Optimization study towards more potent thiazolidine-2,4-dione IKK-β modulator: Synthesis,biological evaluation and in silico docking simulation

Inhibition of IKK-β (inhibitor of nuclear factor kappa-B kinase subunit beta) has been broadly documented as a promising approach for treatment of acute and chronic inflammatory diseases, cancer, and autoimmune diseases. Recently, we have identified a novel class of thiazolidine-2,4-diones as structurally novel modulators for IKK-β. Herein, we report a hit optimization study via analog synthesis strategy aiming to acquire more potent derivative(s), probe the structure activity relationship (SAR), and get reasonable explanations for the elicited IKK-β inhibitory activities though an in silico docking simulation study. Accordingly, a new series of eighteen thiazolidine-2,4-dione derivatives was rationally designed, synthesized, identified with different spectroscopic techniques and biologically evaluated as noteworthy IKK-β potential modulators. Successfully, new IKK-β potent modulators were obtained, including the most potent analog up-to-date 7m with IC₅₀ value of 260 nM. A detailed structure activity relationship (SAR) was discussed and a mechanistic study for 7m was carried out indicating its irreversible inhibition mode with IKK-β (K_inact value = 0.01 (min⁻¹). Furthermore, the conducted in silico simulation study provided new insights for the binding modes of this novel class of modulators with IKK-β.     

NO inhibitory diterpenoids as potential anti-inflammatory agents from Euphorbia antiquorum

Two new ent-atisane-type diterpenoids (1 and 2), three new lathyrane-type diterpenoids (3–5), and seven known analogues (6–12) were isolated from Euphorbia antiquorum. The structures of these diterpenoids were established by analysis of their NMR, MS, and electronic circular dichroism data. The anti-inflammatory activities were evaluated biologically and compounds 1, 4, 7, 8, and 10 displayed strong NO inhibitory effects with IC₅₀ values less than 40 μM. The potential anti-inflammatory mechanism was also investigated using molecular docking and Western blotting.     

Novel inhibitors of leukocyte transendothelial migration

Leukocyte transendothelial migration is one of the most important step in launching an inflammatory immune response and chronic inflammation can lead to devastating diseases. Leukocyte migration inhibitors are considered as promising and potentially effective therapeutic agents to treat inflammatory and auto-immune disorders. In this study, based on previous trioxotetrahydropyrimidin based integrin inhibitors that suboptimally blocked leukocyte adhesion, twelve molecules with a modified scaffold were designed, synthesized, and tested in vitro for their capacity to block the transendothelial migration of immune cells. One of the molecules, namely, methyl 4-((2-(tert-butyl)-6-((2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene) methyl) phenoxy) methyl) benzoate, (compound 12), completely blocked leukocyte transendothelial migration, without any toxic effects on immune or endothelial cells (IC₅₀ = 2.4 µM). In vivo, compound 12 exhibited significant therapeutic effects in inflammatory bowel disease (IBD)/Crohn’s disease, multiple sclerosis, fatty liver disease, and rheumatoid arthritis models. A detailed acute and chronic toxicity profile of the lead compound in vivo did not reveal any toxic effects. Such a type of molecule might therefore provide a unique starting point for designing a novel class of leukocyte transmigration blocking agents with broad therapeutic applications in inflammatory and auto-immune pathologies.     

New triazinoindole bearing thiazole/oxazole analogues: Synthesis, α-amylase inhibitory potential and molecular docking study

New triazinoindole bearing thiazole/oxazole analogues (1–21) were synthesized and characterized through spectroscopic techniques such as HREI-MS, ¹H and ¹³C NMR. The configuration of compound 2i and 2k was confirmed through NOESY. All analogues were evaluated against α-amylase inhibitory potential. Among the synthesized analogues, compound 1h, 1i, 1j, 2a and 2f having IC₅₀ values 1.80 ± 0.20, 1.90 ± 0.30, 1.2 ± 0.30, 1.2 ± 0.01 and 1.30 ± 0.20 μM respectively, showed excellent α-amylase inhibitory potential when compared with acarbose as standard (IC₅₀ = 0.91 ± 0.20 µM). All other analogues showed good to moderate inhibitory potential. Structural activity relationship (SAR) has been established and binding interactions were confirmed through docking studies.     

