Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis,Biological Activity Evaluation,and Docking Studies

Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1–20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC₅₀ values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC₅₀ value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.     

Synthesis and Biological Studies of Novel Aminophosphonates and Their Metal Carbonyl Complexes (Fe,Ru)

The quest to find new inhibitors of biologically relevant targets is considered an important strategy to introduce new drug candidates for the treatment of neurodegenerative diseases. A series of (aminomethyl)benzylphosphonates 8a–c and their metallocarbonyl iron 9a–c and ruthenium 10a–c complexes were designed, synthesized, and evaluated for their inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by determination of IC₅₀. Metallocarbonyl derivatives, in general, did not show significant inhibition activity against these enzymes, the most potent inhibitor was the (aminomethyl)benzylphosphonate 8a (IC₅₀ = 1.215 µM against AChE). Molecular docking analysis of AChE and (aminomethyl)benzylphosphonates 8a–c showed the strongest interactions of 8a and AChE compared to isomers 8b and 8c. Cytotoxicity studies of synthesized compounds towards the V79 cell line were also performed and discussed.     

Synthesis of New Biscoumarin Derivatives,In Vitro Cholinesterase Inhibition,Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells

A series of novel C4-C7-tethered biscoumarin derivatives (12a–e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC₅₀ = 6.30 µM) and butyrylcholinesterase (BChE, IC₅₀ = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease.     

MAO Inhibitory Activity of 2‐Arylbenzofurans versus 3‐Arylcoumarins: Synthesis,in vitro Study,and Docking Calculations

Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3‐arylcoumarin derivatives were previously described as interesting selective MAO‐B inhibitors. Preserving the trans‐stilbene structure, a series of 2‐arylbenzofuran and corresponding 3‐arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO‐A and MAO‐B. In general, both types of derivatives were found to be selective MAO‐B inhibitors, with IC₅₀ values in the nano‐ to micromolar range. 5‐Nitro‐2‐(4‐methoxyphenyl)benzofuran ( 8 ) is the most active compound of the benzofuran series, presenting MAO‐B selectivity and reversible inhibition (IC₅₀=140 nM ). 3‐(4′‐Methoxyphenyl)‐6‐nitrocoumarin ( 15 ), with the same substitution pattern as that of compound 8 , was found to be the most active MAO‐B inhibitor of the coumarin series (IC₅₀=3 nM ). However, 3‐phenylcoumarin 14 showed activity in the same range (IC₅₀=6 nM ), is reversible, and also severalfold more selective than compound 15 . Docking experiments for the most active compounds into the MAO‐B and MAO‐A binding pockets highlighted different interactions between the derivative classes (2‐arylbenzofurans and 3‐arylcoumarins), and provided new information about the enzyme–inhibitor interaction and the potential therapeutic application of these scaffolds.     

New huprine derivatives functionalized at position 9 as highly potent acetylcholinesterase inhibitors

A series of 24 huprine derivatives diversely functionalized at position 9 have been synthesized and evaluated for their inhibitory activity against human recombinant acetylcholinesterase (AChE). These derivatives were prepared in one to five steps from huprine 1 bearing an ester function at position 9. Ten analogues ( 1 , 2 , 6 – 9 , 13 – 15 , and 23 ) are active in the low nanomolar range (IC₅₀ <5 nM ), very close to the parent compound huprine X. Compounds 2 , 6 , and 7 show a very good selectivity for AChE, with AChE inhibitory activities 700–1160‐fold higher than those for butyrylcholinesterase (BChE). The inhibitory potency of these compounds decreases with the steric bulk of the substituents at position 9. According to docking simulations, small substituents fit into the acyl‐binding pocket, whereas the larger ones stick out of the active site gorge of AChE. Determination of the kinetic parameters of three of the most potent huprines ( 2 , 6 , and 7 ) showed that most of the difference in K_D is accounted by a decrease in k_on, which is correlated to the increase of the substituent size. A first in vivo evaluation has been performed in mice for the most active compound 2 (IC₅₀=1.1 nM ) and showed a rather weak toxicity (LD₅₀=40 mg kg^?1) and an ability to cross the blood–brain barrier with doses above 15 mg kg^?1.     

