Synthesis,Pharmacological Evaluation,and Docking Studies of Novel Pyridazinone‐Based Cannabinoid Receptor Type 2 Ligands

In recent years, cannabinoid type 2 receptors (CB₂R) have emerged as promising therapeutic targets in a wide variety of diseases. Selective ligands of CB₂R are devoid of the psychoactive effects typically observed for CB₁R ligands. Based on our recent studies on a class of pyridazinone 4‐carboxamides, further structural modifications of the pyridazinone core were made to better investigate the structure–activity relationships for this promising scaffold with the aim to develop potent CB₂R ligands. In binding assays, two of the new synthesized compounds [6‐(3,4‐dichlorophenyl)‐2‐(4‐fluorobenzyl)‐cis‐N‐(4‐methylcyclohexyl)‐3‐oxo‐2,3‐dihydropyridazine‐4‐carboxamide ( 2 ) and 6‐(4‐chloro‐3‐methylphenyl)‐cis‐N‐(4‐methylcyclohexyl)‐3‐oxo‐2‐pentyl‐2,3‐dihydropyridazine‐4‐carboxamide ( 22 )] showed high CB₂R affinity, with K_i values of 2.1 and 1.6 nm , respectively. In addition, functional assays of these compounds and other new active related derivatives revealed their pharmacological profiles as CB₂R inverse agonists. Compound 22 displayed the highest CB₂R selectivity and potency, presenting a favorable in silico pharmacokinetic profile. Furthermore, a molecular modeling study revealed how 22 produces inverse agonism through blocking the movement of the toggle‐switch residue, W6.48.     

Bioisosteric approach in designing new monastrol derivatives: An investigation on their ADMET prediction using in silico derived parameters

Medicinal chemists are facing an increasing challenge to deliver safer and more effective medicines. An appropriate balance between drug-like properties such as solubility, permeability, metabolic stability, efficacy and toxicity is one of the most challenging problems during lead optimization of a potential drug candidate. Insoluble and impermeable compounds can result in erroneous biological data and unreliable SAR in enzyme and cell-based assays. The weak inhibitory activity and non-drug-like properties of monastrol, the first small mitotic kinesin Eg5 inhibitor, has hampered its further development. In this investigation, a bioisosteric approach was applied that resulted in the replacement of C-5 carbonyl of monastrol with thio-carbonyl. Further lead optimization of drug-like properties was evaluated through in silico predictions by using ADMET predictor software. This minor structural modification resulted in upgraded human effective jejunal permeability (Peff) and improved permeability in Madin–Darby canine kidney (MDCK) cells. Furthermore, C-5 thiocarbonyl analogue of monastrol (named as Special-2) was found safe to administer orally with no phospholipidosis toxicity, no raised levels of serum glutamate oxaloacetate transaminase (SGOT) and no potential towards cardiotoxicity. Molecular docking study was also carried out to understand the binding modes of these compounds. The docking study showed high binding affinity of the designed compounds against KSP. Hence a combination of in silico ADMET studies and molecular docking can help to improve prediction success and these compounds might be act as potential candidate for KSP inhibition.     

Preparation of Photodegradable Oligomers Containing Metal–Metal Bonds Using ADMET

ADMET was evaluated as a method for preparing organometallic polymers with metal–metal bonds in the main chain. The Cp₂Mo₂CO₄(Ph₂P(CH₂)₆CH=CH₂)₂ complex was synthesized, and the X-ray crystal structure is reported. The molecule did not undergo ADMET polymerization with Grubbs’ or Schrock’s catalysts. In a control experiment to test if the Ph₂P(CH₂)₆CH=CH₂ ligand was interfering with the ADMET reaction, the phosphine was reacted with Grubbs’ 2nd generation catalyst. The dimerized metathesis product Ph₂P(CH₂)₆CH=CH(CH₂)₆PPh₂ was obtained with no observed degradation or deactivation of the catalyst. To test the inherent ADMET reactivity of the Ph₂P(CH₂)₆CH=CH₂ ligand when it is bonded to a metal center, the mononuclear cis-Mo(CO)₄(Ph₂P(CH₂)₆CH=CH₂)₂ complex was synthesized and polymerized using Grubbs’ 2nd generation catalyst. These control experiments suggest that the inability of Cp₂Mo₂CO₄(Ph₂P(CH₂)₆CH=CH₂)₂ to polymerize is not due to electronic effects pertaining to the C=C unit of the Ph₂P(CH₂)₆CH=CH₂ ligand. Accordingly, steric effects are implicated in the inability of the Cp₂Mo₂CO₄(Ph₂P(CH₂)₆CH=CH₂)₂ to polymerize by ADMET.     

