Synthesis and cytotoxic activity evaluation of novel imidazopyridine carbohydrazide derivatives.

Two series of novel imidazo[1,2-a]pyridine-2-carbohydrazide derivatives have been designed, synthesized, and evaluated for cytotoxic activity. Target compounds were designed in two series: aryl hydrazone derivatives that were devoid of triazole moiety (7a-e) and aryl triazole bearing group (11a-e). In vitro cytotoxicity screening was carried out using MTT assay against three human cancer cells including breast cancer (MCF-7), colon cancer (HT-29), and leukemia (K562) cell lines as well as a non-cancer cell line (Vero). Compound 7d bearing 4-bromophenyl pendant from aryl hydrazone series exhibited the highest cytotoxic potential with IC50 values of 22.6 µM and 13.4 µM against MCF-7 and HT-29 cells, respectively, while it was not toxic towards non-cancer cells up to the concentration of 100 µM. Cell cycle analysis revealed that 7d increased the number of MCF-7 cells in the G0/G1 phase and also induced apoptosis in these cells as revealed by Hoechst 33,258 staining. The molecular mechanism contributing to the anti-proliferative effect of the most potent compound was investigated in silico using Super Pred software and introduced PDGFRA as a plausible target for 7d. Molecular docking and molecular dynamic studies demonstrated Lys627 and Asp836 as key residues interacting with the active compound. Overall, 7d could serve as a suitable candidate for further modifications as a lead anticancer structure.

Novel quinazoline-1,2,3-triazole hybrids with anticancer and MET kinase targeting properties.

Oncogenic activation of receptor tyrosine kinases (RTKs) such as MET is associated with cancer initiation and progression. We designed and synthesized a new series of quinazoline derivatives bearing 1,2,3-triazole moiety as targeted anticancer agents. The MET inhibitory effect of synthesized compounds was assessed by homogeneous time-resolved fluorescence (HTRF) assay and western blot analysis. Sulforhodamine B assay was conducted to examine the antiproliferative effects of synthetic compounds against 6 cancer cell lines from different origins including MET-dependent AsPC-1, EBC-1 and MKN-45 cells and also Mia-Paca-2, HT-29 and K562 cells. The growth inhibitory effect of compounds in a three-dimensional spheroid culture was examined by acid phosphatase (APH) assay, while apoptosis induction was evaluated by Annexin V/propidium iodide method. Compound 8c bearing p-methyl benzyl moiety on the triazole ring exhibited the highest MET inhibitory capacity among tested agents that was further confirmed by western blot findings. Derivatives 8c and 8h exhibited considerable antiproliferative effects against all tested cell lines, with more inhibitory effects against MET-positive cells with IC50 values as low as 6.1 µM. These two agents also significantly suppressed cell growth in spheroid cultures and induced apoptosis in MET overexpressing AsPC-1 cells. Moreover, among a panel of 24 major oncogenic kinases, the PDGFRA kinase was identified as a target of 8c and 8h compounds. The docking study results of compounds 8c and 8h were in agreement with experimental findings. The results of the present study suggest that quinazoline derivatives bearing 1,2,3-triazole moiety may represent promising targeted anticancer agents.

Novel spiroindoline quinazolinedione derivatives as anticancer agents and potential FLT3 kinase inhibitors.