Flavonoids from Machilus japonica Stems and Their Inhibitory Effects on LDL Oxidation

Stems of Machilus japonica were extracted with 80% aqueous methanol (MeOH) and the concentrated extract was successively extracted with ethyl acetate (EtOAc), normal butanol (n-BuOH), and water. Six flavonoids were isolated from the EtOAc fraction: (+)-taxifolin, afzelin, (−)-epicatechin, 5,3''-di-O-methyl-(−)-epicatechin, 5,7,3''-tri-O-methyl-(−)-epicatechin, and 5,7-di-O-methyl-3'',4''-methylenedioxyflavan-3-ol. The chemical structures were identified using spectroscopic data including NMR, mass spectrometry and infrared spectroscopy. This is the first report of isolation of these six compounds from M. japonica. The compounds were evaluated for their diphenyl picryl hydrazinyl scavenging activity and inhibitory effects on low-density lipoprotein oxidation. Compounds 1 and 3–6 exhibited DPPH antioxidant activity equivalent with that of ascorbic acid, with half maximal inhibitory concentration (IC₅₀) values of 0.16, 0.21, 0.17, 0.15 and 0.07 mM, respectively. The activity of compound 1 was similar to the positive control butylated hydroxytoluene, which had an IC₅₀ value of 1.9 µM, while compounds 3 and 5 showed little activity. Compounds 1, 3, and 5 exhibited LDL antioxidant activity with IC₅₀ values of 2.8, 7.1, and 4.6 µM, respectively.     

In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aβ_1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a–v) were evaluated by docking simulations as inhibitors of AChE and Aβ_1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aβ_1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski’s rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aβ_1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aβ_1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB.     

Design,Synthesis, and Preliminary Biological Evaluation of Pyrrolo[3,4‐c]quinolin‐1‐one and Oxoisoindoline Derivatives as Aggrecanase Inhibitors

A small set of aggrecanase inhibitors based on the pyrrolo[3,4‐c]quinolin‐1‐one or oxoisoindoline frameworks bearing a 4‐(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS‐5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS‐5 and ADAMTS‐4. Among the compounds containing the pyrrolo[3,4‐c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS‐5 and ADAMTS‐4, with IC₅₀ values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11 . Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS‐5 and ‐4. The structure–activity relationship analysis of pyrroloquinolinone derivatives 2 a – i suggests that the carboxylate or hydroxamate groups of compounds 2 a , b play a key role in the interaction of these compounds with ADAMTS‐5 and ‐4. On the other hand, the oxoisoindoline derivatives 3 a , b lack significant ADAMTS‐4 inhibitory activity and inhibit ADAMTS‐5 showing IC₂₅ values in the micromolar range.     

Optimisation of Tetrahydroisoquinoline‐Based Chimeric Microtubule Disruptors

Tetrahydroisoquinoline (THIQ)‐based “chimeric” microtubule disruptors were optimised through modification of the N‐benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro antiproliferative activities (e.g. 15 : GI₅₀ 20 nM in DU‐145). The broad anticancer activity of these novel structures was confirmed in the NCI 60‐cell line assay, with 12 e , f displaying MGM values in the 40 nM region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15 , for example, inhibited tubulin polymerisation with an IC₅₀ of 1.8 μM , close to that of the clinical drug combretastatin A‐4, and also proved effective at blocking colchicine binding. Additionally, compound 20 b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC₅₀=1.6 μM ). Compound 12 f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development.     

Potent Alkaline Phosphatase Inhibitors,Pyrazolo-Oxothiazolidines: Synthesis,Biological Evaluation,Molecular Docking,and Kinetic Studies

