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.     

Docking study, in vitro anticancer screening and radiosensitizing evaluation of some new fluorine-containing quinoline and pyrimidoquinoline derivatives bearing a sulfonamide moiety

The present work reports the synthesis of 20 novel fluorine-containing quinoline and pyrimido[4,5-b]quinoline derivatives bearing a sulfonamide moiety. The new synthesized compounds were designed in compliance with the general pharmacophoric requirements for carbonic anhydrase (CA) inhibiting anticancer drugs, as this may play a role in their anticancer activity. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 11 and 12 exhibited better activities than the reference drug doxorubicin (IC₅₀ = 71.8 μM) with IC₅₀ values of 52.6 μM and 67.3 μM, respectively. On the other hand, compounds 6, 10, and 13 showed IC₅₀ values (71.8 μM, 69.8 μM, and 70.8 μM, respectively) comparable to that of the reference drug doxorubicin. In addition, docking of the synthesized compounds into human carbonic anhydrase isozyme II (hCA II) active site was performed in order to predict the affinity and the orientation of these compounds at the isozyme active site. Also, the most active compounds, 11 and 12, were selected and evaluated for their ability to enhance the cell killing effect of γ-radiation.     

Syntheses,Cholinesterases Inhibition,and Molecular Docking Studies of Pyrido[2,3‐b]pyrazine Derivatives

Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3‐b]pyrazines ( 6a ‐ 6q ) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3‐b]pyrazines showed 3‐(3′‐nitrophenyl)pyrido[2,3‐b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC₅₀ values of 0.466 ± 0.121 and 1.89 ± 0.05 μm , respectively. The analogues 3‐(3′‐methylphenyl)pyrido[2,3‐b]pyrazine 6c and 3‐(3′‐fluorophenyl)pyrido[2,3‐b]pyrazine 6f were found to be selective inhibition for BChE with IC₅₀ values of 0.583 ± 0.052 μm and AChE with IC₅₀ value of 0.899 ± 0.10 μm , respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors.     

Synthesis,biological evaluation,and molecular docking studies of new pyrazol‐3‐one derivatives with aromatase inhibition activities

A new series derived from 4‐(2‐chloroacetyl)‐1,2‐dihydro‐1,5‐dimethyl‐2‐phenyl‐3H‐pyrazol‐3‐one was synthesized, characterized and its pharmacological activity toward aromatase enzyme inhibition was screened and compared to the reference native ligand letrozole. The most active compound of the series was 16 , showing IC₅₀ value of 0.0023 ± 0.0002 μm compared to letrozole with IC₅₀ of 0.0028 ± 0.0006 μm . In addition, compounds 26 and 36 exhibit good inhibition activities close to letrozole with IC₅₀ values 0.0033 ± 0.0001 and 0.0032 ± 0.0003 μm , respectively. Moreover, molecular docking studies were conducted to support the findings.     

Synthesis,characterization, and biological studies of chalcone derivatives containing Schiff bases: Synthetic derivatives for the treatment of epilepsy and Alzheimer's disease

In this study, first, Schiff base-containing chalcone derivatives were synthesized. The human carbonic anhydrase (hCA) isoenzymes I and II were then purified from human erythrocytes using Sepharose-4B-l -tyrosine-sulfanilamide affinity chromatography. In addition, the inhibitory effects of the newly synthesized compounds on the activities of hCA and acetylcholinesterase (AChE) were investigated in vitro, using the esterase and acetylcholine iodide method. The IC₅₀ values were determined and the K_i values of AChE and hCA activities were calculated from the Lineweaver–Burk graphs determined in this study. The hCA I isoform was inhibited by these chalcone derivatives containing Schiff bases ( 3a–j and 5a–f ) in low nanomolar levels, whose K_i values ranged between 141.88 ± 24.10 and 2,234.47 ± 38.11 nM. Against the physiologically dominant isoform hCA II, the compounds demonstrated K_i values varying from 199.31 ± 40.45 to 602.79 ± 263.22 nM. Also, these compounds effectively inhibited AChE, with K_i values ranging from 20.41 ± 6.04 to 125.94 ± 23.88 nM. According to these results, the newly synthesized molecules were found to be potent inhibitors of these enzymes.     