Despite considerable recent progress in therapeutic strategies, cancer still remains one of the leading causes of death. Molecularly targeted therapies, in particular those focused on blocking receptor tyrosine kinases have produced promising outcomes in recent years. In this study, a new series of spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione derivatives (5a-5l) were synthesized and evaluated as potential kinase inhibitors with anticancereffects. The anti-proliferative activity was measured by MTT assay, while the cell cycle was studied using flow cytometry. Moreover, kinase inhibition profiles of the most promising compounds were assessed against a panel of 25 oncogenic kinases. Compounds 5f,5g,5i, and 5jshowed anti-proliferative effect against EBC-1, A549, and HT-29 solid tumor models in addition to leukemia cell line K562. In particular, compound 5f, bearing 4-methylphenyl pendant on the isatin ring displayed considerable potency with IC50 values of 2.4 to 13.4 µM against cancer cells. The most potent derivatives also altered the distribution of cells in different phases of cell cycle and increased the sub-G1 phase cells in K562 cells. Moreover, kinase inhibition assays identified FLT3 kinase was as the primary targetof these derivatives. Compound 5f at 25 µM concentration showed inhibitory activities of 55% and 62% against wild-type FLT3 and its mutant, D835Y, respectively. Finally, the docking and simulation studies revealed the important interactions of compound 5f with wild type and mutant FLT3. The results of this study showed that some novel spiroindoline quinazolinedione compounds could be potential candidates for further development as novel targeted anticancer agents.

Discovery of anticancer agents with c-Met inhibitory potential by virtual and experimental screening of a chemical library.

c-Met receptor tyrosine kinase has recently emerged as an important target with therapeutic implications in pancreatic cancer. In this study, we carried out a docking virtual screening on an in-house library of 441 synthesized compounds and selected the compounds with the best interactions with the c-Met protein to be subjected to experimental tests. Ten compounds belonging to 3 different classes of chemical structures were selected for this purpose and their antiproliferative effects were studied against 4 pancreatic ductal adenocarcinoma (PDAC) cell lines including AsPC-1, Suit-2, Panc-1 and Mia-Paca-2 cells, primary PDAC cells and also c-Met amplified EBC-1 cell line by sulforhodamine-B assay. Apoptosis induction was examined by Hoechst 33258 staining and annexin V-FITC/propidium iodide flow cytometric assay. The best compound was also assayed in three-dimensional cultures of AsPC-1 cells and its c-Met inhibitory potential was studied by immunoblotting and a homogenous time resolved fluorescence (HTRF) assay. The compound with a phenanthrotriazine hydrazinyl scaffold bearing nitrophenyl pendant (PhTH) was the most active derivative, with IC50 values in the range of 5-8 µM. This compound exerted antiproliferative effect against AsPC-1 cells also in the presence of hepatocyte growth factor (HGF). PhTH induced apoptosis, dose-dependently inhibited spheroid growth, inhibited c-Met activity in cell-free HTRF assay and also inhibited the phosphorylation of c-Met and its downstream effector ERK1/2 in AsPC-1 cells. Molecular docking and dynamics simulation and MM-PBSA analysis confirmed close interactions of PhTH with c-Met kinase domain. Some of the tested compounds in this study seem to be potential c-Met inhibitors with promising activities against PDAC cells.

Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors.

The advent of novel receptor tyrosine kinase inhibitors has provided an important therapeutic tool for cancer patients. In this study, a series of quinazolinone hydrazide triazole derivatives were designed and synthesized as novel MET (c-MET) receptor tyrosine kinase inhibitors. The antiproliferative effect of the synthesized compounds was examined against EBC-1, A549, HT-29 and U-87MG cells by MTT assay. MET kinase inhibitory effect was tested by a Homogenous Time Resolved Fluorescence (HTRF) assay. The antiproliferative effect of compounds in a three-dimensional spheroid culture was studied by acid phosphatase (APH) assay, while apoptosis induction was examined by Hoechst 33258 staining. We found that compound CM9 bearing p-bromo benzyl pendant inhibited MET kinase activity at the concentrations of 10-50 µM (% Inhibition = 37.1-66.3%). Compound CM9 showed antiproliferative effect against cancer cells, in particular lung cancer cells with MET amplification (EBC-1) with an IC50 value of 8.6 µM. Moreover, this derivative inhibited cell growth in spheroid cultures in a dose-dependent manner and induced apoptosis in cancer cells. Assessment of inhibitory effect of CM9 against a panel of 18 different protein kinases demonstrated that this compound also inhibits ALK, AXL, FGFR1, FLT1 (VEGFR1) and FLT4 (VEGFR3) more than 50% at 25 µM. Finally, molecular docking and dynamics simulation corroborated the experimental findings and showed critical structural features for the interactions between CM9 and target kinases. The findings of this study present quinazolinone hydrazide triazole derivatives as kinase inhibitors with considerable anticancer effects.