Novel Pyrazoloquinolin-2-ones: Design,synthesis, docking studies,and biological evaluation as antiproliferative EGFR-TK inhibitors

Two new series of diethyl 2-[2-(substituted-2-oxo-1,2-dihydroquinolin-4-yl)hydrazono]-succinates 6a-g and 1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazoles 7a-f have been designed and synthesized. The structures of the synthesized compounds were proved by IR, mass, NMR (2D) spectra and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, seven compounds were further examined against the most sensitive cell lines, leukemia CCRF-CEM, and MOLT-4. 5-Amino-1-(6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazole-3,4-dicarbonitrile (7f) was the most active product, with IC₅₀ = 1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively. Also, it showed a remarkable inhibitory activity compared to erlotinib on the EGFR TK with IC₅₀ = 247.14 nM and 208.42 nM, respectively. Cell cycle analysis of MOLT-4 cells treated with 7f showed cell cycle arrest at G2/M phase (supported by Caspases, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking study indicated that both the pyrazole moiety and the quinolin-2-one ring showed good fitting into EGFR (PDB code: 1M17). In order to interpret SAR of the designed compounds, and provide a basis for further optimization, molecular docking of the synthesized compounds to known EGFR inhibitors was performed. The study illustrated the effect of several factors on the compounds’ activity.     

Exploiting the 7-methylimidazo[1,5-a]pyrazin-8(7H)-one scaffold for the development of novel chemical inhibitors for Bromodomain and Extraterminal Domain (BET) family

The bromodomain and extraterminal (BET) family of proteins play a crucial role in promoting gene expression of critical oncogenes. Novel BET bromodomain inhibitors with excellent potency, drug metabolism and pharmacokinetics (DMPK) properties were in strong need for development. We reported a series of potential BET inhibitors through incorporation of imidazole into pyridine scaffold. Among them, a novel BET inhibitor with 7-methylimidazo[1,5-a]pyrazin-8(7H)-one core, compound 28, was considered to be the most promising for in-depth study. Compound 28 exhibited excellent BRD4-inhibitory activity with IC₅₀ value of 33 nM and anti-proliferation potency with IC₅₀ value of 110 nM in HL-60 (human promyelocytic leukemia) cancer cell lines. Western Blot indicated that compound 28 can effectively trigger apoptosis in BxPc3 cells by modulating the intrinsic apoptotic pathway. In conclusion, these results suggested that compound 28 has merely potential for leukemia treatment.     

The first synthesis,carbonic anhydrase inhibition and anticholinergic activities of some bromophenol derivatives with S including natural products

Starting from vanillin, known four benzyl bromides with Br were synthesized. The first synthesis of natural product 3,4-dibromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (2) and 3,4,6-tribromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (3) and derivatives were carried out by demethylation, acetylatilation, oxidation and hydrolysis reactions of the benzyl bromides. Also, these compounds were tested against some important enzymes like acetylcholinesterase and butyrylcholinesterase enzymes, carbonic anhydrase I, and II isoenzymes. The novel bromophenols showed Ki values of in range of 53.75 ± 12.54–234.68 ± 46.76 nM against hCA I, 42.84 ± 9.36 and 200.54 ± 57.25 nM against hCA II, 0.84 ± 0.12–14.63 ± 3.06 nM against AChE and 0.93 ± 0.20–18.53 ± 5.06 nM against BChE. Induced fit docking process performed on the compounds inhibiting hCA I, hCA II, AChE, and BChE receptors. Hydroxyl group should exist at the aromatic ring of the compounds for inhibition of the enzymes. The moieties reported in this study will be useful for design of more potent and selective inhibitors against the enzymes.     