Potential antioxidant,anticholinergic, antidiabetic and antiglaucoma activities and molecular docking of spiraeoside as a secondary metabolite of onion (Allium cepa)

Onion contains many dietary and bioactive components including phenolics and flavonoids. Spiraeoside (quercetin-4-O-β-D-glucoside) is one of the most putative flavonoids in onion. Several antioxidant techniques were used in this investigation to assess the antioxidant capabilities of spiraeoside, including 1,1-diphenyl-2-picrylhydrazyl radical (DPPH·) scavenging, N,N-dimethyl-p-phenylenediamine radical (DMPD^•+) scavenging, 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS^•+) scavenging activities, cupric ions (Cu²⁺) reducing and potassium ferric cyanide reduction abilities. In contrast, the water-soluble α-tocopherol analogue trolox and the conventional antioxidants butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), and α-tocopherol were utilized as the standards for evaluation. Spiraeoside scavenged the DPPH radicals an IC₅₀ of 28.51 μg/mL (r²: 0.9705) meanwhile BHA, BHT, trolox, and α-tocopherol displayed IC₅₀ of 10.10 μg/mL (r²: 0.9015), 25.95 μg/mL (r²: 0.9221), 7.059 μg/mL (r²: 0.9614) and 11.31 μg/mL (r²: 0.9642), accordingly. The results exhibited that spiraeoside had effects similar to BHT, but less potent than α-tocopherol, trolox and BHA. Also, inhibitory effects of spiraeoside were evaluated toward some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase II (CA II) and α-glycosidase, which are related to a number of illnesses, such as Alzheimer’s disease (AD), diabetes mellitus and glaucoma disorder. Spiraeoside exhibited IC₅₀ values of 4.44 nM (r²: 0.9610), 7.88 nM (r²: 0.9784), 19.42 nM (r²: 0.9673) and 29.17 mM (r²: 0.9209), respectively against these enzymes. Enzyme inhibition abilities were compared to clinical used inhibitors including acetazolamide (for CA II), tacrine (for AChE and BChE) and acarbose (for α-glycosidase). Spiraeoside demonstrated effective antioxidant, anticholinergic, antidiabetic and antiglaucoma activities. With these properties, it has shown that Spiraeoside has the potential to be a medicine for some metabolic diseases.     

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.     

Identification of non-alkaloid natural compounds of Angelica purpurascens (Avé-Lall.) Gilli. (Apiaceae) with cholinesterase and carbonic anhydrase inhibition potential

In current study is done antioxidant, anticholinesterase, and carbonic anhydrase isoenzymes I and II inhibition assays, screening of biological active compounds and electronic microscopy analysis of secretory canals of fruits, flowers, roots, and aerial parts extracts and essential oils of Angelica purpurascens. Phenolic constituents, antioxidant, and anti-lipid peroxidation potentials of variants were estimated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and thiobarbituric acid (TBA) processes. Cholinesterase inhibition effect was detected through Ellman’s method. The GC/ Mass Spectrometry (MS) and gas chromatography (GC)-flame Ionization Detector (FID) was used for essential oils analysis. NMR techniques was used for identification of the isolated compounds. The fruit hexane and dichloromethane fractions exhibited a greater antioxidant capacity and total phenolic content. The dichloromethane fraction of fruit demonstrated the most higher acetylcholinesterase inhibition (39.86 ± 2.63%), while the fruit hexane fraction displayed the best inhibition towards butyrylcholinesterase (84.02 ± 1.28%). Cytosolic isoenzymes of human carbonic anhydrase (hCA) I, and II isoenzymes were influentially suppressed by flower and fruit dichloromethane fractions with 1.650 and 2.020 µM IC₅₀ values, respectively. The electronic microscopy analysis of secretory canals found that the small number of secretory canals were at leaf while the largest shape of secretory canals was at the fruit. The secretory canals of roots, aerial parts, and fruits include more monoterpene hydrocarbons, while the canals, existing in the flowers are qualified by a higher presence of sesquiterpenes β-caryophyllene (12.1%), germacrene D (4.5%) and ether octyl acetate (11.9%). The highest level of monoterpene β-phellandrene (47.6%) and limonene (8.2%) were found in the fruit essential oil. The next isolated compounds from fruits of A. purpurascens like stigmasterol, β-sitosterol, bergapten, and oxypeucedanin have shown high anticholinesterase and antioxidant activities.     

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.     