Cinnamomum verum J. Presl. Bark essential oil: in vitro investigation of anti-cholinesterase, anti-BACE1, and neuroprotective activity.

BACKGROUND: Cinnamomum verum J. Presl. (Lauraceae), Myrtus communis L. (Myrtaceae), Ruta graveolens L. (Rutaaceae), Anethum graveolens L. (Apiaceae), Myristica fragrans Houtt. (Myristicaceae), and Crocus sativus L. (Iridaceae) have been recommended for improvement of memory via inhalation, in Iranian Traditional Medicine (ITM). In this respect, the essential oils (EOs) from those plants were obtained and evaluated for cholinesterase (ChE) inhibitory activity as ChE inhibitors are the available drugs in the treatment of Alzheimer's disease (AD). METHODS: EOs obtained from the plants under investigation, were evaluated for their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro based on the modified Ellman's method. The most potent EO was candidate for the investigation of its beta-secretase 1 (BACE1) inhibitory activity and neuroprotectivity. RESULTS: Among all EOs, C. verum demonstrated the most potent activity toward AChE and BChE with IC50 values of 453.7 and 184.7 µg/mL, respectively. It also showed 62.64% and 41.79% inhibition against BACE1 at the concentration of 500 and 100 mg/mL, respectively. However, it depicted no neuroprotective potential against ß-amyloid (Aß)-induced neurotoxicity in PC12 cells. Also, identification of chemical composition of C. verum EO was achieved via gas chromatography-mass spectrometry (GC-MS) analysis and the major constituent; (E)-cinnamaldehyde, was detected as 68.23%. CONCLUSION: Potent BChE inhibitory activity of C. verum EO can be considered in the development of cinnamon based dietary supplements for the management of patients with advanced AD.

Aminoimidazo[1,2-a]pyridine Bearing Different Pyrazole Moieties as the Structural Scaffold for the Development of BACE1 Inhibitor; Synthesis, Structural Characterization, in vitro and in silico Studies.

Regarding the critical role of amyloid-ß plaques in the pathogenesis of Alzheimer's disease, a series of aminoimidazo[1,2-a]pyridine derivatives were designed and synthesized as potential anti-BACE1 agents targeting the production of amyloid-ß plaques. In vitro biological results demonstrated that compounds 7b and 7f exhibited the best inhibitory potency against BACE1 with IC50 values of 22.48 ± 2.06 and 30.61 ± 3.48 µM, respectively. Also, the ligandprotein docking evaluations revealed that compounds 7b and 7f could effectively bind with the different pockets of BACE1 through different interactions with the residue of the active site. The results of current studies underline the potential role of aminoimidazo[1,2-a] pyridine-containing pyrazole derivatives for developing novel BACE1 inhibitors.

Synthesis and anti-Toxoplasma activity of indole-triazole compounds on tachyzoites of RH strain.

