Synthesis, biological evaluation and molecular modeling of novel azaspiro dihydrotriazines as influenza virus inhibitors targeting the host factor dihydrofolate reductase (DHFR)

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: EC = 0.29 μM; 6: EC = 0.19 μM), which was comparable to that of zanamivir (EC = 0.14 μM), and better than that of ribavirin (EC = 3.2 μM). In addition, these two compounds proved to be also effective against RSV (4: EC = 0.40 μM, SI ≥ 250; 6: EC = 1.8 μM, SI ≥ 56), surpassing the potency and selectivity index (SI) of ribavirin (EC = 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.

The Natural Compound Homoharringtonine Presents Broad Antiviral Activity In Vitro and In Vivo

“…Due to the intrinsically high mutation rate of RNA viruses, resistance to antiviral drugs that act against viral targets can occur rapidly [ 47 ]. Focus on antivirals that target host factors is, thus, expected to be an advantageous strategy, because escape mutations are rarer [ 48 , 49 ]. Cellular translation is necessary for viral replication, and inhibition of protein production may impair or delay the proliferation of viral pathogens; however, the inhibition of host factors is often a problematic issue in drug development, due to pleiotropic unwanted side effects [ 50 , 51 ].…”

Trimethoprim: An Old Antibacterial Drug as a Template to Search for New Targets. Synthesis, Biological Activity and Molecular Modeling Study of Novel Trimethoprim Analogs

“…It is believed that the most important residues involved in the DHFR inhibition activity are Ile-7, Glu-30, Phe-34, and Val-115 [52,53]. This is reflected in the high binding energy of MTX, which exhibits interactions with these residues.…”

Development of antibacterial compounds that block evolutionary pathways to resistance

“…By an efficient virtual screening protocol to scan large databases, two hits of novel scaffolds were identified, which showed inhibitory activity against both WT and resistant mutant forms of DHFR. Unlike conventional approaches primarily focused on chemical synthesis of derivatives based on known inhibitor scaffolds (Francesconi et al, 2018; Hopper et al, 2019; Lam et al, 2014; Reeve et al, 2016), we deployed an efficient novel multi-tier approach to come up with chemically novel inhibitors. To further improve DHFR inhibitory activity of the two hits, a rapid round of compound optimization was conducted through a structural similarity search.…”