Insights into the interaction of ulipristal acetate and human serum albumin using multi-spectroscopic methods,molecular docking,and dynamic simulation

Interaction between ulipristal acetate (UPA) and human serum albumin (HSA) was investigated in simulated physiological environment using multi-spectroscopic and computational methods. Fluorescence experiments showed that the quenching mechanism was static quenching, which was confirmed by the time-resolved fluorescence. Binding constants (K_a) were found to be 1?×?10⁵ L mol^?1, and fluorescence data showed one binding site. Thermodynamic constants suggested the binding process was mainly controlled by electrostatic interactions. Results from the competition experiments indicated that UPA bound to site I of HSA. Fourier transform infrared spectra, circular dichroism spectra, synchronous fluorescence spectra, and 3D fluorescence indicated that UPA can induce conformation change in the HSA. The content of α-helix and β-sheet increased, while β-turn decreased. Hydrophobicity around the tryptophan residues declined, whereas its polarity increased. Molecular docking results were consistent with the experimental results. Results suggested that UPA located at the hydrophobic cavity site I of HSA, and hydrophobic force played the key role in the binding process. Moreover, molecular dynamics simulation was performed to determine the stability of free HSA and HSA-UPA system. Results indicated that UPA can stabilize HSA to a certain degree and enhance the flexibility of residues around site I.

Communicated by Ramaswamy H. Sarma     

Docking-based 3D-QSAR (CoMFA,CoMFA-RG,CoMSIA) study on hydroquinoline and thiazinan-4-one derivatives as selective COX-2 inhibitors

A series of 26 selective COX-2 inhibitors which reported previously by our laboratory was selected to generate three-dimensional quantitative structure activity relationship (3D-QSAR) model. Active conformation of each molecule was predicted by docking studies and used for molecular alignment. Activity of 20 molecules as a train set was predicted using three methods including comparative molecular field analysis (CoMFA), CoMFA region focusing (CoMFA-RG) and comparative molecular similarity index analysis (CoMSIA). The best models of CoMFA-RG and CoMSIA revealed correlation coefficients r² of 0.955 and 0.947, the leave one out cross-validation coefficients q² of 0.573 and 0.574, respectively. In addition, CoMFA-RG and CoMSIA models were validated by a test set of six molecules with predicted coefficients r²_pred of 0.644 and 0.799, respectively. Contour maps of generated models provided fruitful information about structural aspect of molecules that affected their COX-2 inhibitory activity. Based on three models results, steric and electrostatic properties are the most important factors in controlling the activity of the molecules. Results of CoMFA-RG and CoMSIA models were utilized to design new molecules. Comparison of experimental and predicted pIC₅₀ values of designed molecules indicated that CoMFA-RG had the more predictive ability.

Communicated by Ramaswamy H. Sarma     

Insights into the inhibitory mechanism of a resveratrol and clioquinol hybrid against Aβ42 aggregation and protofibril destabilization: A molecular dynamics simulation study

Amyloid-β (Aβ) peptide instinctively aggregate and form plaques in the brain of Alzheimer’s disease (AD) patients. At present, there is no cure or treatment for AD, and significant effort has, therefore, been made to discover potent drugs against AD. Previous studies reported that a resveratrol and clioquinol hybrid compound [(E)-5-(4-hydroxystyryl)quinolone-8-ol], C1, strongly inhibit Aβ₄₂ aggregation and disassemble preformed fibrils. However, the atomic level details of the inhibitory mechanism of C1 against Aβ₄₂ aggregation and protrofibril disassembly remains elusive. In this regard, molecular docking and molecular dynamics (MD) simulation of Aβ₄₂ monomer, Aβ₄₂ monomer–C1 complex, Aβ₄₂ protofibril, and Aβ₄₂ protofibril–C1 complex were performed in the present study. MD simulations highlighted that C1 bind in the central hydrophobic core (CHC) region, i.e., KLVFF (16–20) of Aβ₄₂ monomer, which plays a critical role in Aβ₄₂ aggregation. C1 promote the formation of native helical conformation in the Aβ₄₂ monomer and decrease the probability of D23–K28 salt bridge interaction that is critical in the formation of aggregation-prone β-sheet conformation. Further, C1 destabilize Aβ₄₂ protofibril structure by increasing the interchain distance between chains A–B, disrupting the salt–bridge interaction between D23–K28, and decreasing the number of backbone hydrogen bonds between chains A–B of the Aβ₄₂ protofibril structure. The insights into the underlying inhibitory mechanism of small molecules that display potential in vitro anti–aggregation activity against Aβ₄₂ will be beneficial for the rational design of more potent drug molecules against AD.

Communicated by Ramaswamy H. Sarma