To develop new alkaline phosphatase inhibitors (ALP), a series of pyrazolo-oxothiazolidine derivatives were synthesized and biologically assessed, and the results showed that all of the synthesized compounds significantly inhibited ALP. Specifically, compound 7g displayed the strongest inhibitory activity (IC₅₀ = 0.045 ± 0.004 μM), which is 116-fold more active than monopotassium phosphate (IC₅₀ = 5.242 ± 0.472 μM) as a standard reference. The most potent compound among the series (7g) was checked for its mode of binding with the enzyme and shown as non-competitively binding with the target enzyme. The antioxidant activity of these compounds was examined to investigate the radical scavenging effect. Moreover, the MTT assay method was performed to evaluate their toxic effects on the viability of MG-63 human osteosarcoma cells, and all compounds have no toxic effect on the cells at 4 μM. Computational research was also conducted to examine the binding affinity of the ligands with alkaline phosphatase, and the results revealed that all compounds showed good binding energy values within the active site of the target. Therefore, these novel pyrazolo-oxothiazolidine derivatives might be employed as promising pharmacophores for potent and selective alkaline phosphatase inhibitors.     

Access to New Cytotoxic Triterpene and Steroidal Acid-TEMPO Conjugates by Ugi Multicomponent-Reactions

Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue 6 possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC₅₀ 7.4 ± 0.7 μM) and colon cancer HT29 (IC₅₀ 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative 8 acts strongly against these two cancer cell lines (PC3: IC₅₀ 6.0 ± 1.1 μM; HT29: IC₅₀ 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue 9 was also found to be active towards HT29 with IC₅₀ 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound 8 increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound 18 was successfully achieved, since mitochondria are the major source of ROS generation.     

2,3-Dihydro-1H-cyclopenta[b]quinoline Derivatives as Acetylcholinesterase Inhibitors-Synthesis, Radiolabeling and Biodistribution

In the present study we describe the synthesis and biological assessment of new tacrine analogs in the course of inhibition of acetylcholinesterase. The obtained molecules were synthesized in a condensation reaction between activated 6-BOC-hydrazinopyridine-3-carboxylic acid and 8-aminoalkyl derivatives of 2,3-dihydro-1H-cyclopenta[b]quinoline. Activities of the newly synthesized compounds were estimated by means of Ellman's method. Compound 6h (IC(50) = 3.65 nM) was found to be most active. All obtained novel compounds present comparable activity to that of tacrine towards acetylcholinesterase (AChE) and, simultaneously, lower activity towards butyrylcholinesterase (BChE). Apart from 6a, all synthesized compounds are characterized by a higher affinity for AChE and a lower affinity for BChE in comparison with tacrine. Among all obtained molecules, compound 6h presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling showed that all compounds demonstrated a similar binding mode with AChE and interacted with catalytic and peripheral sites of AChE. Also, a biodistribution study of compound 6a radiolabeled with (99m)Tc was performed.     

Synthesis and Structure–Activity Relationship Studies of Derivatives of the Dual Aromatase–Sulfatase Inhibitor 4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate

4‐{[(4‐Cyanophenyl)(4H‐1,2,4‐triazol‐4‐yl)amino]methyl}phenyl sulfamate and its ortho‐halogenated (F, Cl, Br) derivatives are first‐generation dual aromatase and sulfatase inhibitors (DASIs). Structure–activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para‐cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC₅₀ values against aromatase and steroid sulfatase in a JEG‐3 cell preparation of 0.2 and 2.5 nM , respectively. The parent phenol of this compound inhibits aromatase with an IC₅₀ value of 0.028 nM in the same assay.     

Evaluation of Antioxidant,Antidiabetic and Anticholinesterase Activities of Smallanthus sonchifolius Landraces and Correlation with Their Phytochemical Profiles

The present study aimed to investigate the phytochemical profile of leaf methanol extracts of fourteen Smallanthus sonchifolius (yacon) landraces and their antioxidant, anticholinesterase and antidiabetic activities that could lead to the finding of more effective agents for the treatment and management of Alzheimer’s disease and diabetes. For this purpose, antioxidant activity was assessed using different tests: ferric reducing ability power (FRAP), 2,2-diphenyl-1-picryl hydrazyl (DPPH), nitric oxide (˙NO) and superoxide (O₂˙⁻) scavenging and lipid peroxidation inhibition assays. Anticholinesterase activity was investigated by quantifying the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, whereas antidiabetic activity was investigated by α-amylase and α-glucosidase inhibition tests. To understand the contribution of metabolites, phytochemical screening was also performed by high performance liquid chromatography-diode array detector (HPLC-DAD) system. Among all, methanol extract of PER09, PER04 and ECU44 landraces exhibited the highest relative antioxidant capacity index (RACI). ECU44 was found to be rich in 4,5-di-O-caffeoylquinic acid (CQA) and 3,5-di-O-CQA and displayed a good α-amylase and α-glucosidase inhibition, showing the lowest IC₅₀ values. Flavonoids, instead, seem to be involved in the AChE and BChE inhibition. The results of this study revealed that the bioactive compound content differences could be determinant for the medicinal properties of this plant especially for antioxidant and antidiabetic activities.     

