Microwave assisted synthesis of novel hybrid tacrine-sulfonamide derivatives and investigation of their antioxidant and anticholinesterase activities

A novel series of tacrine derivatives containing sulfonamide group were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The result showed that all the synthesized tacrine-sulfonamides (VIIIa–o) exhibited inhibitory activity on both cholinesterases. VIIIg showed the highest inhibitory activity on AChE IC₅₀ = 0.009 μM. This value is 220-fold greater than that of galantamine (IC₅₀ = 2.054 μM) and 6-fold greater than tacrine (IC₅₀ = 0.055 μM). VIIIf displayed the strongest inhibition of BuChE (IC₅₀ = 2.250 μM), which is close to donepezil (IC₅₀ = 2.680 μM) and 8-fold greater than that of galantamine (IC₅₀ = 18.130 μM) Furthermore, all of the synthesized tacrine derivatives showed higher inhibition of BuChE than that of galantamine. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were investigated for the antioxidant activity. Among them, VIIIb (IC₅₀ = 94.390 ± 2.310 μM) showed significantly better ABTS cation radical scavenging ability than all of the new synthesized compounds.     

Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: Synthesis,biological evaluation and molecular modeling studies

A series of new biphenyl bis-sulfonamide derivatives 2a–3p were synthesized in good to excellent yield (76–98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC₅₀ 0.04 ± 0.0001 μM for AChE) and (IC₅₀ 0.85 ± 0.0001 μM for BChE), the IC₅₀ values of these compounds were ranged from 2.27 ± 0.01 to 123.11 ± 0.04 μM for AChE and 7.74 ± 0.07 to <400 μM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE (IC₅₀ 2.27 ± 0.01 μM), whereas 3g exhibited the highest inhibition for BChE (IC₅₀ 7.74 ± 0.07 μM). Structure–activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies.     

Two new 2,5-diketopiperazines produced by Streptomyces sp. SC0581

Two new diketopiperazines, cyclo(l-Phe-l-NMe-DOPA) (2) and cyclo[l-Phe-l-(NMe-3-(NMe-3-O-α-l-rhamnopyranosyl)-DOPA] (3), along with a known diketopiperazine (1), were isolated from the cultures of Streptomyces sp. SC0581. Their structures were elucidated by extensive spectroscopic analysis, single-crystal X-ray crystallographic analysis, and chemical correlation. Compounds 1 − 3 exhibited more potent ABTS radical cation scavenging activity (IC₅₀ values: 3.7 − 14.6 μM) than l-ascorbic acid (IC₅₀: 17.7 μM). Compounds 2 and 3 also showed remarkable DPPH radical scavenging activity.     

Pyridine sulfonamide as a small key organic molecule for the potential treatment of type-II diabetes mellitus and Alzheimer’s disease: In vitro studies against yeast α-glucosidase,acetylcholinesterase and butyrylcholinesterase

This paper presents the efficient high yield synthesis of novel pyridine 2,4,6-tricarbohydrazide derivatives (4a–4i) along with their α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition activities. The enzymes inhibition results showed the potential of synthesized compounds in controlling both type-II diabetes mellitus and Alzheimer’s disease. In vitro biological investigations revealed that most of compounds were more active against yeast α-glucosidase than the reference compound acarbose (IC₅₀ 38.25 ± 0.12 μM). Among the tested series the compound 4c bearing 4-flouro benzyl group was noted to be the most active (IC₅₀ 25.6 ± 0.2 μM) against α-glucosidase, and it displayed weak inhibition activities against AChE and BChE. Compound 4a exhibited the most desired results against all three enzymes, as it was significantly active against all the three enzymes; α-glucosidase (IC₅₀ 32.2 ± 0.3 μM), AChE (IC₅₀ 50.2 ± 0.8 μM) and BChE (IC₅₀ 43.8 ± 0.8 μM). Due to the most favorable activity of 4a against the tested enzymes, for molecular modeling studies this compound was selected to investigate its pattern of interaction with α-glucosidase and AChE targets.     

