A New N-Substituted 1H-Isoindole-1,3(2H)-Dione Derivative—Synthesis, Structure and Affinity for Cyclooxygenase Based on In Vitro Studies and Molecular Docking

Abstract

Isoindoline-1,3-dione derivatives constitute an important group of medicinal substances. In this study, nine new 1H-isoindole-1,3(2H)-dione derivatives and five potential pharmacophores were obtained in good yield (47.24–92.91%). The structure of the new imides was confirmed by the methods of elemental and spectral analysis: FT–IR, H NMR, and MS. Based on the obtained results of ESI–MS the probable path of the molecules decay and the hypothetical structure of the resulting pseudo-molecular ions have been proposed. The physicochemical properties of the new phthalimides were determined on the basis of Lipiński’s rule. The biological properties were determined in terms of their cyclooxygenase (COX) inhibitory activity. Three compounds showed greater inhibition of COX-2, three compounds inhibited COX-1 more strongly than the reference compound meloxicam. From the obtained results, the affinity ratio COX-2/COX-1 was calculated. Two compounds had a value greater than that of meloxicam. All tested compounds showed oxidative or nitrosan stress (ROS and RNS) scavenging activity. The degree of chromatin relaxation outside the cell nucleus was lower than the control after incubation with all test compounds. The newly synthesized phthalimide derivatives showed no cytotoxic activity in the concentration range studied (10–90 µM). A molecular docking study was used to determined interactions inside the active site of cyclooxygenases.

Spectroscopic and Theoretical Analysis of the Interaction between Plasma Proteins and Phthalimide Analogs with Potential Medical Application

“…The binding of one molecule to a protein reduces the affinity for binding to another site in the protein. As previous studies have shown, the four phthalimide derivatives studied in this work show good anti-inflammatory properties [ 3 ]. The interaction with albumin of drugs with such an effect was studied by Mohammadnia [ 28 ].…”

“…The synthesis of compounds analyzed was performed in the Department of Medicinal Chemistry, Wroclaw Medical University, and described in work [ 3 ]. Studied proteins, BSA, AAG, GG, and 0.01 M phosphate buffer tablets were bought from Sigma-Aldrich Chemie GmbH, (St. Louis, MO, USA).…”

“…These molecules have many biological activities, such as antibacterial, anticonvulsant, anti-inflammatory, or antifungal [ 1 , 2 ]. Their use and their importance in medicine were described in our previous work about N-substituted 1H-isoindole-1,3(2H)-dione derivatives [ 3 ]. We have shown there that newly tested imides are characterized by a good affinity for both isoforms of cyclooxygenase and are non-toxic.…”

“…In this study, we have chosen four phthalimide derivatives: A, B, C, and D ( Figure 1 ) for analysis, previously described in work [ 3 ]. The final products A–D were obtained by aminoalkylation of the acidic proton on the imide nitrogen atom of the isoindoline-1,3-dione.…”

Synthesis and antinociceptive activity of four 1H‐isoindolo‐1,3(2H)‐diones

“…Compounds F1-F4 fulfill the obtained in this study are consistent with the previously described properties of phthalimide derivatives. [22] As previously determined, the type of substituent in the benzene ring, its position (o, m, p) and the presence of the OH/C═O group, and the length of the alkyl linker have a significant influence on the affinity and selectivity of the compound towards the COX- Medical University. [9][10][11] The InChI codes of the investigated compounds, together with some biological activity data, are provided as Supporting Information.…”