Design,synthesis and biological evaluation of novel oseltamivir derivatives as potent neuraminidase inhibitors

Neuraminidase (NA) is one of the particular potential targets for novel antiviral therapy. In this work, a series of neuraminidase inhibitors with the cyclohexene scaffold were studied based upon the combination of 3D-QSAR, molecular docking, and molecular dynamics techniques. The results indicate that the built 3D-QSAR models yield reliable statistical information: the correlation coefficient (r²) and cross-validation coefficient (q²) of CoMFA (comparative molecular field analysis) are 0.992 and 0.819; the r² and q² of CoMSIA (comparative molecular similarity analysis) are 0.992 and 0.863, respectively. Molecular docking and MD simulations were conducted to confirm the detailed binding mode of enzyme-inhibitor system. The new NA inhibitors had been designed, synthesized, and their inhibitory activities against group-1 neuraminidase were determined. One agent displayed excellent neuraminidase inhibition, with IC₅₀ value of 39.6?μM against NA, while IC₅₀ value for oseltamivir is 61.1?μM. This compound may be further investigated for the treatment of infection by the new type influenza virus.     

Synthesis and biological evaluation of novel benzyl-substituted (S)-phenylalanine derivatives as potent dipeptidyl peptidase 4 inhibitors

A series of novel benzyl-substituted (S)-phenylalanine derivatives were synthesized and evaluated for their dipeptidyl peptidase 4 (DPP-4) inhibitory activity and selectivity. It was found that most synthesized target compounds were potent DPP-4 inhibitors with IC₅₀ values in 3.79–25.52 nM, which were significantly superior to that of the marketed drug sitagliptin. Furthermore, the 4-fluorobenzyl substituted phenylalanine derivative 6g not only displayed the potent DPP-4 inhibition with an IC₅₀ value of 3.79 nM, but also showed better selectivity against DPP-4 over other related enzymes including DPP-7, DPP-8, and DPP-9. In an oral glucose tolerance test (OGTT) in normal Sprague Dawley rats, compound 6g reduced blood glucose excursion in a dose-dependent manner.     

Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes

A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC₅₀ = 0.017 μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4 = 1324; DPP-9/DPP-4 = 1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague–Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent.     

Synthesis, pharmacophore modeling and in vitro activity of 10,11-dihydrodibenzo[b,f]oxepine-4-carboxamide derivatives as novel and potent antagonists of the prostaglandin EP4 receptor

The construction of a EP(4) antagonists pharmacophore model and the discovery of a highly potent oxepinic series of EP(4) antagonists is discussed. Compound 1a exhibits an excellent selectivity profile toward EP(2) receptor subtype and low cytochrome P450 inhibition potential.     

Discovery of potent dipeptidyl peptidase IV inhibitors derived from β-aminoamides bearing substituted [1,2,3]-triazolopiperidines for the treatment of type 2 diabetes

A series of novel [1,2,3]-triazolopiperidine derivatives 5a-5y were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes, most of the compounds exhibited excellent in vitro potency (IC₅₀ <50 nM) against DPP-4. Among these, compound 5d with potent in vitro activity against DPP-4 and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in ICR mice. On the base of these properties, compound 5d was selected as a potential new candidate for the treatment of type 2 diabetes.     

Discovery of FIXa inhibitors by combination of pharmacophore modeling,molecular docking,and 3D-QSAR modeling

Human Coagulation Factor IXa (FIXa), specifically inhibited at the initiation stage of the blood coagulation cascade, is an excellent target for developing selective and safe anticoagulants. To explore this inhibitory mechanism, 86 FIXa inhibitors were selected to generate pharmacophore models and subsequently SAR models. Both best pharmacophore model and ROC curve were built through the Receptor–Ligand Pharmacophore Generation module. CoMFA model based on molecular docking and PLS factor analysis methods were developed. Model propagations values are q²?=?0.709, r²?=?0.949, and r²_pred?=?0.905. The satisfactory q² value of 0.609, r² value of 0.962, and r²_pred value of 0.819 for CoMSIA indicated that the CoMFA and CoMSIA models are both available to predict the inhibitory activity on FIXa. On the basis of pharmacophore modeling, molecular docking, and 3D-QSAR modeling screening, six molecules are screened as potential FIXa inhibitors.     

Design,synthesis, structure–activity relationships,and docking studies of pyrazole-containing derivatives as a novel series of potent glucagon receptor antagonists

Glucagon receptor antagonists possess a great potential for treatment of type 2 diabetes mellitus. A series of pyrazole-containing derivatives were designed, synthesized and evaluated by biological assays as glucagon receptor antagonists. Most of the compounds exhibited good in vitro efficacy. Two of them, compounds 17f and 17k, displayed relatively potent antagonist effects on glucagon receptors with IC₅₀ values of 3.9 and 3.6 μM, respectively. The possible binding modes of 17f and 17k with the cognate receptor were explored by molecular docking simulation.     

