Synthesis,molecular structure and urease inhibitory activity of novel bis-Schiff bases of benzyl phenyl ketone: A combined theoretical and experimental approach

BackgroundUrease belongs to the family of amid hydrolases with two nickel atoms in their core structure. On the basis of literature survey, this research work is mainly focused on the study of bis-Schiff base derivatives of benzyl phenyl ketone nucleus.ObjectiveSynthesis of benzyl phenyl ketone based bis-Schiff bases in search of potent urease inhibitors.MethodIn the current work, bis-Schiff bases were synthesized through two steps reaction by reacting benzyl phenyl ketone with excess of hydrazine hydrate in ethanol solvent in the first step to get the desired hydrazone. In last, different substituted aromatic aldehydes were refluxed in catalytic amount of acetic acid with the desired hydrazone to obtain bis-Schiff base derivatives in tremendous yields. Using various spectroscopic techniques including FTIR, HR-ESI-MS, and ¹H NMR spectroscopy were used to clarify the structures of the created bis-Schiff base derivatives.ResultsThe prepared compounds were finally screened for their in-vitro urease inhibition activity. All the synthesized derivatives (3–9) showed excellent to less inhibitory activity when compared with standard thiourea (IC₅₀ = 21.15 ± 0.32 µM). Compounds 3 (IC₅₀ = 22.21 ± 0.42 µM), 4 (IC₅₀ = 26.11 ± 0.22 µM) and 6 (IC₅₀ = 28.11 ± 0.22 µM) were found the most active urease inhibitors near to standard thiourea among the synthesized series. Similarly, compound 5 having IC₅₀ value of 34.32 ± 0.65 µM showed significant inhibitory activity against urease enzyme. Furthermore, three compounds 7, 8, and 9 exhibited less activity with IC₅₀ values of 45.91 ± 0.14, 47.91 ± 0.14, and 48.33 ± 0.72 µM respectively. DFT used to calculate frontier molecular orbitals including; HOMO and LUMO to indicate the charge transfer from molecule to biological transfer, and MEP map to indicate the chemically reactive zone suitable for drug action. The electron localization function (ELF), non-bonding orbitals, AIM charges are also calculated. The docking study contributed to the analysis of urease protein binding.     

Synthetic transformation of 6-Fluoroimidazo[1,2-a]Pyridine-3-carbaldehyde into 6-Fluoroimidazo[1,2-a]Pyridine-Oxazole Derivatives: In vitro urease inhibition and in silico study

PurposeUlcer is a serious disease that is caused due to different bacteria and over usage of various NSAIDs which caused to reduce the defensive system of stomach. Therefore, some novel series are needed to overcome these issues.MethodsOxazole-based imidazopyridine scaffolds (4a-p) were designed and synthesized by two step reaction protocol and then subjected to urease inhibition profile (in vitro). All the newly afforded analogs (4a-p) were found potent and demonstrated moderate to significant inhibition profile.ResultsParticularly, the analogs 4i (IC₅₀ = 5.68 ± 1.66 μM), 4o (IC₅₀ = 7.11 ± 1.24 μM), 4 g (IC₅₀ = 9.41 ± 1.19 μM) and 4 h (IC₅₀ = 10.45 ± 2.57 μM) were identified to be more potent than standard thiourea drug (IC₅₀ = 21.37 ± 1.76 μM). Additionally, the variety of spectroscopic tools such as ¹H NMR, ¹³C NMR and HREI-MS analysis were employed to confirm the precise structures of all the newly afforded analogs.DiscussionThe structure–activity relationship (SAR) studies showed that analogs possess the substitution either capable of furnishing strong HB like –OH or had strong EW nature such as -CF₃ & –NO₂ groups displayed superior inhibitory potentials than the standard thiourea drug. A good PLI (protein–ligand interaction) profile was shown by most active analogs when subjected to molecular study against corresponding target with key significant interactions such as pi-pi stacking, pi-pi T shaped and hydrogen bonding.     

Discovery of [1,2,3]triazolo[4,5-d]pyrimidine derivatives as highly potent,selective, and cellularly active USP28 inhibitors

Ubiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound 19 potently inhibited USP28 (IC₅₀ = 1.10 ± 0.02 μmol/L, K_d = 40 nmol/L), showing selectivity over USP7 and LSD1 (IC₅₀ > 100 μmol/L). Compound 19 was cellularly engaged to USP28 in gastric cancer cells. Compound 19 reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition (EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound 19. Collectively, compound 19 could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.     

