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Synthesis, biological evaluation and molecular modeling of novel azaspiro dihydrotriazines as influenza virus inhibitors targeting the host factor dihydrofolate reductase (DHFR)
- Source :
- European Journal of Medicinal Chemistry
- Publication Year :
- 2018
- Publisher :
- Elsevier Masson SAS., 2018.
-
Abstract
- Recently we identified cycloguanil-like dihydrotriazine derivatives, which provided host-factor directed antiviral activity against influenza viruses and respiratory syncytial virus (RSV), by targeting the human dihydrofolate reductase (hDHFR) enzyme. In this context we deemed interesting to further investigate the structure activity relationship (SAR) of our first series of cycloguanil-like dihydrotriazines, designing two novel azaspiro dihydrotriazine scaffolds. The present study allowed the exploration of the potential chemical space, around these new scaffolds, that are well tolerated for maintaining the antiviral effect by means of interaction with the hDHFR enzyme. The new derivatives confirmed their inhibitory profile against influenza viruses, especially type B. In particular, the two best compounds shared potent antiviral activity (4: EC50 = 0.29 μM; 6: EC50 = 0.19 μM), which was comparable to that of zanamivir (EC50 = 0.14 μM), and better than that of ribavirin (EC50 = 3.2 μM). In addition, these two compounds proved to be also effective against RSV (4: EC50 = 0.40 μM, SI ≥ 250; 6: EC50 = 1.8 μM, SI ≥ 56), surpassing the potency and selectivity index (SI) of ribavirin (EC50 = 5.8 μM, SI > 43). By a perspective of these results, the above adequately substituted azaspiro dihydrotriazines may represent valuable hit compounds worthy of further structural optimization to develop improved host DHFR-directed antiviral agents.<br />Graphical abstract Image 1<br />Highlights • Azaspiro dihydrotriazines proved to be active against influenza viruses. • The antiviral activity was related to the inhibition of the host factor DHFR. • Docking studies revealed two H-bonds with key residues I7 and S59 of hDHFR enzyme.
- Subjects :
- 0301 basic medicine
Models, Molecular
030106 microbiology
Azaspiro dihydrotriazine derivatives, Anti-influenza A and B viruses activity, Host (human) DHFR inhibition, Docking studies
Context (language use)
Antiviral Agents
Virus
Article
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
Zanamivir
Drug Discovery
Dihydrofolate reductase
medicine
Structure–activity relationship
Spiro Compounds
Docking studies
Host factor
Pharmacology
chemistry.chemical_classification
Aza Compounds
biology
Dose-Response Relationship, Drug
Molecular Structure
Triazines
Ribavirin
Azaspiro dihydrotriazine derivatives
Organic Chemistry
General Medicine
Orthomyxoviridae
Virology
Anti-influenza A and B viruses activity
Host (human) DHFR inhibition
Tetrahydrofolate Dehydrogenase
030104 developmental biology
Enzyme
chemistry
biology.protein
Folic Acid Antagonists
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 17683254 and 02235234
- Volume :
- 155
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....9739424b321381c93a4ccc588ac5d6d3