Various N-fused isoquinoline derivatives were synthesized using a new one-pot reaction of 1-bromo-2-(2,2-difluorovinyl)benzenes with N–H group containing heterocycles followed by intramolecular palladium-catalyzed C–H arylation. The method described gives convenient access to diverse structures of N-fused polycyclic isoquinolines. Sixteen of the synthesized compounds were screened as potential human nucleotide pyrophosphatase/phosphodiesterase 1 and 3 (h-NPP-1 and h-NPP-3) inhibitors. The most effective h-NPP-1 inhibitor showed an IC₅₀ value as high as 0.36 ± 0.06 μM, whereas the most potent h-NPP-3 inhibitor posessed an inhibitory value of 0.48 ± 0.01 μM. Kinetic and molecular docking studies of both most effective inhibitors were carried out.

Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydrophobic interactions. With TLR-4, rutin had the highest binding energy (−10.4 kcal/mol), poncirin had the highest binding energy (−9.4 kcal/mol) with NF-κB and JNK (−9.5 kcal/mol), respectively, and icariin had the highest binding affinity (−9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin’s greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simulation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maximum toxic dose. Moreover, the blood–brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties.

G protein-coupled estrogen receptor-1 (GPER-1) is a seven transmembrane receptor, responsible for mediating rapid estrogen signaling in many physiological responses in reproductive, nervous, endocrine, immune and cardiovascular systems. Due to unavailability of the crystal structure of GPER-1, we have performed sequential ligand-based virtual screening (LBVS) and structure-based screening (SBVS) to identify potential GPER-1 modulators. LBVS and SBVS approaches were validated retrospectively using the Receiver Operating Curve (ROC) plot and the early Enrichment Factor (EF). LBVS was performed based on a GPER-1 agonist, G1, as a query model for screening of the eMolecules library using the Rapid Overlay of Chemical Structure (ROCS) and the electrostatic potential screening (EON) approaches. Top-scored hits from LBVS were further screened by SBVS. SBVS was based on generating homology models of GPER-1 and subsequent molecular docking studies. Using Chemguass4 score, we filtered the final hits with the higher score in comparison to G1 (Chemguass4 score = −11.575). The top-ranked hits were clustered based on similarity in their scaffolds. Prospective validation was performed by evaluating the antiproliferative activity of synthesized compounds (SK0 and SK0P) which were representative of top hits obtained from our virtual screening approach.

Anthocleista vogelii Planch is a medicinal plant traditionally used in West Africa for the management and treatment of diabetes mellitus. To determine the antidiabetic activities of chloroform fraction (CF) of Anthocleista vogelii Planch root bark in rats with diet- and alloxan-induced obesity-diabetes. Inhibitory activities of CF against α-amylase and α-glucosidase activities were determined in vitro. Three weeks old rats were fed with high-fat diet for 9 weeks to induce obesity prior to further induction of diabetes using alloxan (150 mg/kg body weight, i.p.). Blood glucose levels and body weight were measured every 7 days throughout the experiment. Glucose tolerance was assessed in normal and CF-treated rats on day 21. Terminal blood samples were collected from sacrificed animals for the measurement of serum insulin levels. Pancreases were excised from treated and untreated animals for histopathological examination. LCMS/MS chromatographic profile of CF via positive and negative modes revealed 13 and 23 compounds respectively. Further analysis revealed quebrachitol (QCT), loganin, sweroside, oleoside 11-methyl ester and ferulic acid, which have been previously reported for their antidiabetic activities, as constituents of CF. CF inhibited activities of α-amylase (IC50 = 51.60 ± 0.92 µg/ml) and α-glucosidase (IC50 = 5.86 ± 0.97 µg/ml) in a dose-dependent manner. Treatment of animals with obesity-diabetes with 100 and 200 mg/kg CF significantly improved glucose tolerance (P < 0.001) and enhanced serum insulin levels (P < 0.05) compared to diabetic control rats. Antidiabetic activities of CF might be mediated via inhibition of α-amylase and α-glucosidase activities, elevation of serum insulin concentration, and enhancement of insulin and leptin sensitivity in obesity-diabetes rats. This study further substantiates the traditional use of A. vogelii in the management and treatment of diabetes in Africa and encourages further studies to investigate its mechanism of action.