Development,pharmacological and toxicological evaluation of a new tablet formulation based on Cassia grandis fruit extract

The treatment of Diabetes mellitus (DM) involves drugs for controlling the blood glucose level, and for treating concomitant disorders such as obesity. Based on the potent antioxidant activity, the α-glycosidase and lipase inhibitory effect, and the potent hypoglycemic effect of the fruit extract of Cassia grandis Lf (CgE), in this work it was developed a novel tablet formulation (CgET) using CgE as the active ingredient. The excipients proportion was optimized by using a D-optimal mixture design. The effect of the compaction force (10, 13, 16, 19, and 22 kN) on the technological properties of tablets was evaluated. The optimized granules formulation was compressed at 16 kN, for producing tablets with excellent technological properties. Tablets showed a potent antioxidant effect (IC₅₀ = 1.45 μg/mL), and α-glycosidase inhibitory activity (IC₅₀ = 34.96 μg/mL) more potent than Acarbose (IC₅₀ = 63.25 μg/mL). Tablets exhibited a strong antiglycant effect by the oxidative (IC₅₀ = 22.45 ± 1.80 μg/mL) and non-oxidative (IC₅₀ = 25.49 ± 1.80 μg/mL) pathways, and produced (at 100 mg/kg) a hypoglycemic effect statistically equal to glibenclamide (25 mg/kg). CgET did not show oral acute toxicity (LC₅₀ > 2000 mg/kg), framed as a non-toxic products. Fruits of the Cassia grandis L f, an underutilized species from the Cuban’ eastern region; allow developing a novel tablet formulation that could be used for the treatment of diabetic patients.     

Promising selective MAO-B inhibition by sesamin,a lignan from Zanthoxylum flavum stems

Monoamine oxidase inhibition is an important therapeutic approach for various neurodegenerative disorders. Reversible MAO inhibitors selectively targeting only one isoform possess substantial merit in terms of safety, efficacy, and side effect profile. This study aimed to isolate the secondary metabolites of Zanthoxylum flavum stems and evaluate their recombinant human MAO inhibition, antimicrobial, and antiprotozoal activities. As a result, fourteen compounds were isolated and identified (nine of them were reported from Z. flavum for the first time). Compound 3 (sesamin) exhibited potent selective MAO-B inhibition (IC₅₀ value of 1.45 ± 0.05 µM) which reported herein for the first time. Compound 2 showed selective MAO-A inhibition activity, compound 5 exhibited good trypanocidal activity, and compound 7 displayed moderate antibacterial activity. The promising MAO-B inhibitory activity of sesamin provoked us to further explore the kinetic properties, the binding mode, and the underlying mechanism of MAO-B inhibition by this lignan. This detailed investigation substantiated a reversible binding and mixed MAO-B catalytic function inhibition via sesamin (K_i: 0.473 ± 0.076 μM). Selectivity and reversibility of sesamin on MAO-B provide exciting prerequisites for further in vivo investigation to confirm its therapeutic potentiality.     

Discovery of WS-157 as a highly potent,selective and orally active EGFR inhibitor

EGFR tyrosine kinase inhibitor (EGFR-TKI) has been used successfully in clinic for the treatment of solid tumors. In the present study, we reported the discovery of WS-157 from our in-house diverse compound library, which was validated to be a potent and selective EGFR-TKI. WS-157 showed excellent inhibitory activities against EGFR (IC₅₀ = 0.81 nmol/L), EGFR^[d746−750] (IC₅₀ = 1.2 nmol/L) and EGFR^[L858R] (IC₅₀ = 1.1 nmol/L), but was less effective or even inactive against other nine kinases. WS-157 also displayed excellent antiproliferative activities against a panel of human cancer cell lines, and exhibited the ability to reduce colony formation and wound healing the same as gefitinib. We found that WS-157 upon oral administration showed better anti-tumor activity in A431 bearing xenograft mouse models compared to gefitinib. In addition, WS-157 showed better intestinal absorption than gefitinib and had favorable pharmacokinetic properties and microsomal metabolic stability in different species. These studies indicate that WS-157 has strong antitumor activity in vitro and in vivo, and could be used for the development of anti-lung cancer agent targeting EGFR.     