Effects of Novel Diarylpentanoid Analogues of Curcumin on Secretory Phospholipase A2, Cyclooxygenases,Lipo‐oxygenase,and Microsomal Prostaglandin E Synthase‐1

Arachidonic acid and its metabolites have generated a heightened interest due to their significant role in inflammation. Inhibiting the enzymes involved in arachidonic acid metabolism has been considered as the synergistic anti‐inflammatory effect. A series of novel curcumin diarylpentanoid analogues were synthesized and evaluated for their inhibitory effects on activity of secretory phospholipase A₂, cyclooxygenases, soybean lipo‐oxygenase as well as microsomal prostaglandin E synthase‐1. Among the curcumin analogues, compounds 3 , 6 , 9 , 12, and 17 exhibited strong inhibition of secretory phospholipase A₂ activity, with IC₅₀ values ranging from 5.89 to 11.02 μm . Seven curcumin analogues 1 , 3 , 6 , 7 , 9 , 11, and 12 showed inhibition of cyclooxygenases‐2 with IC₅₀ values in the range of 46.11 to 94.86 μm , which were lower than that of curcumin. Compounds 3 , 6 , 7 , 12, and 17 showed strong inhibition of lipo‐oxygenase enzyme activity. Preliminary screening of diarylpentanoid curcumin analogues for microsomal prostaglandin E synthase‐1 activity revealed that four diarylpentanoid curcumin analogues 5 , 6 , 7 , and 13 demonstrated higher inhibition of microsomal prostaglandin E synthase‐1 activity with IC₅₀ ranging from 2.41 to 4.48 μm , which was less than that of curcumin. The present results suggest that some of these diarylpentanoid analogues were able to inhibit the activity of these enzymes. This raises the possibility that diarylpentanoid analogues of curcumin might serve as useful starting point for the design of improved anti‐inflammatory agents.     

Synthesis and Evaluation of Salicylanilide Derivatives as Potential Epidermal Growth Factor Receptor Inhibitors

Two series of novel salicylanilide were synthesized as potential epidermal growth factor receptor (EGFR) inhibitors. The enzyme inhibitory activity against EGFR of all compounds was carried out, and their antiproliferative activities against the A549 and A431 cell lines were also evaluated. Of the compounds studied, majority of them exhibited high antiproliferative activities compared with gefitinib; especially, 12a and 12b exhibited stronger inhibitory activity against EGFR with IC₅₀ values of 10.4 ± 2.25 and 15.4 ± 2.33 nm , respectively, which were comparable to the positive control of gefitinib (IC₅₀ = 12.1 ± 2.21 nm ). Compound 12b also showed outstanding inhibitory activity against A431 and A549 cell lines with the IC₅₀ values of 0.42 ± 0.43 μm and 0.57 ± 0.43 μm , which was better than the positive controls. In the molecular modeling study, compound 12b was bound into the active pocket of EGFR with two hydrogen bond and with minimum binding free energy ▵G_b = −25.1125 kcal/mol. The result also suggested that compound 12b could bind the EGFR kinase well.     

N‐substituted hydroxynaphthalene imino‐oxindole derivatives as new class of PI3‐kinase inhibitor and breast cancer drug: Molecular validation and structure–activity relationship studies

N‐substituted hydroxynaphthalene imino‐oxindole derivatives ( 5a–g ) were emerged as the inhibitors of the phosphoinositide 3‐kinase (PI3K), which is a crucial regulator of apoptosis or programmed cell death. Electron donor‐/acceptor‐substituted indole‐imine ( 5a–g ) was achieved, and the structures were elucidated by FTIR, 1H NMR, 13C NMR and HRMS. Inhibition potency of PI3Ks was assessed by competitive ELISA. Subsequently, an anticancer activity against breast cancer (MCF‐7) cell lines was evaluated. In both activities, compounds 5c , 5d and 5f showed most potent activities. Percentage inhibition for anticancer activity was 78.22 ± 1.02 ( 5c ) and 78.98 ± 1.08 ( 5f ), and the IC₅₀ was 2.02 ± 0.92 μm ( 5c ) and 1.98 ± 0.18 μm ( 5f ). Compounds 5a and 5g were found inactive for both activities, and rest all showed a moderate activity. To get more insight into the binding mode and inhibitor binding affinity, 5a–g were docked into the active site of PI3Ks p110α (PDB ID: 2ENQ). Results suggested that the hydrophobic interactions in the binding pockets of PI3Ks conquered affinity of the most favourable binding ligands ( 5c and 5f : inhibitory constant (k_i) = 102.4 and 128.23 nm ). The SAR studies demonstrate the efficiency of 5a–g as the PI3Ks precise inhibitors with the impending to treat various cancers.     