3D‐QSAR‐Assisted Drug Design: Identification of a Potent Quinazoline‐Based Aurora Kinase Inhibitor

We describe the 3D‐QSAR‐assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D‐QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC₅₀ values toward Aurora kinase A ranging from 33 nM to 10.5 μM . The best 3D‐QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r²_CV=0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R²_pred=0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent‐exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC₅₀=43 nM ; HCT‐116 IC₅₀=400 nM ) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC₅₀=25 nM ; HCT‐116 IC₅₀=23 nM ). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24 , and holds potential for further development.     

Novel 2-(Adamantan-1-ylamino)Thiazol-4(5H)-One Derivatives and Their Inhibitory Activity towards 11β-HSD1—Synthesis,Molecular Docking and In Vitro Studies

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing’s syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11β-HSD1. Inhibition of 11β-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing’s syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5H)-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11β-HSD isoforms. For most of them, over 50% inhibition of 11β-HSD1 and less than 45% inhibition of 11β-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11β-HSD1 correctly reproduced the experimental IC₅₀ values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one (3i) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC₅₀ value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests.     

Novel N-Substituted 3-Aryl-4-(diethoxyphosphoryl)azetidin-2-ones as Antibiotic Enhancers and Antiviral Agents in Search for a Successful Treatment of Complex Infections

A novel series of N-substituted cis- and trans-3-aryl-4-(diethoxyphosphoryl)azetidin-2-ones were synthesized by the Kinugasa reaction of N-methyl- or N-benzyl-(diethyoxyphosphoryl)nitrone and selected aryl alkynes. Stereochemistry of diastereoisomeric adducts was established based on vicinal H3–H4 coupling constants in azetidin-2-one ring. All the obtained azetidin-2-ones were evaluated for the antiviral activity against a broad range of DNA and RNA viruses. Azetidin-2-one trans-11f showed moderate inhibitory activity against human coronavirus (229E) with EC₅₀ = 45 µM. The other isomer cis-11f was active against influenza A virus H1N1 subtype (EC₅₀ = 12 µM by visual CPE score; EC₅₀ = 8.3 µM by TMS score; MCC > 100 µM, CC₅₀ = 39.9 µM). Several azetidin-2-ones 10 and 11 were tested for their cytostatic activity toward nine cancerous cell lines and several of them appeared slightly active for Capan-1, Hap1 and HCT-116 cells values of IC₅₀ in the range 14.5–97.9 µM. Compound trans-11f was identified as adjuvant of oxacillin with significant ability to enhance the efficacy of this antibiotic toward the highly resistant S. aureus strain HEMSA 5. Docking and molecular dynamics simulations showed that enantiomer (3R,4S)-11f can be responsible for the promising activity due to the potency in displacing oxacillin at β-lactamase, thus protecting the antibiotic from undesirable biotransformation.     

Small-Molecule Inhibitors Targeting Sterol 14α-Demethylase (CYP51): Synthesis,Molecular Modelling and Evaluation Against Candida albicans