BACKGROUND: Conventional treatment for toxoplasmosis have severe side effects and the inability to completely eradicate the disease. Therefore, the acquisition of new anti-Toxoplasma drugs has always been of interest among researchers. In the present study, we prepare a new indole-triazole derivatives and evaluated their potential anti-parasitic activity against tachyzoites of Toxoplasma RH strain. MATERIALS AND METHODS: In this study, after synthesis of the two new compounds of indole-triazole, the effect of their different concentrations (2-1024 µg/ml) were determined on Toxoplasma tachyzoites using flow cytometry. Furthermore, tachyzoites were exposed to different concentrations of compounds (4, 16, 64, 265, 1024 µg/ml) for 1.5 h and their infectivity were evaluated in BALB/c mice. RESULTS: The flow cytometry results indicated the benzyl derivative of indole-triazole in various concentrations had a lethal effect on tachyzoites between 11.93% and 89.66%, while the naphthalene derivative had a lethality of 26.63%-66.82%. The infectivity analysis showed that the survival time of mice at concentrations of 1024 µg/ml and 512 µg/ml of benzyl derivatives was significantly increased (P = 0.008 and P = 0.016, respectively), compared to that in the negative control group. Furthermore, survival time of mice was statistically significant at the concentration of 1024 µg/ml for naphthyl derivative (P = 0.012). CONCLUSION: Findings of the current study suggested indole triazole compounds, based on their structure and enzymes targeting, have a considerable effect on tachyzoites of T. gondii RH strain and can be considered as a new anti-Toxoplasma agent.

5-Oxo-hexahydroquinoline and 5-oxo-tetrahydrocyclopentapyridine derivatives as promising antiproliferative agents with potential apoptosis-inducing capacity.

Discovery of novel anticancer agents is of crucial importance to expand the therapeutic options for cancer patients. In this study, a series of 49 5-oxo-hexahydroquinoline and 5-oxo-tetrahydrocyclopentapyridine analogs, containing different pyridine alkyl carboxylates at C3 and various aliphatic, aromatic, and heteroaromatic substitutions at the C4 position of the central core, were synthesized. The target compounds were tested for antiproliferative effect against three human cancer cell lines including MOLT-4 (acute lymphoblastic leukemia), K562 (chronic myelogenous leukemia), and MCF-7 (breast adenocarcinoma) by MTT assay, and the effect of the most potent derivatives on cell cycle was evaluated by RNase/propidium iodide (PI) flow cytometric assay. Generally, 5-oxo-hexahydroquinoline derivatives (E series) possessed superior antiproliferative activities compared to their 5-oxo-tetrahydrocyclopentapyridine counterparts (F series). 5-Oxo-hexahydroquinoline compounds bearing 2-pyridyl propyl carboxylate (group D) and 3-pyridyl propyl carboxylate (group E) were better antiproliferative agents than those bearing other pyridyl alkyl carboxylates. Five best compounds with IC50 values in the range of 9.5-22.9 µM against MOLT-4 cells were selected for cell-cycle analysis, which revealed that derivatives D5, E3, and E5 with 2,3-dichlorophenyl, 3-nitrophenyl, and 2-nitrophenyl substitutions at C4 position, respectively, may induce apoptosis in MOLT-4 cells. Molecular docking analysis, which was employed to make some predictions on the interaction of the most active derivatives with the binding site of Bcl-2 and Bcl-xL proteins, suggested that the compounds may be well accommodated within the binding sites of these anti-apoptotic proteins via hydrogen-bonding and hydrophobic interactions. The findings of this study present 5-oxo-hexahydroquinoline derivatives as antiproliferative agents with potential apoptosis-inducing ability in cancer cells.

Synthesis and evaluation of novel arylisoxazoles linked to tacrine moiety: in vitro and in vivo biological activities against Alzheimer's disease.