New phenolic glycosides with cyclooxygenase inhibition from the roots of Tecoma mollis

Three new phenolic glycosides (1–3) together with nine known ones were isolated from the roots of Tecoma mollis using DPPH radical scavenging bioassay-guided chromatographic separation. The structures of the new compounds were established using extensive spectroscopic data and HR-MS. The antioxidant, COX-2 inhibition, and cytotoxic activities were evaluated for the isolated compounds. Compound 4 displayed the strongest radical scavenging activity relative to ascorbic acid with IC₅₀ 8.7 μM. Compounds 5, 6, and 10 showed promising COX-2 inhibitory action, IC₅₀ values of 11.3 μM, 9.4 μM, and 13.4 μM, respectively. All compounds exhibited weak cytotoxic activity against Hela and A549 cancer cell lines.     

Nitric oxide inhibitory principles from Derris trifoliata stems

Nine rotenoids were isolated from the hexane and dichloromethane extracts of Derris trifoliata stems and were tested for nitric oxide (NO) inhibitory activity using RAW264.7 cells. The result indicated that 12a-hydroxyrotenone (7) possessed very potent NO inhibitory activity with an IC₅₀ value of 0.002 μM, followed by 1 (deguelin, IC₅₀=0.008 μM), 9 (12a-hydroxyelliptone, IC₅₀=0.010 μM) and 2 (α-toxicarol, IC₅₀=0.013 μM), respectively. In addition, the DPPH scavenging activity of rotenoids was also investigated. It was found that 6a,12a-dehydrodeguelin (5) possessed the highest activity against DPPH with an IC₅₀ value of 7.4 μM, followed by deguelin (1, IC₅₀=27.4 μM). All compounds did not show any cytotoxicity at their IC₅₀ values for NO inhibitory activity.Structure–activity relationships (SARs) of these rotenoids against NO release are as follows: (1) hydroxylation at C12a dramatically increased activity, (2) prenylation at furan ring increased activity markedly and (3) hydrogenation of a double bond at C6a–C12a conferred higher activity. For the DPPH radical scavenging effect, it was found that (1) introduction of a double bond at C6a–C12a increased activity and (2) hydroxylation of C11 at the D-ring decreased activity. As regards active compounds of Derris trifoliata stems, the isolated compounds are responsible for the NO inhibitory effect, especially 7, 1, 9 and 2, whereas 5 and 1 are those for the DPPH scavenging activity.     

Glutathione S-transferase pi (GST-pi) inhibition and anti-inflammation activity of the ethyl acetate extract of Streptomyces sp. strain MJM 8637

To investigate the anti-cancer properties of soil-borne actinobacteria, MJM 8637, the glutathione S-transferase pi (GST-pi) assay, anti-tumor necrosis factor (TNF)-α assay, the level of antioxidant potential by DPPH radical scavenging activity, NO scavenging activity, and ABTS radical scavenging activity in ethyl acetate extract were determined. The 16S rDNA sequencing analysis revealed that Streptomyces sp. strain MJM 8637, which was isolated from Hambak Mountain, Korea, has 99.5% similarity to Streptomyces atratus strain NBRC 3897. The physiological and the morphological characteristics of the strain MJM 8637 were also identified. The ethyl acetate extract of MJM 8637 inhibited TNF-α production approximately 61.8% at concentration 100 μg/ml. The IC₅₀ value of the strain MJM 8637 extract on GST-pi was identified to be 120.2 ± 1.6 μg/ml. In DPPH, NO, and ABTS radical scavenging assays, the IC₅₀ values of the strain MJM 8637 extract were found to be 977.2 μg/ml, 1143.7 μg/ml, and 454.4 μg/ml, respectively. The ethyl acetate extract of the strain MJM 8637 showed 97.2 ± 1.3% of cell viability at 100 μg/ml in RAW 264.7 cell viability assay. The results obtained from this study suggest that the ethyl acetate extract of Streptomyces sp. strain MJM 8637 could be considered as a potential source of drug for the cancers that have multidrug resistance with its GST-pi inhibition and anti-inflammation activities, and low cytotoxicity.     

Antioxidant aromatic butenolides from an insect-associated Aspergillus iizukae

Four new aromatic butenolides named aspernolides H-K (1–4), along with three known compounds (5–7), were isolated from the metabolites of Aspergillus iizukae, which resided in the guts of cricket species Gryllus testaceus. The structures were elucidated by extensive spectroscopic analysis, modified Mosher methods and Mo₂(OAc)₄-induced electronic circular dichroism (ECD) experiments. Their antioxidant activities were evaluated through ABTS and DPPH radical scavenging assays. Compounds 3, 5, and 7 exhibited significant activities with IC₅₀ values of 29.46, 9.59 and 12.36 μM, respectively, compared with the positive control trolox (IC₅₀ 13.11 μM).     