Fungal infections are a global issue affecting over 150 million people worldwide annually, with 750 000 of these caused by invasive Candida infections. Azole drugs are the frontline treatment against fungal infections; however, resistance to current azole antifungals in C. albicans poses a threat to public health. Two series of novel azole derivatives, short and extended derivatives, have been designed, synthesised and investigated for CYP51 inhibitory activity, binding affinity and minimum inhibitory concentration (MIC) against C. albicans strains. The short derivatives were more potent against the C. albicans strains (e. g., MIC 2-(4-chlorophenyl)-N-(2,4-dichlorobenzyl)-3-(1H-imidazol-1-yl)propanamide ( 5 f ) <0.03 μg/mL, N-(4-((4-chlorophenyl)sulfonamido)benzyl)-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propanamide ( 12 c ), 1 μg/mL, fluconazole 0.125 μg/mL) but both displayed comparable enzyme binding and inhibition ( 5 f K_d 62±17 nM, IC₅₀ 0.46 μM; 12 c K_d 43±18 nM, IC₅₀ 0.33 μM, fluconazole K_d 41±13 nM, IC₅₀ 0.31 μM, posaconazole K_d 43±11 nM, IC₅₀ 0.2 μM). The short series had poor selectivity for CaCYP51 over the human homologue, whereas the selectivity of the extended series, for example, compound 12 c , was higher (21.5-fold) than posaconazole (4.7-fold) based on K_d values, although posaconazole was more selective (615-fold) than 12 c (461-fold) based on IC₅₀ values. Based on inhibitory activity and selectivity profile, the extended series are the better of the two series for further development.     

N-Heterocycles Scaffolds as Quorum Sensing Inhibitors. Design,Synthesis, Biological and Docking Studies

Quorum sensing is a communication system among bacteria to sense the proper time to express their virulence factors. Quorum sensing inhibition is a therapeutic strategy to block bacterial mechanisms of virulence. The aim of this study was to synthesize and evaluate new bioisosteres of N-acyl homoserine lactones as Quorum sensing inhibitors in Chromobacterium violaceum CV026 by quantifying the specific production of violacein. Five series of compounds with different heterocyclic scaffolds were synthesized in good yields: thiazoles, 16a–c, thiazolines 17a–c, benzimidazoles 18a–c, pyridines 19a–c and imidazolines 32a–c. All 15 compounds showed activity as Quorum sensing inhibitors except 16a. Compounds 16b, 17a–c, 18a, 18c, 19c and 32b exhibited activity at concentrations of 10 µM and 100 µM, highlighting the activity of benzimidazole 18a (IC₅₀ = 36.67 µM) and 32b (IC₅₀ = 85.03 µM). Pyridine 19c displayed the best quorum sensing inhibition activity (IC₅₀ = 9.66 µM). Molecular docking simulations were conducted for all test compounds on the Chromobacterium violaceum CviR protein to gain insight into the process of quorum sensing inhibition. The in-silico data reveal that all 15 the compounds have higher affinity for the protein than the native AHL ligand (1). A strong correlation was found between the theoretical and experimental results.     

Multitarget Therapeutic Leads for Alzheimer’s Disease: Quinolizidinyl Derivatives of Bi‐ and Tricyclic Systems as Dual Inhibitors of Cholinesterases and β‐Amyloid (Aβ) Aggregation

Multitarget therapeutic leads for Alzheimer’s disease were designed on the models of compounds capable of maintaining or restoring cell protein homeostasis and of inhibiting β‐amyloid (Aβ) oligomerization. Thirty‐seven thioxanthen‐9‐one, xanthen‐9‐one, naphto‐ and anthraquinone derivatives were tested for the direct inhibition of Aβ(1–40) aggregation and for the inhibition of electric eel acetylcholinesterase (eeAChE) and horse serum butyrylcholinesterase (hsBChE). These compounds are characterized by basic side chains, mainly quinolizidinylalkyl moieties, linked to various bi‐ and tri‐cyclic (hetero)aromatic systems. With very few exceptions, these compounds displayed inhibitory activity on both AChE and BChE and on the spontaneous aggregation of β‐amyloid. In most cases, IC₅₀ values were in the low micromolar and sub‐micromolar range, but some compounds even reached nanomolar potency. The time course of amyloid aggregation in the presence of the most active derivative (IC₅₀=0.84 μM ) revealed that these compounds might act as destabilizers of mature fibrils rather than mere inhibitors of fibrillization. Many compounds inhibited one or both cholinesterases and Aβ aggregation with similar potency, a fundamental requisite for the possible development of therapeutics exhibiting a multitarget mechanism of action. The described compounds thus represent interesting leads for the development of multitarget AD therapeutics.