Alzheimer's disease (AD) is now ranked as the third leading cause of death after heart disease and cancer. There is no definite cure for AD due to the multi-factorial nature of the disease, hence, multi-target-directed ligands (MTDLs) have attracted lots of attention. In this work, focusing on the efficient cholinesterase inhibitory activity of tacrine, design and synthesis of novel arylisoxazole-tacrine analogues was developed. In vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assay confirmed high potency of the title compounds. Among them, compounds 7l and 7b demonstrated high activity toward AChE and BChE with IC50 values of 0.050 and 0.039 µM, respectively. Both compounds showed very good self-induced Aß aggregation and AChE-induced inhibitory activity (79.4 and 71.4% for compound 7l and 61.8 and 58.6% for compound 7b, respectively). Also, 7l showed good anti-BACE1 activity with IC50 value of 1.65 µM. The metal chelation test indicated the ability of compounds 7l and 7b to chelate biometals (Zn2+, Cu2+, and Fe2+). However, they showed no significant neuroprotectivity against Aß-induced damage in PC12 cells. Evaluation of in vitro hepatotoxicity revealed comparable toxicity of compounds 7l and 7b with tacrine. In vivo studies by Morris water maze (MWM) task demonstrated that compound 7l significantly reversed scopolamine-induced memory deficit in rats. Finally, molecular docking studies of compounds 7l and 7b confirmed establishment of desired interactions with the AChE, BChE, and BACE1 active sites.

Imino-2H-Chromene Based Derivatives as Potential Anti-Alzheimer's Agents: Design, Synthesis, Biological Evaluation and in Silico Study.

A new series of imino-2H-chromene derivatives were rationally designed and synthesized as novel multifunctional agents against Alzheimer's disease. A set of phenylimino-2H-chromenes as well as the newly synthesized iminochromene derivatives were evaluated as BACE1, acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) inhibitors. The results indicated that among the iminochromene set, 10c bearing fluorobenzyl moiety was the most potent BACE1 inhibitor with an IC50 value 6.31 µM. In vitro anti-cholinergic activities demonstrated that compound 10a bearing benzyl pendant was the best inhibitor of AChE (% inhibition at 30 µM=24.4) and BuChE (IC50 =3.3 µM). Kinetic analysis of compound 10a against BuChE was also performed and showed a mixed-type inhibition pattern. The neuroprotective assessment revealed that compound 11b, a phenylimino-2H-chromene derivative with hydroxyethyl moiety, provided 32.3 % protection at 25 µM against Aß-induced PC12 neuronal cell damage. In addition, docking and simulation studies of the most potent compounds against BACE1 and BuChE confirmed the experimental results.

The possible effect of microRNA-155 (miR-155) and BACE1 inhibitors in the memory of patients with down syndrome and Alzheimer's disease: Design, synthesis, virtual screening, molecular modeling and biological evaluations.

MiR-155 plays main roles in several physiological and pathological mechanisms, such as Down syndrome (DS), immunity and inflammation and potential anti-AD therapeutic target. The miR-155 is one of the overexpressed miRNAs in DS patients that contribute directly and indirectly to the onset or progression of the DS. Since the miR-155 can simultaneously reduce the translation of several genes at post-transcriptional levels, targeting the miR-155 might set the stage for the treatment of DS. One of the rational strategies in providing therapeutic interventions in this respect is to design and develop novel small molecules inhibiting the miR-155 function or biogenesis or maturation. In the present study, we aim to introduce small molecule compounds with the potential to inhibit the generation of the selectively miR-155 processing by employing computational drug design approaches, as well as in vitro studies. We designed and synthesized a novel series of imidazo[1,2-a]pyridines derivatives as new nonpeptic candidates for the treatment of DS with AD. The designed compounds were investigated for their BACE1 and miR-155 binder inhibitory potential in vitro and in cell. In addition, we present a systematic computational approach that includes 3 D modeling, docking-based virtual screening, and molecular dynamics simulation to identify Small - molecule inhibitors of pre-miR-155 maturation. To confirm the inhibitory potential of compound 8k on miR-155 maturation, qRT- PCR was performed. All our results confirm that compound 8k, in addition to being a good inhibitor of BACE1, can also be a good inhibitor of miR-155.Communicated by Ramaswamy H. Sarma.

Novel Cytotoxic Phenanthro-triazine-3-thiol Derivatives as Potential DNA Intercalators and Bcl-2 Inhibitors.