Design,synthesis, and biological evaluation of quinazoline derivatives as dual HDAC1 and HDAC6 inhibitors for the treatment of cancer

Fifty‐eight quinazoline‐based compounds were designed and synthesized based on the structural optimizations from the lead compound 23bb in an attempt to search for more potent dual HDAC1 and HDAC6 inhibitors. Among them, 32c (HDAC1, IC₅₀ = 31.10 ± 0.37 nM; HDAC6, IC₅₀ = 16.15 ± 0.62 nM) and 32d (HDAC1, IC₅₀ = 37.00 ± 0.24 nM; HDAC6, IC₅₀ = 35.00 ± 0.71 nM) were not only identified as potent dual‐acting HDAC1 and HDAC6 inhibitors with over 10‐fold selectivity to the other HDACs, but also displayed activities in tubulin acetylation and histone H₃ acetylation induction. Importantly, both of them displayed strong antiproliferative activities against various tumor cell lines in vitro with IC₅₀ values less than 40 nM, especially for hematologic tumors cells (U266 and RPMI8226, IC₅₀ < 1 nM), which were even better than 23bb and SAHA. Furthermore, 32c showed a significant tumor growth inhibition (antitumor rate = 63.98%, p < 0.05) in the resistant MCF‐7/ADR xenograft model without any obvious body weight changes and abnormal behaviors. Our findings validate that 32c is a potent dual inhibitor of HDAC1/6 that can be an efficacious treatment for breast cancer with Adriamycin resistance.     

Bioactivity-guided isolation of a bioactive compound with α-glucosidase inhibitory activity from the leaves extract of Sauropus androgynus

Naturally-derived antidiabetic medications have been explored as alternatives to the current widely-used drugs which can cause mild to severe side effects. Sauropus androgynus has been traditionally utilized to treat diabetes patients. In this report, a flavonoid glycoside, astragalin (1), was isolated from the leaves extract of S. androgynus using bioassay-guided isolation approach. Enrichment processes using macroporous resins resulted in two enriched fractions with 1 contents of 0.083% and 0.054% for PAD610 and PAD900 fractions, respectively. Compound 1 showed a higher α-glucosidase inhibitory (IC₅₀ = 55.03 ± 0.61 μg/mL) than that of acarbose. In vitro assay for antioxidant and α-glucosidase inhibitory activities showed the greatest inhibition by PAD 610 fractions which has 98.912% and 83.268%, respectively. These findings have shown promising results for further studies on S. androgynus as a potential herbal drug, particularly for the treatment of diabetes.     

Synthesis,characterization and pharmacological evaluation of pyrazolyl urea derivatives as potential anti-inflammatory agents

p38α mitogen activated protein kinase (MAPK) inhibitors provide a novel approach for the treatment of inflammatory disorders. A series of fifteen pyrazolyl urea derivatives (3ao) were synthesized and evaluated for their p38α MAPK inhibition and antioxidant potential. Compounds 3ae, 3g and 3h showed low micromolar range potency (IC₅₀ values ranging from 0.037 ± 1.56 to 0.069 ± 0.07 µmol/L) compared to the standard inhibitor SB 203580 (IC₅₀ = 0.043 ± 3.62 µmol/L) when evaluated for p38α MAPK inhibition by an immunosorbent-based assay. Antioxidant activity was measured by a 2,2′-diphenyl-1-picryl hydrazyl radical (DPPH) free radical scavenging method and one of the compounds, 3c, showed better percentage antioxidant activity (75.06%) compared to butylated hydroxy anisole (71.53%) at 1 mmol/L concentration. Compounds 3ae, 3g and 3h showed promising in vivo anti-inflammatory activity (ranging from 62.25% to 80.93%) in comparison to diclofenac sodium (81.62%). The ulcerogenic liability and lipid peroxidation activity of these compounds were observed to be less in comparison to diclofenac sodium. These compounds also potently inhibited the lipopolysaccharide (LPS)-induced TNF-α release in mice (ID₅₀ of 3ac = 19.98, 11.32 and 9.67 mg/kg, respectively). Among the screened compounds, derivative 3c was found to be the most potent and its binding mode within the p38α MAPK is also reported.     

