4,5-b]pyridine
Number of references:
150