Controlled synthesis of photosensitive graft copolymers with high azobenzene-chromophore loading densities in the main and side chains by combining ATRP and ADMET polymerization

Photosensitive graft copolymers containing azobenzene chromophores in the main and side chains were successfully synthesized by combining living atom transfer radical polymerization (ATRP) and acyclic diene metathesis (ADMET) chemistry based on the results of proper heterodifunctional inimer and azobenzene monomer design. The precise copolymer architectural features were manipulated by combining the macromonomer technique and the macroinitiator method. The as-prepared copolymer containing azobenzene chromophores in the main and side chains showed unique reversible isomerization processes, suggesting that the photoisomerization of azobenzene chromophores occured mainly in one of the two types of azobenzene groups in the main or side chains with similar probabilities due to their main and side-on structure.     

A Multistage In Silico Study of Natural Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Among a group of 310 natural antiviral natural metabolites, our team identified three compounds as the most potent natural inhibitors against the SARS-CoV-2 main protease (PDB ID: 5R84), M^pro. The identified compounds are sattazolin and caprolactin A and B. A validated multistage in silico study was conducted using several techniques. First, the molecular structures of the selected metabolites were compared with that of GWS, the co-crystallized ligand of M^pro, in a structural similarity study. The aim of this study was to determine the thirty most similar metabolites (10%) that may bind to the M^pro similar to GWS. Then, molecular docking against M^pro and pharmacophore studies led to the choice of five metabolites that exhibited good binding modes against the M^pro and good fit values against the generated pharmacophore model. Among them, three metabolites were chosen according to ADMET studies. The most promising M^pro inhibitor was determined by toxicity and DFT studies to be caprolactin A (292). Finally, molecular dynamics (MD) simulation studies were performed for caprolactin A to confirm the obtained results and understand the thermodynamic characteristics of the binding. It is hoped that the accomplished results could represent a positive step in the battle against COVID-19 through further in vitro and in vivo studies on the selected compounds.     

SAHA-based novel HDAC inhibitor design by core hopping method

The catalytic activity of the histone deacetylase (HDAC) is directly relevant to the pathogenesis of cancer, and HDAC inhibitors represented a promising strategy for cancer therapy. SAHA (suberoanilide hydroxamic acid), an effective HDAC inhibitor, is an anti-cancer agent against T-cell lymphoma. However, SAHA has adverse effects such as poor pharmacokinetic properties and severe toxicities in clinical use. In order to identify better HDAC inhibitors, a compound database was established by core hopping of SAHA, which was then docked into HDAC-8 (PDB ID: 1T69) active site to select a number of candidates with higher docking score and better interaction with catalytic zinc ion. Further ADMET prediction was done to give ten compounds. Molecular dynamics simulation of the representative compound 101 was performed to study the stability of HDAC8-inhibitor system. This work provided an approach to design novel high-efficiency HDAC inhibitors with better ADMET properties.     

Metal-Containing Polymers Synthesized via Acyclic Diene Metathesis (ADMET) Polymerization Using Electrochemically Reduced Tungsten-Based Catalyst: Polycarbogermanes

Various germanium-containing dienes, bis(4-pentenyl)diethylgermanium (1), bis(4-pentenyl)dimethylgermanium (2) and bis(3-butenyl)diethylgermanium (3), were synthesized and polymerized using an electrochemically reduced tungsten-based catalyst system via acyclic diene metathesis (ADMET) polymerization. All polymer structures were characterized by ¹H- and ¹³C-NMR spectroscopy. These results indicate the retention of the double bonds in the polymer structure with high trans content (57–70%) as expected from a step condensation reaction. These polymers have low molecular weight (M _W) that range from 7400 to 19,100. The thermal stability of polymers was evaluated by thermogravimetric analysis. The glass transition temperatures of the polymer of monomer 1, 2 and 3 were −24, −9 and −47°C, respectively. Synthesis, characterization and the general limitations of ADMET polymers obtained by this catalyst are discussed. An erratum to this article can be found at