Synthesis,cholinesterase inhibition and molecular modelling studies of coumarin linked thiourea derivatives

Alzheimer’s disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC₅₀ value of 0.04 ± 0.01 μM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC₅₀ value of 0.06 ± 0.02 μM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.     

Synthesis of 6-chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives: Antidiabetic,antioxidant, β-glucuronidase inhibiton and their molecular docking studies

6-Chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives 1–26 were synthesized and characterized by various spectroscopic techniques. All these derivatives were evaluated for their antiglycation, antioxidant and β-glucuronidase potential followed their docking studies. In antiglycation assay, compound 2 (IC₅₀ = 240.10 ± 2.50 μM) and 4 (IC₅₀ = 240.30 ± 2.90 μM) was found to be most active compound of this series, while compounds 3 (IC₅₀ = 260.10 ± 2.50 μM), 6 (IC₅₀ = 290.60 ± 3.60 μM), 13 (IC₅₀ = 288.20 ± 3.00 μM) and 26 (IC₅₀ = 292.10 ± 3.20 μM) also showed better activities than the standard rutin (IC₅₀ = 294.50 ± 1.50 μM). In antioxidant assay, compound 1 (IC₅₀ = 69.45 ± 0.25 μM), 2 (IC₅₀ = 58.10 ± 2.50 μM), 3 (IC₅₀ = 74.25 ± 1.10 μM), and 4 (IC₅₀ = 72.50 ± 3.30 μM) showed good activities. In β-glucuronidase activity, compounds 3 (IC₅₀ = 29.25 ± 0.50 μM), compound 1 (IC₅₀ = 30.10 ± 0.60 μM) and compound 4 (IC₅₀ = 46.10 ± 1.10 μM) showed a significant activity as compared to than standard D-Saccharic acid 1,4-lactonec (IC₅₀ = 48.50 ± 1.25 μM) and their interaction with the enzyme was confirm by docking studies.     

Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers

A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H₃ receptor antagonists and free radical scavengers for Alzheimer’s disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H₃ receptor antagonistic activity with the IC₅₀ value of 0.049 μM. Besides, it also displayed high binding affinity to H₃ receptor (K_i = 4.26 ± 2.55 nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy.     

Design,synthesis and evaluation of novel indandione derivatives as multifunctional agents with cholinesterase inhibition,anti-β-amyloid aggregation,antioxidant and neuroprotection properties against Alzheimer’s disease

A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)-1H-indene-1,3(2H)-diones were designed, synthesized and appraised as multifunctional anti-Alzheimer agents. In vitro studies of compounds 27–38 showed that these compounds exhibit moderate to excellent AChE, BuChE and Aβ aggregation inhibitory activity. Notably, compounds 34 and 38 appeared as most active multifunctional agents in the entire series and exhibited excellent inhibition against AChE (IC₅₀ = 0.048 μM: 34; 0.036 μM: 38), Aβ aggregation (max% inhibition 82.2%, IC₅₀ = 9.2 μM: 34; max% inhibition 80.9%, IC₅₀ = 10.11 μM: 38) and displayed significant antioxidant potential in ORAC-FL assay. Both compounds also successfully diminished H₂O₂ induced oxidative stress in SH-SY5Y cells. Fascinatingly, compounds 34 and 38 showed admirable neuroprotective effects against H₂O₂ and Aβ induced toxicity in SH-SY5Y cells. Additionally, both derivatives showed no considerable toxicity in neuronal cell viability assay and represented drug likeness properties in the primarily pharmacokinetics study. All these results together, propelled out that compounds 34 and 38 might serve as promising multi-functional lead candidates for treatment of AD in the future.     

Design,synthesis and evaluation of novel 4-dimethylamine flavonoid derivatives as potential multi-functional anti-Alzheimer agents

A series of 4-dimethylamine flavonoid derivatives 5a–5r were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents. The results showed that most of the synthesized compounds exhibited high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity at the micromolar range (IC₅₀, 1.83–33.20 μM for AChE and 0.82–11.45 μM for BChE). A Lineweaver–Burk plot indicated a mixed-type inhibition for compound 5j with AChE, and molecular modeling study showed that 5j targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, the derivatives showed potent self-induced Aβ aggregation inhibitory activity at 20 μM with percentage from 25% to 48%. In addition, some compounds (5j–5q) showed potent oxygen radical absorbance capacity (ORAC) ranging from 1.5- to 2.6-fold of the Trolox value. These compounds should be further investigated as multi-potent agents for the treatment of Alzheimer’s disease.     

Synthesis,in vitro α-glucosidase inhibitory activity and molecular docking studies of new thiazole derivatives

Current study based on the synthesis of new thiazole derivatives via “one pot” multicomponent reaction, evaluation of their in vitro α-glucosidase inhibitory activities, and in silico studies. All synthetic compounds were fully characterized by ¹H NMR, ¹³C NMR and EIMS. CHN analysis was also performed. These newly synthesized compounds showed activities in the range of IC₅₀ = 9.06 ± 0.10–82.50 ± 1.70 μM as compared to standard acarbose (IC₅₀ = 38.25 ± 0.12 μM). It is worth mentioning that most of the compounds such as 1 (IC₅₀ = 23.60 ± 0.39 μM), 2 (IC₅₀ = 22.70 ± 0.60 μM), 3 (IC₅₀ = 22.40 ± 0.32 μM), 4 (IC₅₀ = 26.5 ± 0.40 μM), 6 (IC₅₀ = 34.60 ± 0.60 μM), 7 (IC₅₀ = 26.20 ± 0.43 μM), 8 (IC₅₀ = 14.06 ± 0.18 μM), 9 (IC₅₀ = 17.60 ± 0.28 μM), 10 (IC₅₀ = 27.16 ± 0.41 μM), 11 (IC₅₀ = 19.16 ± 0.19 μM), 12 (IC₅₀ = 9.06 ± 0.10 μM), 13 (IC₅₀ = 12.80 ± 0.21 μM), 14 (IC₅₀ = 11.94 ± 0.18 μM), 15 (IC₅₀ = 16.90 ± 0.20 μM), 16 (IC₅₀ = 12.60 ± 0.14 μM), 17 (IC₅₀ = 16.30 ± 0.29 μM), and 18 (IC₅₀ = 32.60 ± 0.61 μM) exhibited potent inhibitory potential. Molecular docking study was performed in order to understand the molecular interactions between the molecule and enzyme. Newly identified α-glucosidase inhibitors except few were found to be completely non-toxic.     

Design and synthesis of novel anti-Alzheimer’s agents: Acridine-chromenone and quinoline-chromenone hybrids

A novel series of acridine-chromenone and quinoline-chromenone hybrids were designed, synthesized, and evaluated as anti-Alzheimer’s agents. All synthesized compounds were evaluated as cholinesterases (ChEs) inhibitors and among them, 7-(4-(6-chloro-2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)phenoxy)-4-methyl-2H-chromen-2-one (8e) exhibited the most potent anti-acetylcholinesterase (AChE) inhibitory activity (IC₅₀ = 16.17 μM) comparing with rivastigmine (IC₅₀ = 11.07 μM) as the reference drug. Also, compound 8e was assessed for its β-secretase (BACE1) inhibitory and neuroprotective activities which demonstrated satisfactory results. It should be noted that both kinetic study on the inhibition of AChE and molecular modeling revealed that compound 8e interacted simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE.     

Design,synthesis and anti-Alzheimer properties of dimethylaminomethyl-substituted curcumin derivatives

Eight dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized. The antioxidant test revealed that the synthesized compounds had higher free radical scavenging activity towards both 2,2-diphenyl-1-picrylhydrazyl free radicals (DPPH) (IC₅₀ 1.5–29.9 μM) and galvinoxyl radicals (IC₅₀ 4.9–41.1 μM) than the lead compound curcumin. Besides, compound 3a could effectively inhibit the Aβ self-aggregation in vitro. Investigated in phosphate-buffered solutions (pH = 7.4) in the presence or absence of 0.1% FBS 3a showed a good stability while curcumin did not. Furthermore, 3a showed a good lipophilicity (log P = 3.48), suggesting a potential ability to penetrate the blood–brain-barrier. The aqueous solubility of the hydrochloride salt of 3a (16.7 mg/mL) has also been significantly improved as compared with curcumin (<0.1 mg/mL).     

