Pyrazolo[1,5-a]quinazoline scaffold as 5-deaza analogue of pyrazolo[5,1-c][1,2,4]benzotriazine system: synthesis of new derivatives, biological activity on GABA_A receptor subtype and molecular dynamic study

Figures & data

Scheme 1. Pyrazolo[1,5-a]quinazoline (A) and pyrazolo[5,1-c][1,2,4]benzotriazine (B).

Scheme 2. Reagent and conditions: (i) DMF, K₂CO₃, benzyl chloride (for 1c, a mixture of 2c and 5 were obtained).

Scheme 3. (i) Tosylchloride, NEt₃, and DCM. (ii) DMF, t-BuOK, and benzyl alcohol. (iii) POCl₃, DIPEA. (iv) DMF and excess of suitable Ar(Het)NH₂. (v) Sodium hydroxide 10% solution, then HCl.

Scheme 4. Reagent and conditions: (i) EtOH, Pd/C 10%, and HCOONH₄; (ii) toluene and Pd/C 10% reflux.

Figure 1. (a) Average frequency contacts (expressed in %) of hydrogen bond interaction measured during the dynamic simulation of ligand-receptor complex. White columns, affine ligands; grey columns, low affine ligands; black columns, inactive ligands. (b) Average frequency contacts (expressed in %) of Van der Waals interaction measured during the dynamic simulation of ligand–receptor complex. White columns, affine ligands; grey columns, low affine ligands; black columns, inactive ligands.

Scheme 5. The data-set.

Figure 2. Principal components analysis. The “biplot” shows the value of the first two components of the original variables. The original variables considered are the average frequency (expressed in %) of hydrogen bonds (hb) and van der Waals (vdw) interactions between the ligand and the amino acids γT142, αY160, αY210, αV203, γM81, γY141, and αA161. The squares represent the ligands (white, affine; grey, low affine; black, inactive), the lines represent the component weights of the original variables.

Figure 3. Interaction between affine compound 17 and receptor protein. Hydrogen bond interaction: blue solid line; Van der Waals interaction: pink dashed line.

Figure 4. Interaction between affine compound 1b and receptor protein. In particular, only Van der Waals interactions are evidenced, pink dashed line and they lack the hydrogen bond interactions.

Figure 5. Interaction between affine compound 21 and receptor protein. In particular, Van der Waals interactions, pink dashed line, and the hydrogen bond interaction with αY160 are evidenced.