Synthesis and Biological Evaluation of Novel Ursolic acid Derivatives as Potential Anticancer Prodrugs

Ursolic acid ( UA ) is a natural product which has been shown to possess a wide range of pharmacological activities, in particular those with anticancer activity. In this study, 13 novel ursolic acid derivatives were designed and synthesized in an attempt to further improve compound potency. The structures of the newly synthesized compounds were confirmed using mass spectrometry, infrared spectroscopy, and ¹H NMR. The ability of the UA derivatives to inhibit cell growth was assayed against both various tumor cell lines and a non‐pathogenic cell line, HELF. Analysis of theoretical toxicity risks for all derivatives was performed using OSIRIS and indicated that the majority of compounds would present moderate to low risks. Pharmacological results indicated that the majority of the derivatives were more potent growth inhibitors than UA . In particular, 5b demonstrated IC₅₀ values ranging from 4.09 ± 0.27 to 7.78 ± 0.43  μ m against 12 different tumor cell lines. Flow cytometry analysis indicated that 5b induced G0/G1 arrest in three of these cell lines. These results were validated by structural docking studies, which confirmed that UA could bind to cyclins D1 (Cyc D1) and cyclin‐dependent kinases (CDK6), the key regulators of G0/G1 transition in cell cycle, while the piperazine moiety of 5b could bind with glucokinase (GK), glucose transporter 1 (GLUT1), and ATPase, which are the main proteins involved in cancer cell metabolism. Acridine orange/ethidium bromide staining confirmed that 5b was capable of inducing apoptosis and decreasing cell viability in a dose‐dependent manner.     

Synthesis, characterization, in vitro anticancer activity, and docking of Schiff bases of 4-amino-1,2-naphthoquinone

A series of Schiff bases of 4-amino-1,2-naphthoquinone were synthesized, purified, characterized, and evaluated for cytotoxicity against a panel of human cancer cell lines (Hep-G₂, MG-63, and MCF-7). The cells were dosed with these Schiff bases at varying concentrations, and cell viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Significant anticancer activities were observed in vitro for some members of the series and compounds 4-(3,4,5-trimethoxybenzylideneamino)naphthalene-1,2-dione (S10) as well as 4-(4-hydroxy-3-methoxybenzylideneamino)naphthalene-1,2-dione (S13) are active cytotoxic agents against different cancer cell lines with IC₅₀ values in the range of 5.91–9.98 μM. The structures of synthesized compounds were established by spectroscopic (FT-IR, ¹H NMR, ¹³C NMR) and elemental analysis. To study the molecular basis of interaction and affinity of binding of the target molecules, all the compounds were docked into the ATPase domain of Topoisomerase-II (TP-II) by using Schrödinger molecular modeling software package. Docking experiments showed a good correlation between their predicted glide scores and the observed IC₅₀ values of synthesized compounds. Structure–activity relationships indicated that presence of electron donating groups on phenyl ring of Schiff bases enhances the activity but Schiff base with electron withdrawing substituents on phenyl ring shows diminished activity.     

Design, synthesis, molecular modeling, and biological evaluation of sulfanilamide-imines derivatives as potential anticancer agents

A series of sulfanilamide Schiff base derivatives (1 to 15) have been designed as potential antitubulin agents depending on the chemical structures of combretastatine A-4 and isoquinoline sulfamate (antimitotic agents under investigation). The designed compounds were synthesized by microwave chemical synthesis, their purity was confirmed by melting point and HPLC and chemical structures were determined by FT-IR, UV, and ¹H and ¹³C-NMR spectroscopic techniques. The synthesized compounds have been docked in the colchicine binding site of β-tubulin using molecular modeling programs and the antitumor activities were screened on human breast and lung cancer cells by cell counting assay. Some tested compounds showed potent and selective activity against breast cancer (MCF-7) with IC₅₀ range of 90 to 166 μM. With regarding broad-spectrum activity, compounds 4, 8, and 13 have shown potent antitumor activity against human breast and human lung cells with IC₅₀ range of 96 to 140 μM. The obtained results suggest that the sulfanilamide Schiff base derivatives might potentially constitute an interesting novel class of anticancer agents, which deserve further studies.     

