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  • Herein we explored by docking studies

    2020-07-28

    Herein, we explored by docking studies the effectiveness of replacing the dimethyl substitution at C (6) of dihydrotriazine with a folded azaspiro-containing substituent, along with the introduction of differently substituted phenyl- and benzyl-rings or alkyl chains, linked at the position 1 of the main core of the derivatives (see Fig. 1, Fig. 2, Fig. 3). This kind of decoration was designed with the aim to clarify the relevance of steric properties for dihydrotriazines targeting the hDHFR. In fact, azaspiro derivatives could allow to better fulfil the requirements set forth by the pyridopyrimidine scaffold and the aniline ring of reference QX 314 chloride I. Indeed, the docking results suggest a beneficial role played by the azaspiro group bearing an aromatic substituent, since it aptly superposed on the aniline moiety of the reference compound I, displayed a comparable pattern of hydrophobic contacts with the surrounding residues, which are predicted to stabilize the inhibitor in the enzyme cavity (Table 1S). The concomitant presence of a meta substituted phenyl ring tethering the azaspiro dihydrotriazine core impaired the activity of these derivatives with respect to cycloguanil-like dihydrotriazine derivatives lacking of the azaspiro moiety, especially when decorated with electron-donor groups. On the contrary, the presence of lipophilic and electron-withdrawing groups (e.g., chlorine), at the meta position of the phenyl ring sometimes allows the inhibitor to maintain one of the two key H-bonds with the enzyme, involving I7 (see Fig. 6). Interestingly, the most potent compounds 4 and 6 featuring valuable anti-influenza B activity (mean EC50 ∼ 0.2 μM) displayed additional π−π stacking interactions projecting the aforementioned phenyl ring towards Y121, and also one H-bond between their carbonyl oxygen atom and the S59 side-chain. Based on these data, the combination of a carbonyl H-bond acceptor moiety and an aromatic lipophilic group (such as the benzoyl moiety) would be preferred. Accordingly, the predicted energy values of the complexes hDHFR-4 and hDHFR-6 listed in Table 1S were lower than that of the congeners featuring aliphatic groups at piperidine nitrogen (see 2, 3). This seems to be further supported by the lack of activity for all the derivatives being unsubstituted in this position and bearing a variable phenyl ring at N (1) of dihydrotriazine (see 1, 7; EC50 > 100 μM). When derivatives characterized by an alkyl chain at N (1) of dihydrotriazine (12–21, Fig. 3) are considered, only compound 20 (Influenza B virus, EC50 = 3.0 μM) exhibited an effective docking mode within the enzyme cavity. As shown in Fig. 7, its flexible alkyl side chain permitted to the dihydrotriazine portion of the ligand to fill the binding crevice better than reference compound I and previous congeners, which were decorated with conformationally rigid aromatic rings at N (1) of dihydrotriazine. Notably, this allowed to detect one H-bond with I7, while the sulfone moiety displayed H-bonds with S59. More interestingly, the presence of an oxygen atom along with the aliphatic chain placed at N (1) allowed intramolecular hydrogen contacts with the surrounding NH2 group onto the dihydrotriazine core. As a consequence, the overall positioning of the ligand oriented the second NH2 group towards I7, while the azaspiro portion and the sulfone group properly recapitulate the binding mode of the aniline fragment in reference compound I.