Design,synthesis and cytotoxic evaluation of nitric oxide‐releasing derivatives of isosteviol

Twenty‐six novel isosteviol derivatives coupled with two types of nitric oxide (NO) donors (furoxans and NONOates) were synthesized and screened for cytotoxic activities against four human cancer cell lines with sunitinib as the positive control. The results showed that seven furoxan‐based derivatives ( 8a , 8b , 8c , 8d , 8e , 9e , and 9f ) exhibited desirable cytotoxic activities, while NONOate‐based derivatives displayed poor potency because of unstability. Compared with sunitinib, compounds 8a and 8e were more active on all tested cell lines, especially in HCT116 ( 8a , IC₅₀ = 0.48 ± 0.02 μm ; 8e , IC₅₀ = 0.94 ± 0.01 μm ); compounds 8b and 8d were more potent on HCT116 (IC₅₀ = 3.39 ± 0.06 and 3.29 ± 0.03 μm ), HepG2 (IC₅₀ = 1.05 ± 0.03 and 5.37 ± 0.08 μm ), and SW620 (IC₅₀ = 1.33 ± 0.02 and 4.11 ± 0.05 μm ) cell lines, and 8c exhibited higher activities on HepG2 cells with an IC₅₀ = 4.76 ± 0.14 μm . NO‐releasing experiment of compounds 8a – e , 17a , 18a , 19a , and 21a reminded us that NO‐releasing amount of this series of isosteviol derivatives positively correlates with their cytotoxic activities.     

2-(2′-Pyridyl) benzimidazole derivatives and their urease inhibitory activity

Pyridyl-benzimidazole analogues 1–11 with variable substituent on phenyl ring of phenacyl moiety were synthesized and evaluated for their urease inhibitory activity. The compounds exhibited urease inhibition with IC₅₀ between 19.22 and 77.31 µM. Compounds 4 (IC₅₀ = 19.22 ± 0.49 µM) showed a urease inhibition comparable to thiourea (IC₅₀ = 21.00 ± 0.01 µM) and twofold more active than acetohydroxamic acid (IC₅₀ = 42.00 ± 1.26 µM) (standards), respectively. Moreover, compounds 5 (IC₅₀ = 21.55 ± 0.36 µM), 1 (IC₅₀ = 24.37 ± 0.41 µM), 7 (IC₅₀ = 25.44 ± 0.19 µM), 6 (IC₅₀ = 27.62 ± 0.25 µM), 3 (IC₅₀ = 31.32 ± 0.75 µM), 8 (40.88 ± 0.36 µM) and 9 (41.22 ± 0.42 µM) also exhibited excellent activities when compared to the standards. Compounds 2 (IC₅₀ = 65.46 ± 0.75 µM), 10 (68.99 ± 0.33 µM) and 11 (77.31 ± 0.51 µM) showed a moderate activity. The size of the substituents and their electron donating or withdrawing affects as well as their position on phenyl apparently modulates the enzyme inhibitory activity.     

Unsymmetrical 1,3-disubstituted urea derivatives as α-chymotrypsin inhibitors

The objective of this study was to synthesize potent and/or novel inhibitors for α-chymotrypsin activity. Eighteen derivatives of N-methylphenyl-N′-(alkyl/aryl) urea (1–18) were synthesized, and their inhibitory effects on α-chymotrypsin enzyme were evaluated. Two compounds exhibited potent inhibitory activities. The most potent, N-(2-methylphenyl)-2-oxo-1-pyrrolidinecarboxamide (15) having a methyl group at ortho position was the most active inhibitor with an IC₅₀ value of 8.10 ± 0.14 μM, which was comparable to standard chymostatin (IC₅₀ = 8.24 ± 0.11 μM). A slightly less potent, N-(2-acetylphenyl)-N′-(3-methylphenyl) urea (10), exhibited an IC₅₀ of 13.6 ± 0.23 μM. Compounds 3, 4, 7, 11, and 13 exhibited moderate activities. The results demonstrated that α-chymotrypsin inhibition is related to the position of the methyl group and the presence of substituent at the nitrogen of the urea bridge. The inhibitory trend suggests that α-chymotrypsin inhibitory activity declines with ortho > meta > para substitution order. In conclusion, our data suggest that the compound 15 may serve as a lead compound for further designing of other potent or novel α-chymotrypsin inhibitors.     

Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC₅₀ = 5.31 ± 1.2 μmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^?/? mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.     