Pharmacophore based 3D-QSAR modeling and free energy analysis of VEGFR-2 inhibitors

VEGFR-2, a transmembrane tyrosine kinase receptor is responsible for angiogenesis and has been an attractive target in treating cancers. The inhibition mechanism of structurally diverse urea derivatives, reported as VEGFR-2 inhibitors, was explored by pharmacophore modeling, QSAR, and molecular dynamics based free energy analysis.The pharmacophore hypothesis AADRR, resulted in a highly significant atom based 3D-QSAR model (r² = 0.94 and q² = 0.84). Binding free energy analysis of the docked complexes of highly active and inactive compounds, after 7 ns MD simulation, revealed the importance of van der Waals interaction in VEGFR-2 inhibition. The decomposition of binding free energy on a per residue basis disclosed that the residues in hinge region and hydrophobic pocket play a role in discriminating the active and inactive inhibitors. Thus, the present study proposes a pharmacophore hypothesis representing the identified interactions pattern and its further application as a template in screening databases to identify novel VEGFR-2 inhibitor scaffolds.     

Design,synthesis, and evaluation of novel l-phenylglycine derivatives as potential PPARγ lead compounds

In accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l-phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator-activated receptor gamma (PPARγ) activated activity, α-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105.04% at 10?μg·mL^?1 compared with the positive control pioglitazone, with 100% activity). Therefore, M5 was selected as the hit compound from which the TM3 and TM4 series of compounds were further designed and synthesized. Based on the PPRE relative activities of TM3 and TM4, we discovered another new molecule, TM4h, which had the strongest PPRE relative activity (120.42% at 10?μg·mL^?1). In addition, the concentration-dependent activity of the highly active compounds was determined by assaying their half-maximal effective concentration (EC₅₀) values. The molecular physical parameter calculation and the molecular toxicity prediction were used to theoretically evaluate the lead-likeness and safety of the active compounds. In conclusion, we identified a potential PPARγ lead molecule and developed a tangible strategy for antidiabetic drug development.     

Molecular modeling study on chemically diverse series of cyclooxygenase-2 selective inhibitors: generation of predictive pharmacophore model using Catalyst

Cyclooxygenase (COX) enzymes catalyse the biosynthesis of prostaglandins and thromboxane from arachidonic acid (AA). We summarize in this paper, the development of pharmacophores of a dataset of inhibitors for COX-2 by using the Catalyst/Hypogen module using six chemically diverse series of compounds. Training set consisting of 24 compounds was carefully selected. The activity spread of the training set molecules was from 0.1 to 10000 nM. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, one hydrogen bond donor, one hydrogen bond acceptor, one hydrophobic aliphatic and one ring aromatic feature, had a correlation (r) of 0.954 and a root mean square deviation of 0.894. The entropy (configuration cost) value of the hypotheses was 16.79, within the allowed range. The difference between the null hypothesis and the fixed cost and between the null hypothesis and the total cost of the best hypothesis (hypothesis 1) was 88.37 and 78.51, respectively. The model was validated on a test set consisting of six different series of structurally diverse 22 compounds and performed well in classifying active and inactive molecules correctly. This validation approach provides confidence in the utility of the predictive pharmacophore model developed in this work as a 3D query tool in the virtual screening of drug like molecules to retrieve new chemical entities as potent COX-2 inhibitors. The model can also be used to predict the biological activities of compounds prior to their costly and time-consuming synthesis. Figure 3D Pharmacophore model generated using structurally diverse COX-2 inhibitors     

Design,synthesis and biological evaluation of novel 5-phenyl-1H-pyrazole derivatives as potential BRAFV600E inhibitors

A series of novel 5-phenyl-1H-pyrazole derivatives (5a–5u) containing niacinamide moiety were synthesized and evaluated for biological activity as potential BRAF^V600E inhibitors. Among them, compound 5h exhibited the most potent inhibitory activity with an IC₅₀ value of 0.33 μM for BRAF^V600E. Antiproliferative assay results indicated that compound 5h has better antiproliferative activity against WM266.4 and A375 in vitro with IC₅₀ value of 2.63 and 3.16 μM, respectively, being comparable with the positive control vemurafenib. Molecular docking of 5h into the BRAF^V600E active site was performed to determine the probable binding mode. Furthermore, molecular docking and 3D QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives.