Archiv der Pharmazie

Diarylpyrazole Ligated Dihydropyrimidine Hybrids as Potent Non-Classical Antifolates and Their Efficacy Against Plasmodium falciparum ()
A series of diarylpyrazole clubbed dihydropyrimidine derivatives (J1–J30) was synthesized under microwave-assisted heating conditions by employing Biginelli reaction methodology and utilizing triethylammonium acetate both as a catalyst and as reaction medium, leading towards a greener reaction pathway. The synthesized entities were screened for their antimalarial efficacy against a Plasmodium falciparum strain in vitro. The active entities (J9, J15, J21, J25, and J27) obtained out of the in vitro screening were further evaluated for their enzyme inhibitory potency against the Pf-DHFR enzyme in vitro as well as in silico using Glide. Furthermore, the active scaffolds were tested for their cytotoxicity against Vero cells, proving their nontoxic behavior and selectivity. The ADME parameters were also evaluated and predicted in silico, indicating good oral bioavailability of the compounds. Novel hybrid diarylpyrazole clubbed dihydropyrimidine motifs were synthesized under microwave irradiation using TEAA as reaction medium, and screened for their antimalarial efficacy, revealing five active scaffolds: J9, J15, J21, J25, and J27. Enzyme inhibitory studies against Pf-DHFR proved their potency as dihydrofolate reductase inhibitors. The obtained ADME parameters predicted oral bioavailability of these active molecules.
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Synthesis of Some Novel 2,6-Disubstituted Pyridazin-3(2H)-one Derivatives as Analgesic, Anti-Inflammatory, and Non-Ulcerogenic Agents ()
Some novel 2,6-disubstituted pyridazine-3(2H)-one derivatives were synthesized and evaluated for in vitro cyclooxygenase-2 (COX-2) inhibitory efficacy. Compounds 2-{[3-(2-methylphenoxy)-6-oxopyridazin-1(6H)-yl]methyl}-1H-isoindole-1,3(2H)-dione (5a), 2-propyl-6-(o-tolyloxy)pyridazin-3(2H)-one (6a), and 2-benzyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one (16a) showed the most potent COX-2 inhibitory activity with IC50 values of 0.19, 0.11, and 0.24 μM, respectively. The synthesized compounds with the highest COX-2 selectivity indices were evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities. Compounds 6a and 16a demonstrated the most potent and consistent anti-inflammatory activity over the synthesized compounds, which was significantly higher than that of celecoxib in the carrageenin rat paw edema model and with milder ulcer scoring than that of indomethacin in the ulcerogenicity screening. Novel 2,6-disubstituted pyridazine-3(2H)-one derivatives were synthesized and evaluated for their in vitro COX-2 inhibitory efficacy. The three most potent compounds showed IC50 values of 0.19, 0.11, and 0.24 μM, respectively. In addition, compounds 6a and 16a demonstrated anti-inflammatory activities higher than that of celecoxib, with milder ulcer scoring than that of indomethacin.
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New Coumarin Derivatives as Anti-Breast and Anti-Cervical Cancer Agents Targeting VEGFR-2 and p38α MAPK ()
Breast and cervical cancers are the most common gender-specific cancers affecting women worldwide. In this investigation, we highlighted the synthesis, VEGFR-2 and p38α MAPK inhibitory activity of new series of fluorinated coumarin-based derivatives featuring a variety of bioactive chemical moieties attached or fused to the coumarin nucleus at the 3 and/or 4 position. The bioactive inhibitors were further assessed for their anti-proliferative effect against human MCF-7 breast cancer and HeLa cervical cancer cell lines, respectively. Most of the tested compounds showed potent preferential inhibition effects against human VEGFR-2 and remarkable anticancer activities in the human breast cancer cell line MCF-7. Compounds 29, 24, and 2 displayed the highest inhibitory activity against VEGFR-2 (94% inhibition) and they were the most potent anticancer agents toward MCF-7 cancer cells with IC50 values of 7.90, 8.28, and 8.30 μg/mL, respectively. Compound 13 inhibited p38α MAPK phosphorylation with a significant reduction in % cell viability against HeLa cancer cells at 10 and 30 µM. Docking experiments carried out on VEGFR-2 and p38 MAPK crystallographic structures revealed that the active compounds bind to the active sites through H-bonds, arene–cation, and hydrophobic π–π interactions. QSAR analysis demonstrated considerable correlation coefficient (R2 = 0.76969) and root mean square error (RMSE = 0.10446) values. Also, the residual values between the experimental pIC50 and predicted pIC50 are very close, indicating the reliability of the established QSAR model. The VEGFR-2 and p38α MAPK inhibitory activities of new series of fluorinated coumarin-based derivatives with bioactive chemical moieties attached or fused to the coumarin nucleus at the 3 and/or 4 position are explored. Compounds 29, 24, and 2 displayed the highest inhibitory activity against VEGFR-2 (94% inhibition); they were also the most potent anticancer agents towards MCF-7 cancer cells (IC50 = 7.90, 8.28, and 8.30 μg/mL, respectively).
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Some Novel Mannich Bases of 5-(3,4-Dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one and Their Anti-Inflammatory Activity ()
Non-steroidal anti-inflammatory drugs (NSAIDs), which are widely used for the treatment of rheumatic arthritis, pain, and many different types of inflammatory disorders, cause serious gastrointestinal (GI) side effects. The free carboxylic acid group existing on their chemical structure is correlated with GI toxicity related with all routine NSAIDs. Replacing this functional group with the 1,3,4-oxadiazole bioisostere is a generally used strategy to obtain an anti-inflammatory agent devoid of GI side effects. In the present work, a novel group of 5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one Mannich bases were synthesized and characterized on the basis of IR, 1H NMR, and elemental analysis results. The target compounds were first tested for cytotoxicity to determine a non-toxic concentration for anti-inflammatory screening. Anti-inflammatory effects of the compounds were evaluated by in vitro lipopolysaccharide (LPS)-induced NO production and in vivo carrageenan footpad edema with ulcerogenic profile. In LPS-induced RAW 264.7 macrophages, most of the compounds showed inhibitory activity on nitrite production while compounds 5a, 5h, and 5j exhibited the best profiles by suppressing the NO production. To evaluate the in vivo anti-inflammatory potency of the compounds, the inflammatory response was quantified by increment in paw size in the carrageenan footpad edema assay. The anti-inflammatory data scoring showed that compounds 5a–d, 5g, and 5j, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5g was comparable to that of the reference drug indomethacin with 53.9% and 55.5% inhibition in 60 and 120 min, respectively. A series of novel 1,3,4-oxadiazole-2-one derivatives was synthesized by Mannich reaction of 5-(3,4-dichlorophenyl)-1,3,4-oxadiazole-2(3H)-one and different substituted piperidines. The synthesized compounds were tested for their in vivo and in vitro anti-inflammatory and ulcerogenic profiles. Preliminary pharmacological evaluation of the compounds showed that some of the compounds possess good to moderate anti-inflammatory activity.
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Design, Synthesis, and the Biological Evaluation of a New Series of Acyclic 1,2,3-Triazole Nucleosides ()
A new strategy for the synthesis of N3-benzoylated- and N3-benzylated N1-propargylquinazoline-2,4-diones 30a−d and 31a−d from isatoic anhydride 41 is reported. The alkynes 30a−d and 31a−d were applied in the 1,3-dipolar cycloadditions with azides 27 and 28 to synthesize acyclic 1,2,3-triazole nucleosides. The obtained alkynes and 1,2,3-triazole were evaluated for antiviral activity against a broad range of DNA and RNA viruses. The alkyne 30d showed activity against adenovirus-2 (EC50 = 8.3 μM), while compounds 37a and 37d were also active toward herpes simplex virus-1 wild-type and thymidine kinase deficient (HSV-1 TK−) strains (EC50 values in the range of 4.6–13.8 μM). In addition, compounds 30a, 30b, 37b, and 37c exhibited activity toward varicella-zoster virus (VZV) TK+ and TK− strains (EC50 = 2.1–9.5 μM). The compound 30b proved to be the most selective against VZV and displayed marginal activity against human cytomegalovirus (HCMV). Although the compound 30a had improved anti-HCMV activity, the increase in anti-HCMV activity was accompanied by significant toxicity. Compounds 37a and 37d showed inhibitory effects toward the human T lymphocyte (CEM) cell line (IC50 = 21 ± 7 and 22 ± 1 μM, respectively), while compound 35 exhibited cytostatic activity toward HMEC-1 cells (IC50 = 28 ± 2 μM). Alkyne 30a exhibited activity against adenovirus-2 (EC50 = 8.3 μM), while compounds 30a, 30b, 36b, and 36c were active toward varicella-zoster virus TK+ and TK− strains with EC50 values in the range of 2.1–9.5 μM. Compounds 36a and 36d showed activity against herpes simplex virus-1 (HSV-1 TK–) strains (EC50 = 4.6–13.8 μM) and inhibitory effects toward the human T lymphocyte (CEM) cell line (EC50 = 21 ± 7 μM and 22 ± 1 μM, respectively).
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Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models ()
A series of new pyrimidine–triazine hybrids (4a–t) was designed and synthesized, from which potent anticonvulsant agents were identified. Most of the compounds exhibited promising anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, along with minimal motor impairment with higher safety compared to the standard drugs, phenytoin and carbamazepine. In the series, 5-(4-(4-fluorophenyl)-6-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4o) and 5-(6-(4-hydroxy-3-methoxyphenyl)-4-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4s) emerged as most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED50), 285.02 and 293.42 mg/kg (scPTZ ED50), and 389.11 and 412.16 mg/kg (TD50), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABAA receptor as a possible mechanism of their anticonvulsant action, and in silico ADME studies were carried out to predict the safety and stability of the molecules. The increased GABA level in the experimental animals in the neurochemical estimation assay confirmed their GABAergic modulating activity. The most potent compounds were also evaluated for their neurotoxic and hepatotoxic effects. Fortunately, they did not show any sign of neurotoxicity or hepatotoxicity, suggesting that they have a broad spectrum of anticonvulsant activity with a large safety margin. Together, this research suggested that 4o and 4s may serve as leads in the discovery and development of new anticonvulsant drugs. A series of new pyrimidine–triazine hybrids (4a–t) was designed and synthesized, and their anticonvulsant effects were tested in comparison to the standard drugs, phenytoin and carbamazepine. Two compounds (4o and 4s) emerged as the most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED50), 285.02 and 293.42 mg/kg (scPTZ ED50), and 389.11 and 412.16 mg/kg (TD50), respectively, without showing neurotoxic and hepatotoxic effects.
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Mannich Ketones as Possible Antimycobacterial Agents ()
Twenty-three known unsaturated and fused Mannich ketones and their reduced derivatives (amino alcohols) were selected for an antituberculotic study. They were screened against several mycobacterial strains including Mycobacterium tuberculosis, M. xenopi, and M. gordonae, and minimum inhibitory concentration values were also determined using the standard antituberculotic drug isoniazid (INH) as a reference. Structure–activity relationships were also studied. The mode of action of the test compounds was investigated using transmission electron microscopy, high-performance liquid chromatography, and matrix-assisted desorption/ionization mass spectrometry. Several test substances proved to be as potent as INH, but their antimycobacterial spectra were broader than that of INH. Our findings suggest that their mode of action is probably through the inhibition of mycobacterial cell wall biosynthesis. The antimycobacterial activities of (E)-2-phenylmethylene-6-morpholin-1-ylmethyl-cyclohexanone (1), cis-(E)-2-phenylmethylene-6-morpholin-1-ylmethyl-cyclohexanol (8) and trans-(E)-2-phenylmethylene-6-morpholin-1-ylmethyl-cyclohexanol (9) are compared. Compound 1 is a ketone with a MIC value of 100 µg/mL against the standard Mycobacterium tuberculosis H37Rv strain, while the aminoalcohols 8 and 9 were more efficient (MIC: 12.5 µg/mL). The test compounds may interfere with mycolic acid biosynthesis.
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Cover Picture: Arch. Pharm. Chem. Life Sci. (8/2017) ()

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Editorial Board: Arch. Pharm. Chem. Life Sci. (8/2017) ()

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Fragment-Based Drug Discovery in the Bromodomain and Extra-Terminal Domain Family ()
Bromodomain and extra-terminal domain (BET) inhibition has emerged recently as a potential therapeutic target for the treatment of many human disorders such as atherosclerosis, inflammatory disorders, chronic obstructive pulmonary disease (COPD), some viral infections, and cancer. Since the discovery of the two potent inhibitors, I-BET762 and JQ1, different research groups have used different techniques to develop novel potent and selective inhibitors. In this review, we will be concerned with the trials that used fragment-based drug discovery (FBDD) approaches to discover or optimize BET inhibitors, also showing fragments that can be further optimized in future projects to reach novel potent BET inhibitors. The bromodomain is one of the epigenetic readers that recognizes and binds to acetylated lysine. Since the discovery of potent inhibitors for the bromodomain and extra-terminal domain (BET) family, this protein–protein interaction has been the therapeutic target for human disorders like viral infections, atherosclerosis, and cancer. Using fragments, medicinal chemists developed many selective BET inhibitors with better ligand efficiency and pharmacokinetic properties.
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Oxazolo[4,5-b]pyridine-Based Piperazinamides as GSK-3β Inhibitors with Potential for Attenuating Inflammation and Suppression of Pro-Inflammatory Mediators ()
Recent studies reveal that glycogen synthase kinase-3β (GSK-3β) acts as a pro-inflammatory enzyme, and by inhibiting this kinase, inflammation can be controlled. In this regard, a series of 17 piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was synthesized and evaluated for in vitro GSK-3β inhibitory and in vivo anti-inflammatory activity. The compounds 7d, 7e, 7g, and 7c displayed the best GSK-3β inhibitory activity among all the synthesized compounds, with corresponding IC50 values of 0.34, 0.39, 0.47, and 0.53 µM. Among the compounds 7d, 7e, 7g, and 7c examined for in vivo anti-inflammatory activity in the rat paw edema model, compound 7d exhibited maximum inhibition, reducing the paw volume by 62.79 and 65.91% at 3 and 5 h post-carrageenan administration, respectively, in comparison to indomethacin (76.74% at 3 h and 79.54% at 5 h after carrageenan administration). Furthermore, these compounds (7d, 7e, 7g, and 7c) were also found to substantially inhibit pro-inflammatory mediators, i.e., TNF-α, IL-1β, and IL-6, ex vivo in comparison to indomethacin and did not pose any gastric ulceration risk, indicating the potential of this oxazolopyridine scaffold for the development of GSK-3β inhibitors and their application as anti-inflammatory agents. A series of piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was synthesized and evaluated for in vitro glycogen synthase kinase-3β (GSK-3β) inhibitory and in vivo anti-inflammatory activity. Compounds 7d, 7e, 7g, and 7c, which displayed the best GSK-3β inhibitory activity among all the synthesized compounds, were also found to substantially inhibit pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6.
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Synthesis and Biological Evaluation of New Diarylpyrazole and Triarylimidazoline Derivatives as Selective COX-2 Inhibitors ()
New series of diarylpyrazoles 8a–f and triarylimidazoline-5-ones 11a–g were synthesized and evaluated for their in vitro cyclooxygenase-1 (COX-1) and COX-2 inhibitory activity and in vivo anti-inflammatory activity. The synthesized compounds showed good selectivity for COX-2; compounds 8a, 8d, 8f, 11a, and 11c exhibited the highest COX-2 selectivity indexes (SI = 4.77–5.43) compared to the reference drug celecoxib (SI = 7.8). All compounds showed good in vivo anti-inflammatory activity, especially compounds 8a, 8f, 11c, and 11d, which also showed some similarities to the time interval pattern of celecoxib at all different time intervals (1, 3, and 6 h). New series of diarylpyrazoles (8a–f) and triarylimidazoline-5-ones (11a–g) were synthesized and evaluated for their in vitro cyclooxygenase-1/2 (COX-1/2)-inhibitory and in vivo anti-inflammatory activities. Compounds 8a, 8d, 8f, 11a, and 11c exhibited the highest COX-2 selectivity (SI = 4.77–5.43) compared to celecoxib (SI = 7.8) and all compounds showed good in vivo anti-inflammatory activity.
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Design, Synthesis, and Biological Evaluation of Coumarin–Triazole Hybrid Molecules as Potential Antitumor and Pancreatic Lipase Agents ()
The design, synthesis, and investigation of antitumor and anti-lipase activities of some coumarin–triazole hybrid molecules are reported. The synthesis of these hybrid molecules was performed under microwave irradiation and conventional heating procedures. The newly synthesized hybrid molecules were investigated as inhibitors against four tumor cell lines (BT20 human breast carcinoma, SK-Mel 128 melanoma, DU-145 prostate carcinoma, and A549 lung carcinoma) and porcine pancreatic lipase (PPL). Most of these compounds showed notable antitumor activities against the tested tumor cell lines, and compounds 8i and 8l showed the best anti-lipase activity of 99.30 ± 0.56% and 99.85 ± 1.21%, respectively, at a concentration of 10 μM. Some coumarin–triazole hybrid molecules were designed, synthesized, and tested for their antitumor and anti-lipase activities against four tumor cell lines and porcine pancreatic lipase, respectively. Most of these compounds showed notable antitumor activities against the tested tumor cell lines, and compounds 8i and 8l at 10 µM showed the best anti-lipase activity of 99.30 ± 0.56% and 99.85 ± 1.21%, respectively.
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Design, Synthesis, and Evaluation of Novel Tyrosine-Based DNA Gyrase B Inhibitors ()
The discovery and synthesis of new tyrosine-based inhibitors of DNA gyrase B (GyrB), which target its ATPase subunit, is reported. Twenty-four compounds were synthesized and evaluated for activity against DNA gyrase and DNA topoisomerase IV. The antibacterial properties of selected GyrB inhibitors were demonstrated by their activity against Staphylococcus aureus and Enterococcus faecalis in the low micromolar range. The most promising compounds, 8a and 13e, inhibited Escherichia coli and S. aureus GyrB with IC50 values of 40 and 30 µM. The same compound also inhibited the growth of S. aureus and E. faecalis with minimal inhibitory concentrations (MIC90) of 14 and 28 µg/mL, respectively. A series of novel tyrosine-based inhibitors of DNA gyrase B (GyrB) were designed, synthesized, and evaluated against DNA gyrase and DNA topoisomerase IV. Compounds 8a and 13e, which inhibited E. coli and S. aureus GyrB and displayed inhibitory activity against the growth of S. aureus and E. faecalis were identified as promising compounds for further structural optimization.