5-Bromo-2-aryl benzimidazole derivatives as non-cytotoxic potential dual inhibitors of α-glucosidase and urease enzymes

On the basis of previous report on promising α-glucosidase inhibitory activity of 5-bromo-2-aryl benzimidazole derivatives, these derivatives were further screened for urease inhibitory and cytotoxicity activity in order to get more potent and non-cytotoxic potential dual inhibitor for the patients suffering from diabetes as well as peptic ulcer. In this study, all compounds showed varying degree of potency in the range of (IC₅₀ = 8.15 ± 0.03–354.67 ± 0.19 μM) as compared to standard thiourea (IC₅₀ = 21.25 ± 0.15 μM). It is worth mentioning that derivatives 7 (IC₅₀ = 12.07 ± 0.05 μM), 8 (IC₅₀ = 10.57 ± 0.12 μM), 11 (IC₅₀ = 13.76 ± 0.02 μM), 14 (IC₅₀ = 15.70 ± 0.12 μM) and 22 (IC₅₀ = 8.15 ± 0.03 μM) were found to be more potent inhibitors than standard. All compounds were also evaluated for cytotoxicity towards 3T3 mouse fibroblast cell line and found to be completely non-toxic. Previously benzimidazole 1–25 were also showed α-glucosidase inhibitory potential. In silico studies were performed on the lead molecules i.e. 2, 7, 8, 11, 14, and 22, in order to rationalize the binding interaction of compounds with the active site of urease enzyme.     

Synthesis and SAR study of 4,5-diaryl-1H-imidazole-2(3H)-thione derivatives,as potent 15-lipoxygenase inhibitors

A series of 4,5-diaryl-1H-imidazole-2(3H)-thione was synthesized and their inhibitory potency against soybean 15-lipoxygenase and free radical scavenging activities were determined. Compound 11 showed the best IC₅₀ for 15-LOX inhibition (IC₅₀ = 4.7 μM) and free radical scavenging activity (IC₅₀ = 14 μM). Methylation of SH at C₂ position of imidazole has dramatically decreased the 15-LOX inhibition and radical scavenging activity as it can be observed in the inactive compound 14 (IC₅₀ >250 μM). Structure activity similarity (SAS) showed that the most important chemical modification in this series was methylation of SH group and Docking studies revealed a proper orientation for SH group towards Fe core of the 15-LOX active site. Therefore it was concluded that iron chelating could be a possible mechanism for enzyme inhibition in this series of compounds.     

Beilschglabrines A and B: Two new bioactive phenanthrene alkaloids from the stem bark of Beilschmiedia glabra

Two new phenanthrene alkaloids, beilschglabrines A (1) and B (2) were isolated from the stem bark of Beilschmiedia glabra, together with lupeol, taraxerol, and 24-methylenelanosta-7,9-diene-3β-15α-diol. The structures of the isolated compounds were elucidated by extensive spectroscopic data analysis and comparison with respective literature data. The compounds were tested for DPPH radical scavenging, acetylcholinesterase and lipoxygenase inhibitory activities. Compound 1 displayed considerable activity in the acetylcholinesterase (IC₅₀ 50.4 μM), the DPPH radical scavenging (IC₅₀ 115.9 μM) and the lipoxygenase (IC₅₀ 32.8 μM) assays.     

Synthesis,in vitro evaluation and molecular docking studies of thiazole derivatives as new inhibitors of α-glucosidase

A series of thiazole derivatives 1–21 were prepared, characterized by EI-MS and ¹H NMR and evaluated for α-glucosidase inhibitory potential. All twenty one derivatives showed good α-glucosidase inhibitory activity with IC₅₀ value ranging between 18.23 ± 0.03 and 424.41 ± 0.94 μM when compared with the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). Compound (8) (IC₅₀, 18.23 ± 0.03 μM) and compound (7) (IC₅₀ = 36.75 ± 0.05 μM) exhibited outstanding inhibitory potential much better than the standard acarbose (IC₅₀, 38.25 ± 0.12 μM). All other analogs also showed good to moderate enzyme inhibition. Molecular docking studies were carried out in order to find the binding affinity of thiazole derivatives with enzyme. Studies showed these thiazole analogs as a new class of α-glucosidase inhibitors.