Novel phenanthro-triazine-3-thiol derivatives were designed as potential DNA intercalators and Bcl-2 inhibitors. After being synthesized, the compounds were evaluated for their cytotoxic activity against MOLT-4 (human acute lymphoblastic leukemia) and MCF-7 (human breast adenocarcinoma) cells by MTT assay. P1 (bearing hydrogen substitution) was the most potent derivative against MOLT-4 with an IC50 value of 7.1 ± 1.1 µM, whereas P11 (bearing phenyl substitution) demonstrated considerable cytotoxicity against MCF-7 with an IC50 value of 15.4 ± 2.9 µM. Compounds P7, P8, P14 and P15 exhibited moderate cytotoxic effects. Furthermore, to confirm the potential DNA intercalation and Bcl-2 inhibitory activities of phenanthro-triazine scaffolds, molecular docking analysis was performed. Molecular docking studies indicated that these compounds not only bind to DNA by intercalation mainly through stacking interactions but also are well accommodated in the active site of Bcl-2. Therefore, P1 and P11 having phenanthro-triazine-3-thiol scaffold could be presented as cytotoxic agents with dual DNA intercalation and Bcl-2 inhibitory activities.

Phenanthrotriazine Derivatives Containing Arylidine Hydrazone Moieties as Novel Potential c-Met Inhibitors with Anticancer Effect.

Cancer is the second cause of death in the world and the discovery of novel anticancer agents is of vital importance to provide better therapeutic options for cancer patients. In this study, a new series of 12 arylidene hydrazone phenanthrotriazine derivatives were designed, synthesized, and tested in-vitro for antiproliferative activity against three cancer cell lines including colorectal cancer (HT-29), breast cancer (MCF-7) and leukemia (MOLT-4) cells and also against Vero normal cells. The effect of derivatives on cell cycle and apoptosis induction were studied by flow cytometric propidium iodide/RNase assay and Hoechst 33258 staining, respectively, while docking analysis was used to investigate the interactions of synthesized derivatives with the c-Met receptor kinase domain. Some compounds showed considerable antiproliferative activity against tested cancer cells. The most potent derivative was 9k bearing pyrrole moiety with IC50 values of 14.3, 4.7 and 1.7 µM against HT-29, MCF-7 and MOLT-4 cells, respectively, while it showed negligible activity against Vero normal cells (IC50: 95.4 µM). Derivatives bearing 2-nitrophenyl (9g), 4-cyanophenyl (9j), pyrrole (9k), and thiophene (9l) moieties induced G0/G1 cell cycle arrest and also apoptosis at higher doses in MCF-7 cells. Docking study showed that the phenanthrotriazine backbone form H-bond interactions with Asn1209, while phenyl moieties of the pendants generate different hydrophobic interactions with the Asp1164 and Asp1231 residues of c-Met. In conclusion, phenanthrene 1,2,4-triazines, especially the ones with less influence on normal cells, may constitute promising compounds for the discovery of antiproliferative agents with potential c-Met inhibitory capacity.

Benzylidene-6-hydroxy-3,4-dihydronaphthalenone chalconoids as potent tyrosinase inhibitors.