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Design, Synthesis, and Biological Evaluation of Isothiosemicarbazones with Antimycobacterial Activity ()
A series of benzaldehyde and salicylaldehyde-S-benzylisothiosemicarbazones was synthesized and tested against 12 different strains of mycobacteria, Gram-positive and Gram-negative bacteria, and the significant selectivity toward mycobacteria was proved. Twenty-eight derivatives were evaluated for the inhibition of isocitrate lyase, which is a key enzyme of the glyoxylate cycle necessary for latent tuberculosis infection, and their iron-chelating properties were investigated. Two derivatives, 5-bromosalicylaldehyde-S-(4-fluorobenzyl)-isothiosemicarbazone and salicylaldehyde-S-(4-bromobenzyl)-isothiosemicarbazone, influenced the isocitrate lyase activity and caused a better inhibition at 10 μmol/L than 3-nitropropionic acid, a standard inhibitor. The compounds were also found to act as exogenous chelators of iron, which is an obligate cofactor for many mycobacterial enzymes. Due to their low cytotoxicity, together with the activity against isocitrate lyase and the ability to sequester iron ions, the compounds belong to potential antibiotics with the main effect on mycobacteria. A series of benzaldehyde and salicylaldehyde-S-benzylisothiosemicarbazones was synthesized and tested for antimycobacterial selectivity. Twenty-eight derivatives were evaluated for the inhibition of isocitrate lyase, a key enzyme of the glyoxylate cycle necessary for latent tuberculosis infection. The compounds show promising activity as potential antibiotics with the main effect on mycobacteria.
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Isophthalic Acid-Based HDAC Inhibitors as Potent Inhibitors of HDAC8 from Schistosoma mansoni ()
Schistosoma mansoni histone deacetylase 8 (SmHDAC8) has been recently identified as a new potential target for the treatment of schistosomiasis. A series of newly designed and synthesized alkoxyamide-based and hydrazide-based HDAC inhibitors were tested for inhibitory activity against SmHDAC8 and human HDACs 1, 6, and 8. The front runner compounds showed submicromolar activity against SmHDAC8 and modest preference for SmHDAC8 over its human orthologue hHDAC8. Docking studies provided insights into the putative binding mode in SmHDAC8 and allowed rationalization of the observed selectivity profile. A series of newly designed and synthesized alkoxyamide-based and hydrazide-based histone deacetylase (HDAC) inhibitors were tested for inhibitory activity against Schistosoma mansoni HDAC8 and human HDACs 1, 6, and 8. Docking studies provide insights into the putative binding mode in SmHDAC8 and allow rationalization of the observed selectivity profile.
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Acetamide Derivatives of Chromen-2-ones as Potent Cholinesterase Inhibitors ()
Alzheimer's disease (AD), a neurodegenerative disorder, is a serious medical issue worldwide with drastic social consequences. Inhibition of cholinesterase is one of the rational and effective approaches to retard the symptoms of AD and, hence, consistent efforts are being made to develop efficient anti-cholinesterase agents. In pursuit of this, a series of 19 acetamide derivatives of chromen-2-ones were synthesized and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential. All the synthesized compounds exhibited significant anti-AChE and anti-BChE activity, with IC50 values in the range of 0.24–10.19 μM and 0.64–30.08 μM, respectively, using donepezil hydrochloride as the standard. Out of 19 compounds screened, 3 compounds, viz. 22, 40, and 43, caused 50% inhibition of AChE at 0.24, 0.25, and 0.25 μM, respectively. A kinetic study revealed them to be mixed-type inhibitors, binding with both the CAS and PAS sites of AChE. The above-selected compounds were found to be effective inhibitors of AChE-induced and self-mediated Aβ1–42 aggregation. ADMET predictions demonstrated that these compounds may possess suitable blood–brain barrier (BBB) permeability. Hemolytic assay results revealed that these compounds did not lyse human RBCs up to a thousand times of their IC50 value. MTT assays performed for the shortlisted compounds showed them to be negligibly toxic after 24 h of treatment with the SH-SY5Y neuroblastoma cells. These results provide insights for further optimization of the scaffolds for designing the next generation of compounds as lead cholinesterase inhibitors. From a series of 19 chromen-2-one derivatives screened for cholinesterase (AChE/BChE) inhibitition, three compounds (22, 40, and 43) were found to be potent AChE inhibitors exhibiting mixed-type inhibition along with effective inhibition of AChE-induced and self-mediated Aβ1–42 aggregation. The presence of a lipophilic moiety was found to enhance in particular the BChE inhibition activity. These compounds may possess suitable blood–brain barrier permeability.
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