Synthesis and antiviral activities of a novel class of thioflavone and flavonoid analogues

A novel class of thioflavone and flavonoid derivatives has been prepared and their antiviral activities against enterovirus 71 (EV71) and the coxsackievirus B3 (CVB3) and B6 (CVB6) were evaluated. Compounds 7d and 9b showed potent antiviral activities against EV71 with IC₅₀ values of 8.27 and 5.48 μM, respectively. Compound 7f, which has been synthesized for the first time in this work, showed the highest level of inhibitory activity against both CVB3 and CVB6 with an IC₅₀ value of 0.62 and 0.87 μM. Compounds 4b, 7a, 9c and 9e also showed strong inhibitory activities against both the CVB3 and CVB6 at low concentrations (IC₅₀=1.42?7.15 μM), whereas compounds 4d, 7c, 7e and 7g showed strong activity against CVB6 (IC₅₀=2.91–3.77 μM) together with low levels of activity against CVB3. Compound 7d exhibited stronger inhibitory activity against CVB3 (IC₅₀=6.44 μM) than CVB6 (IC₅₀>8.29 μM). The thioflavone derivatives 7a, 7c, 7d, 7e, 7f and 7g, represent a new class of lead compounds for the development of novel antiviral agents.     

Synthesis and Biological Evaluation of Heterocyclic Carboxylic Acyl Shikonin Derivatives

A series of shikonin derivatives ( 1 – 13 ) that were acylated selectively by various thiophene or indol carboxylic acids at the side chain of shikonin were synthesized, and their biological activities were also evaluated as potential tubulin inhibitors. Among them, compound 3 ((R)‐1‐(5,8‐dihydroxy‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐4‐methylpent‐3‐enyl 3‐(1H‐indol‐3‐yl)propanoate) and compound 8 ((R)‐1‐(5,8‐dihydroxy‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐4‐methylpent‐3‐enyl 2‐(thiophen‐3‐yl)acetate) exhibited good antiproliferative activity of A875 (IC₅₀ = 0.005 ± 0.001 μm , 0.009  ± 0.002 μm ) and HeLa (IC₅₀ = 11.84 ± 0.64 μm , 4.62  ± 0.31 μm ) cancer cell lines in vitro, respectively. Shikonin (IC₅₀ = 0.46 ± 0.002 μm , 4.80 ± 0.48 μm ) and colchicine (IC₅₀ = 0.75 ± 0.05 μm , 17.79 ± 0.76 μm ) were used as references. Meanwhile, they also showed the most potent growth inhibitory activity against tubulin (IC₅₀ of 3.96  ± 0.13 μm and 3.05 ± 0.30 μm , respectively), which were compared with shikonin (IC₅₀ =  15.20 ± 0.25 μm ) and colchicine (IC₅₀ = 3.50 ± 0.35 μm ). Furthermore, from the results of flow cytometer, we found compound 3 can really inhibit HeLa cell proliferation and has low cell toxicity. Based on the preliminary results, compound 3 with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

Bioactivity and molecular docking of lactones isolated from Centaurea pseudosinaica Czerep

Two cytotoxic sesquiterpene lactones, 17-epichlorohyssopifolin A (1) and chlorjanerin (2), and a monoterpene lactone, loliolide (3) were isolated from Centaurea pseudosinaica. The cytotoxicity of the total extract and terpenoids 1–3 were evaluated against three human cancer cells (HepG2, PC-3, and HT-29), along with the human normal primary epidermal keratinocytes (HEKa) cells. With IC₅₀ values ranging between 0.6 ± 0.04 and 5.0 ± 0.61 μg/mL against HepG2; 0.2 ± 0.01 and 11.9 ± 1.31 μg/mL against PC-3, and 0.04 ± 0.013 and 8.9 ± 0.97 μg/mL against HT-29, the total extract, and lactones 1–3 demonstrated cytotoxic effects. Compound 1 displayed the strongest impact on all cancer cells and a slightly safe effect on the normal cells HEKa. Compound 1 caused accumulation of HepG2 and HT-29 cells in G1 phase as displayed cell cycle analysis. On the other hand, the cell distributions were increased in the S phase in PC-3 cells. Furthermore, 1 caused apoptosis in PC-3 and HePG2 cells with 91.50%, and 79.72 %, respectively. A higher fraction of necrotic cells was observed in HT-29 cells amounting to 23.60%. These results suggested that the promising cytotoxicity exhibited by 1 is brought by the apoptosis induction in the cancer cells, which were evaluated. As the compounds showed antiproliferative effect against the HT-29 cells, the docking simulation was performed aiming at determining how they would interact with the EGFR enzyme, whose PDB: 4I23 is considered one of the two distinct wild types of EGFR enzymes. The antibacterial activity results revealed that 3 showed the most remarkable antibacterial effects, especially against the examined Gram-positive bacteria. The total extract exhibited potent activity against all examined bacteria. The total extract showed a potent antifungal effect against two Candida and two Aspergillus pathogens. The antioxidant activity revealed the potency of the total extract and 3 as antioxidant candidates. The obtained results refer to the importance of Centaurea pseudosinaica as a source of potent antiproliferative agents and the whole plant as an antipathogenic and antioxidant agent.     