BACKGROUND AND PURPOSE: Tyrosinase enzyme has a key role in melanin biosynthesis by converting tyrosine into dopaquinone. It also participates in the enzymatic browning of vegetables by polyphenol oxidation. Therefore, tyrosinase inhibitors are useful in the fields of medicine, cosmetics, and agriculture. Many tyrosinase inhibitors having drawbacks have been reported to date; so, finding new inhibitors is a great need. EXPERIMENTAL APPROACH: A variety of 6-hydroxy-3,4-dihydronaphthalenone chalcone-like analogs (C1-C10) have been synthesized by aldol condensation of 6-hydroxy tetralone and differently substituted benzaldehydes. The compounds were evaluated for their inhibitory effect on mushroom tyrosinase by a spectrophotometric method. Moreover, the inhibition manner of the most active compound was determined by Lineweaver-Burk plots. Docking study was done using AutoDock 4.2. The drug-likeness scores and ADME features of the active derivatives were also predicted. RESULTS/FINDINGS: Most of the compounds showed remarkable inhibitory activity against the tyrosinase enzyme. 6-Hydroxy-2-(3,4,5-trimethoxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one (C2) was the most potent derivative amongst the series with an IC50 value of 8.8 µM which was slightly more favorable to that of the reference kojic acid (IC50 = 9.7 µM). Inhibitory kinetic studies revealed that C2 behaves as a competitive inhibitor. According to the docking results, compound C2 formed the most stable enzyme-inhibitor complex, mainly via establishing interactions with the two copper ions in the active site. In silico drug-likeness and pharmacokinetics predictions for the proposed tyrosinase inhibitors revealed that most of the compounds including C2 have proper drug-likeness scores and pharmacokinetic properties. CONCLUSION AND IMPLICATIONS: Therefore, C2 could be suggested as a promising tyrosinase inhibitor that might be a good lead compound in medicine, cosmetics, and the food industry, and further drug development of this compound might be of great interest.

Investigation of anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L): in vitro and in vivo studies / Investigación de la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L): estudios in vitro e in vivo

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Sever cognitive and memory impairments, huge increase in the prevalence of the disease, and lacking definite cure have absorbed worldwide efforts to develop therapeutic approaches. Since many drugs have failed in the clinical trials due to multifactorial nature of AD, symptomatic treatments are still in the center attention and now, nootropic medicinal plants have been found as versatile ameliorators to reverse memory disorders. In this work, anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L.) was investigated via in vitro and in vivo studies. It depicted good amyloid ß (Aß) aggregation inhibitory activity, 82% at 100 µg/mL. In addition, it inhibited beta-secretase 1 (BACE1) with IC50 value of 19.03 µg/mL. Evaluation of neuroprotectivity of the aqueous extract of the plant against H2O2-induced cell death in PC12 neurons revealed 84.5% protection at 1 µg/mL. It should be noted that according to our results obtained from Morris Water Maze (MWM) test, the extract reversed scopolamine-induced memory deficit in rats at concentrations of 1.5 and 3 mg/kg.

La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo relacionado con la edad. Los severos deterioros cognitivos y de la memoria, el enorme aumento de la prevalencia de la enfermedad y la falta de una cura definitiva han absorbido los esfuerzos mundiales para desarrollar enfoques terapéuticos. Dado que muchos fármacos han fallado en los ensayos clínicos debido a la naturaleza multifactorial de la EA, los tratamientos sintomáticos siguen siendo el centro de atención y ahora, las plantas medicinales nootrópicas se han encontrado como mejoradores versátiles para revertir los trastornos de la memoria. En este trabajo, se investigó la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L.) mediante estudios in vitro e in vivo. Representaba una buena actividad inhibidora de la agregación de amiloide ß (Aß), 82% a 100 µg/mL. Además, inhibió la beta-secretasa 1 (BACE1) con un valor de CI50 de 19,03 µg/mL. La evaluación de la neuroprotección del extracto acuoso de la planta contra la muerte celular inducida por H2O2 en neuronas PC12 reveló una protección del 84,5% a 1 µg/mL. Cabe señalar que, de acuerdo con nuestros resultados obtenidos de la prueba Morris Water Maze (MWM), el extracto revirtió el déficit de memoria inducido por escopolamina en ratas a concentraciones de 1,5 y 3 mg/kg.

Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations.

A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of l-dopa and l-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 µM and 0.17 µM in the presence of l-tyrosine and l-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 µM for l-tyrosine and 9.30 µM for l-dopa. According to Lineweaver-Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 µM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.

Design and synthesis of new carbamates as inhibitors for fatty acid amide hydrolase and cholinesterases: Molecular dynamic, in vitro and in vivo studies.

