Exploring isoindolin-1-ones as potential CDK7 inhibitors using cheminformatic tools.

In women who die from cancer, breast cancer is the most common cause of death. The development of small molecular scaffolds as specific Cyclin-dependent kinase (CDK) inhibitors is a promising strategy in the discovery of anti-breast cancer drugs. Isoindolin-1-ones are heterocyclic compounds with useful therapeutic properties. In this study, a library of 48 isoindolinones has been virtually screened by molecular docking that showed high binding affinity up to - 10.1 kcal/mol and conventional hydrogen bonding interactions with active amino acid residues of CDK7. The molecular dynamics simulation (MDS), fragment molecular orbital (FMO), density functional theory (DFT), and pharmacokinetics studies of the best two docked scored ligands 7 and 14 have been studied. Examining the ligand root mean square deviation and hydrogen bonding occupancy of the 100 ns MDS trajectory, both ligands 7 and 14 showed docked pose stability. FMO calculations displayed that LYS139 and LYS41 are majorly contributing to the binding interactions with ligands 7 and 14 in the docked poses. DFT studies of ligands 7 and 14 showed high values of global softness and low values of global hardness and chemical potential thus displaying chemically reactive soft molecules and this influences their anti-cancer activity. Our hits exhibited superior qualities to known CDK7 inhibitors, according to the comprehensive pharmacokinetic parameters that were predicted. The results indicate that isoindolin-1-one moieties are good candidates for anti-cancer action and could serve as effective CDK7 inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00225-0.

Design, Synthesis, and Antibacterial Evaluation of Novel Isoindolin-1-ones Derivatives Containing Piperidine Fragments.

A series of novel isoindoline-1-one derivatives containing piperidine moiety were designed and synthesized using natural compounds as raw materials, and their biological activities were tested for three bacterial and three fungal pathogens. These derivatives exhibited good against phytopathogenic bacteria activities against Pseudomonas syringae pv actinidiae (Psa) and Xanthomonas axonopodis pv.citri (Xac). Some compounds exhibited excellent antibacterial activities against Xanthomonas oryzae pv oryzae (Xoo). The dose of Y8 against Xoo (the maximum half lethal effective concentration (EC50) = 21.3 µg/mL) was better than that of the thiediazole copper dose (EC50 = 53.3 µg/mL). Excitingly, further studies have shown that the molecular docking of Y8 with 2FBW indicates that it can fully locate the interior of the binding pocket through hydrogen bonding and hydrophobic interactions, thereby enhancing its anti-Xoo activity. Scanning electron microscopy (SEM) studies revealed that Y8 induced the Xoo cell membrane collapse. Moreover, the proteomic results also indicate that Y8 may be a multifunctional candidate as it affects the formation of bacterial Xoo biofilms, thereby exerting antibacterial effects.

An Oxidation Study of Phthalimide-Derived Hydroxylactams.

A systematic study of the oxidation of 3-hydroxy-2-substituted isoindolin-1-ones (hydroxylactams) and their conversion to the corresponding phthalimides was undertaken using three oxidants. Of special interest was the introduction of nickel peroxide (NiO2) as an oxidation system for hydroxylactams and comparison of its performance with the commonly used pyridinium chlorochromate (PCC) and iodoxybenzoic acid (IBX) reagents. Using a range of hydroxylactams, optimal conversions of these substrates to the corresponding imides was achieved with 50 equivalents of freshly prepared NiO2 in refluxing toluene over 5-32 h reaction times. By comparison, oxidations of the same substrates using PCC/silica gel (three equivalents) and IBX (three equivalents) required oxidation times of 1-3 h for full conversion but required lengthier purification. While nominal amounts (~25 mg) of substrate hydroxylactams were used to ascertain conversion, scale-up procedures using all three methods gave good to excellent isolated yields of imides.

Synthesis and Broad Antiviral Activity of Novel 2-aryl-isoindolin-1-ones towards Diverse Enterovirus A71 Clinical Isolates.

Enterovirus 71 (EV-A71) is the main causative pathogen of childhood hand, foot and mouth disease. Effective medicine is currently unavailable for the treatment of this viral disease. Using the fragment-hopping strategy, a series of 2-aryl-isoindolin-1-one compounds were designed, synthesized and investigated for their in vitro antiviral activity towards multiple EV-A71 clinical isolates (H, BrCr, Shenzhen98, Jiangsu52) in Vero cell culture in this study. The structure⁻activity relationship (SAR) studies identified 2-phenyl-isoindolin-1-ones as a new potent chemotype with potent antiviral activity against EV-A71. Ten out of the 24 tested compounds showed significant antiviral activity (EC50 < 10 µM) towards four EV-A71 strains. Compounds A3 and A4 exhibited broad and potent antiviral activity with the 50% effective concentration (EC50) values in the range of 1.23⁻1.76 µM. Moreover, the selectivity indices of A3 and A4 were significantly higher than those of the reference compound, pirodavir. The western blotting experiment indicated that the viral VP1 was significantly decreased at both the protein and RNA level in a dose-dependent manner following treatment with compound A3. Moreover, compound A3 inhibited the viral replication by acting on the virus entry stage. In summary, this study led to the discovery of 2-aryl-isoindolin-1-ones as a promising scaffold with potent anti-EV-A71 activities, which deserves further in-depth studies.

Isoindolin-1-one derivatives as urease inhibitors: Design, synthesis, biological evaluation, molecular docking and in-silico ADME evaluation.

An efficient, one-pot and four-component synthesis of a new series of 2,3-disubstituted isoindolin-1-ones is described and their Jack bean urease inhibitory activities are evaluated. Heating a mixture of 1,1-bis(methylthio)-2-nitroethene, a 1,2-diamine, a 2-formylbenzoic acid and a primary amine in EtOH for 3.5 h afforded the corresponding 2,3-disubstituted isoindolin-1-ones in good to excellent yields. All sixteen synthesized isoindolin-1-one derivatives 5a-p showed urease inhibitory activity. Among them, 5c showed the most urease inhibitory activity (IC50 = 10.07 ±â€¯0.28 µM) being over 2-fold more potent than thiourea (IC50 = 22.01 ±â€¯0.10 µM) and 10-fold than hydroxyurea (IC50 = 100.00 ±â€¯0.02 µM) as the standard inhibitors, respectively. Also, results from molecular docking studies were in good agreement with those obtained from in vitro tests.

A simple and convenient one-pot synthesis of substituted isoindolin-1-ones via lithiation, substitution and cyclization of N'-benzyl-N,N-dimethylureas.

Lithiation of N'-benzyl-N,N-dimethylurea and its substituted derivatives with t-BuLi (3.3 equiv) in anhydrous THF at 0 °C followed by reaction with various electrophiles afforded a range of 3-substituted isoindolin-1-ones in high yields.