New halogenated chalcones with cytotoxic and carbonic anhydrase inhibitory properties: 6-(3-Halogenated phenyl-2-propen-1-oyl)-2(3H)-benzoxazolones

In this study, novel halogenated chalcones, 6-(3-halogenated phenyl-2-propen-1-one)-2(3H)-benzoxazolones ( 2a – n ), were synthesized for the first time (except 2a ), and their chemical structures were characterized by ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and high-resolution mass spectrometry spectra. Cytotoxic activities and carbonic anhydrase (CA) inhibitory effects of the compounds were studied to identify new possible drug candidate molecules. Cytotoxicity results pointed out that compound 2m , 6-[3-(3-bromophenyl)-2-propenoyl]-2(3H)-benzoxazolone, had the highest cytotoxicity (CC₅₀) and potency selectivity expression (PSE) values. Thus, compound 2m can be considered as a lead compound of the series in terms of cytotoxicity. When the CA inhibition results of the compounds were evaluated, it was found that the K_i values of the compounds ranged from 30.5 ± 11.3 to 65.5 ± 25.6 µM toward hCA I, and they ranged from 7.3 ± 1.8 to 58.8 ± 12.3 µM toward hCA II. However, the K_i values of the reference drug, acetazolamide (AZA), were 30.2 ± 7.8 and 4.4 ± 0.6 μM toward hCA I and hCA II, respectively. According to the results obtained, compounds 2a – n had lower K_i values than AZA, whereas compounds 2a , 2b , 2e – g , 2l , and 2n had similar K_i values, compared with AZA. So, the compounds 2a , 2b , 2e – g , 2l , and 2n can be considered as lead molecules of this series for further considerations.     

Structure–activity relationship studies of benzyl‐, phenethyl‐, and pyridyl‐substituted tetrahydroacridin‐9‐amines as multitargeting agents to treat Alzheimer's disease

A library of substituted tetrahydroacridin‐9‐amine derivatives were designed, synthesized, and evaluated as dual cholinesterase and amyloid aggregation inhibitors. Compound 8e (N‐(3,4‐dimethoxybenzyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine) was identified as a potent inhibitor of butyrylcholinesterase (BuChE IC₅₀ = 20 nm ; AChE IC₅₀ = 2.2 μm ) and was able to inhibit amyloid aggregation (40% inhibition at 25 μm ). Compounds 9e (6‐chloro‐N‐(3,4‐dimethoxybenzyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine, AChE IC₅₀ = 0.8 μm ; BuChE IC₅₀ = 1.4 μm ; Aβ‐aggregation inhibition = 75.7% inhibition at 25 μm ) and 11b (6‐chloro‐N‐(3,4‐dimethoxyphenethyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine, AChE IC₅₀ = 0.6 μm ; BuChE IC₅₀ = 1.9 μm ; Aβ‐aggregation inhibition = 85.9% inhibition at 25 μm ) were identified as the best compounds with dual cholinesterase and amyloid aggregation inhibition. The picolylamine‐substituted compound 12c (6‐chloro‐N‐(pyridin‐2‐ylmethyl)‐1,2,3,4‐tetrahydroacridin‐9‐amine) was the most potent AChE inhibitor (IC₅₀ = 90 nm ). These investigations demonstrate the utility of 3,4‐dimethoxyphenyl substituent as a novel pharmacophore possessing dual cholinesterase inhibition and anti‐Aβ‐aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease.     

Synthesis, Characterization and Biocidal Activities of Some Schiff Base Metal Complexes

Some new mixed ligand complexes (1-5) of type ML''B (M(II)=Mn(II), Co(II), Ni(II), Cu(II) and Zn(II); HL''= o-vanillidene-2-aminobenzothiazole; B= 1,10-phenanthroline) and Schiff base metal complexes of types (ML₂") (6-10) and (M₂L") (11-15) (HL"= o-vanillidene-2-amino-N-(2-pyridyl)-benzene sulfonamide) were synthesized and characterized by elemental analysis and spectral (IR, ¹H NMR and ¹³C NMR) studies. The free ligands and their metal complexes have been screened for their in vitro biological activities against bacteria, fungi and yeast. The metal complexes show more potent activities compared with Schiff base ligands.     

Synthesis,in vitro evaluation and molecular docking studies of novel coumarin‐isatin derivatives as α‐glucosidase inhibitors

This study synthesized a series of novel coumarin‐isatin derivatives and evaluated them for α‐glucosidase inhibitory activity. The majority of the screened compounds exhibited excellent inhibition activities with IC₅₀ values of 2.56 ± 0.08–268.79 ± 3.04 μm , when compared to acarbose. Among the newly derivatives, compound 5p was found to be the most active compound in the library of coumarin‐isatin derivatives. Furthermore, enzyme kinetic studies showed that compound 5p is a non‐competitive inhibitor with a K_i of 2.14 μm . Molecular docking analysis revealed the existence of hydrophobic and hydrogen interactions between compound 5p and the active site of α‐glucosidase. Our results indicate that coumarin‐isatin derivatives as a new class of α‐glucosidase inhibitors.