Extending the scope of amantadine drug by incorporation of phenolic azo Schiff bases as potent selective inhibitors of carbonic anhydrase II,drug‐likeness and binding analysis

A series of Amantadine‐based azo Schiff base dyes 6a–6e have been synthesized and characterized by ¹H NMR and ¹³C NMR and evaluated for their in vitro carbonic anhydrase II inhibition activity and antioxidant activity. All of the synthesized showed excellent carbonic inhibition. Compound 6b was found to be the most potent derivative in the series, and the IC₅₀ of 6b was found to be 0.0849 ± 0.00245 μm (standard Acetazolamide IC₅₀ = 0.9975 ± 0.049 μm ). The binding interactions of the most active analogs were confirmed through molecular docking studies. Docking studies showed 6b is interacting by making two hydrogen bonds w at His93 and Ser1 residues, respectively. All compounds showed a good drug score and followed Lipinski's rule. In summary, our studies have shown that these amantadine‐derived phenolic azo Schiff base derivatives are a new class of carbonic anhydrase II inhibitors.     

Withametelin: a biologically active withanolide in cancer,inflammation, pain and depression

Withanolides are natural medicinal agents whose safety and therapeutic profiles make them valuable to mankind. Among multiple withanolides, withametelin is underexplored. The present study was aimed to create a general biological profile of isolated withametelin from Datura innoxia Mill. targeting different biological models. In-silico studies include drug-likeliness, pharmacokinetics, toxicity, molecular targets and cytotoxicity to cancer cell lines predictions. In silico directed preliminary in-vitro evaluation comprised of cancer/normal cell cytotoxicity, DPPH and protein kinase inhibition assays while in-vivo bioactivities include antiinflammatory, analgesic, antidepressant and anticoagulant assays. Pharmacological findings were strengthened by molecular docking studies to check interactions with various proteins and to propose the future path of studies. Results indicated compliance with Lipinski drug-likeliness rule (score −0.55). ADMET prediction showed strong plasma protein binding, GI absorption (Caco-2 cells permeability = 46.74 nm/s), blood brain barrier penetration (Cbrain/Cblood = 0.31), efflux by P-glycoprotein, metabolism by CYP1A2, CYP2C19 and CYP3A4, medium hERG inhibition and non-carcinogenicity in rodents. Predicted molecular targets included mainly receptors (glucocorticoid, kappa opioid, delta opioid, adrenergic and dopamine), oxidoreductase (arachidonate 5-lipoxygenase and cyclooxygenase-2), enzymes (HMG-CoA reductase) and kinase (NFκb). Withametelin was more cytotoxic to cancer cells (DU145 IC₅₀ 7.67 ± 0.54 µM) than normal lymphocytes (IC₅₀ 33.55 ± 1.31 µM). It also showed good antioxidant and protein kinase inhibition potentials. Furthermore, withametelin (20 mg/kg) significantly reduced inflammatory paw edema (68.94 ± 5.55%), heat-induced pain (78.94 ± 6.87%) and immobility time (50%) in animals. Molecular docking showed hydrogen bonding interactions (binding energies: −11.3 to −7.8 kcal/mol) with arachidonate 5 lipoxygenase, NFκb and glucocorticoid receptor. Withametelin has potential for advance investigations for its cytotoxic, anti-inflammatory, analgesic and antidepressant activities.     

Inhibition of Acetylcholinesterase (AChE): A Potential Therapeutic Target to Treat Alzheimer's Disease

A new series of icariin derivatives were synthesized and evaluated for their in vitro acetylcholinesterase (AChE) inhibitory activity. Most of the tested compounds exhibited high AChE inhibition and low toxicity, and among which compounds 1 , 2 , and 10 were the most potent (IC₅₀ = 71.52 ± 22.43, 8.28 ± 1.45, 5.830 ± 1.78 nm , respectively).