Tyrosinase inhibition potency of phthalimide derivatives: crystal structure, Hirshfeld surface analysis and molecular docking studies

Abstract

A new series of seven 2-((pyridinylamino)methyl)isoindoline-1,3-dione derivatives were synthesized under mild condition and characterized by spectroscopy analysis. The crystal structures of these derivatives were further determined using single crystal X-ray diffraction technique. All derivatives adopt a V-shape conformation. The dihedral angle between phthalimide and pyridine rings increases as the torsion angle C1–N1–C9–N2 between phthalimide ring and methylene group increases. The torsion angles and molecular conformations are comparable to those related structures from the Cambridge Structural Database (CSD). Furthermore, the intermolecular interactions of all studied crystal structures were quantified and analyzed using Hirshfeld surface (HS) analysis. The quantitative data on the percentage contributions of overall interactions in all compounds are calculated by the two-dimensional (2D) fingerprint plots from the HS analysis. These compounds were evaluated for their antioxidant and antityrosinase properties. Noteworthy, 2-(((6-methoxypyridin-3-yl)amino)methyl)isoindoline-1,3-dione (compound g) exhibited higher tyrosinase inhibitory activity (EC50=753 μg/mL) than the positive control ‘arbutin’ (EC50=403 μg/mL). The inhibitory effect of compound g was further confirmed by computational molecular docking studies and the result revealed the 6-methoxypyridin-3-yl substituent has a better binding affinity toward tyrosinase.

Conformational dimorphism of 2,2′-methylenebis(isoindoline-1,3-dione)

“…Phthalimide (or isoindoline-1,3-dione) derivatives with fivemembered N-heterocycles have been proven to exhibit significant biological and pharmaceutical activities, and have also been used as dyes and heat-resistant polymers in industry (Chidan Kumar et al, 2015;Then et al, 2018). The first reported crystal structure of 2,2 0 -methylenebis(isoindoline-1,3-dione) (1; Jiang et al, 2007) crystallizes in the centrosymmetric triclinic space group P1 [a = 7.6660 (9) Å , b = 9.5810 (8) Å , c = 10.2780 (6) Å , = 104.325 (3) , = 99.768 (4) , = 96.030 (3) , Z = 2, Z 0 = 1 and V = 712.23 (11) Å 3 ; Cambridge Structural Database (CSD; Groom et al, 2016) refcode SINDID].…”

“…The reaction solution was stirred for about 2 h at room temperature. Once the reaction was complete, the resultant mixture was poured into a beaker of ice-cooled water to obtain a precipitate (Then et al, 2018), which was then filtered, washed with distilled water and dried. Crystals suitable for X-ray analysis were obtained by slow evaporation of a methanol solution.…”