As anandamide (N-arachidonoylethanolamine, AEA) shows neuroprotective effects, the inhibition of its degradative enzyme, fatty acid amide hydrolase (FAAH) has been considered as a hopeful avenue for the treatment of neurodegenerative diseases, like Alzheimer's disease (AD). Memory loss, cognitive impairment and diminution of the cholinergic tone, due to the dying cholinergic neurons in the basal forebrain, are common hallmarks in patients with AD. By taking advantage of cholinesterase inhibitors (ChEIs), the degradation of acetylcholine (ACh) is decreased leading to enhanced cholinergic neurotransmission in the aforementioned region and ultimately improves the clinical condition of AD patients. In this work, new carbamates were designed as inhibitors of FAAH and cholinestrases (ChEs) (acetylcholinestrase (AChE), butyrylcholinestrase (BuChE)) inspired by the structure of the native substrates, structure of active sites and the SARs of the well-known inhibitors of these enzymes. All the designed compounds were synthesized using different reactions. All the target compounds were tested for their inhibitory activity against FAAH and ChEs by employing the Cayman assay kit and Elman method respectively. Generally, compounds possessing aminomethyl phenyl linker was more potent compared to their corresponding compounds possessing piperazinyl ethyl linker. The inhibitory potential of the compounds 3a-q extended from 0.83 ± 0.03 µM (3i) to ˃100 µM (3a) for FAAH, 0.39 ± 0.02 µM (3i) to 24% inhibition in 113 ± 4.8 µM (3b) for AChE, and 1.8 ± 3.2 µM (3i) to 23.2 ± 0.2 µM (3b) for BuChE. Compound 3i a heptyl carbamate analog possessing 2-oxo-1,2-dihydroquinolin ring and aminomethyl phenyl linker showed the most inhibitory activity against three enzymes. Also, compound 3i was investigated for memory improvement using the Morris water maze test in which the compound showed better memory improvement at 10 mg/kg compared to reference drug rivastigmine at 2.5 mg/kg. Molecular docking and molecular dynamic studies of compound 3i into the enzymes displayed the possible interactions of key residues of the active sites with compound 3i. Finally, kinetic study indicated that 3i inhibits AChE through the mixed- mode mechanism and non-competitive inhibition mechanism was revealed for BuChE.

Imidazopyridine hydrazone derivatives exert antiproliferative effect on lung and pancreatic cancer cells and potentially inhibit receptor tyrosine kinases including c-Met.

Aberrant activation of c-Met signalling plays a prominent role in cancer development and progression. A series of 12 imidazo [1,2-α] pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized and evaluated for c-Met inhibitory potential and anticancer effect. The inhibitory activity of all synthesized compounds against c-Met kinase was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay at the concentration range of 5-25 µM. Derivatives 6d, 6e and 6f bearing methyl, tertiary butyl and dichloro-phenyl moieties on the triazole ring, respectively, were the compounds with the highest potential. They significantly inhibited c-Met by 55.3, 53.0 and 51.3%, respectively, at the concentration of 25 µM. Synthetic compounds showed antiproliferative effects against lung (EBC-1) and pancreatic cancer cells (AsPc-1, Suit-2 and Mia-PaCa-2) expressing different levels of c-Met, with IC50 values as low as 3.0 µM measured by sulforhodamine B assay. Active derivatives significantly blocked c-Met phosphorylation, inhibited cell growth in three-dimensional spheroid cultures and also induced apoptosis as revealed by Annexin V/propidium iodide flow cytometric assay in AsPc-1 cells. They also inhibited PDGFRA and FLT3 at 25 µM among a panel of 16 kinases. Molecular docking and dynamics simulation studies corroborated the experimental findings and revealed possible binding modes of the select derivatives with target receptor tyrosine kinases. The results of this study show that some imidazopyridine derivatives bearing 1,2,3-triazole moiety could be promising molecularly targeted anticancer agents against lung and pancreatic cancers.