Novel multipotent phenylthiazole–tacrine hybrids for the inhibition of cholinesterase activity, β-amyloid aggregation and Ca2+ overload

In this study, a series of multipotent phenylthiazole–tacrine hybrids (7a–7e, 8, and 9a–9m) were synthesized and biologically evaluated. Screening results showed that phenylthiazole–tacrine hybrids were potent cholinesterase inhibitors with pIC₅₀ (?log IC₅₀) value ranging from 5.78 ± 0.05 to 7.14 ± 0.01 for acetylcholinesterase (AChE), and from 5.75 ± 0.03 to 10.35 ± 0.15 for butyrylcholinesterase (BuChE). The second series of phenylthiazole–tacrine hybrids (9a–9m) could efficiently prevent Aβ_1–42 self-aggregation. The structure–activity relationship revealed that their inhibitory potency relied on the type of middle linker and substitutions at 4′-position of 4-phenyl-2-aminothiazole. In addition, 7a and 7c also displayed the Ca²⁺ overload blockade effect in the primary cultured cortical neurons. Consequently, these compounds emerged as promising molecules for the therapy of Alzheimer’s disease.     

A facile chemo-, regio- and stereoselective synthesis and cholinesterase inhibitory activity of spirooxindole–pyrrolizine–piperidine hybrids

A series of novel hybrid spiro heterocycles comprising pyrrolizine, spiroxindole and piperidine moieties was synthesized chemo-, regio- and stereoselectively in good yields from 1,3-dipolar cycloaddition reaction of a series of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with azomethine ylides generated in situ from 5-choloroisatin and l-proline in methanol. These cycloadducts displayed significant cholinesterase inhibitory activity. Among the compounds screened, 8g and 8e, showed maximum inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinestrase (BChE) with IC₅₀ values of 3.33 and 3.13 μM, respectively.     

Inhibition of cholinesterase and monoamine oxidase-B activity by Tacrine–Homoisoflavonoid hybrids

A series of Tacrine–Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC₅₀ values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood–brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer’s disease (AD).     

Syntheses of coumarin–tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase,Aβ aggregation,and β-secretase

Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer’s disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine–coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (K_i = 16.7 nM) against human AChE and about 2-fold lower potency (K_i = 16.1 nM) against BChE than tacrine (K_i = 35.7 nM for AChE, K_i = 8.7 nM for BChE), respectively. In addition, some of the tacrine–coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine–coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.     

Synthesis,characterization and antimalarial activity of quinoline–pyrimidine hybrids

The aim of this study was to synthesize a series of quinoline–pyrimidine hybrids and to evaluate their in vitro antimalarial activity as well as cytotoxicity. The hybrids were brought about in a two-step nucleophilic substitution process involving quinoline and pyrimidine moieties. They were screened alongside chloroquine (CQ), pyrimethamine (PM) and fixed combinations thereof against the D10 and Dd2 strains of Plasmodium falciparum. The cytotoxicity was determined against the mammalian Chinese Hamster Ovarian cell line. The compounds were all active against both strains. However, hybrid (21) featuring piperazine linker stood as the most active of all. It was found as potent as CQ and PM against the D10 strain, and possessed a moderately superior potency over CQ against the Dd2 strain (IC₅₀: 0.157 vs 0.417 μM, ～threefold), and also displayed activity comparable to that of the equimolar fixed combination of CQ and PM against both strains.     

Novel estrone mimetics with high 17β-HSD1 inhibitory activity

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the reduction of estrone into estradiol, which is the most potent estrogen in humans. Lowering intracellular estradiol concentration by inhibition of this enzyme is a promising new option for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. Combination of ligand- and structure-based design resulted in heterocyclic substituted biphenylols and their aza-analogs as new 17β-HSD1 inhibitors. The design was based on mimicking estrone, especially focusing on the imitation of the D-ring keto group with (substituted) heterocycles. Molecular docking provided insights into plausible protein–ligand interactions for this class of compounds. The most promising compound 12 showed an inhibitory activity in the high nanomolar range and very low affinity for the estrogen receptors α and β. Thus, compound 12 is a novel tool for the elucidation of the pharmacological relevance of 17β-HSD1 and might be a lead for the treatment of estrogen-dependent diseases.     

Chloroquine–astemizole hybrids with potent in vitro and in vivo antiplasmodial activity

A dual activity, conjugated approach has been taken to form hybrid molecules of two known antimalarial drugs, chloroquine (CQ) and the non-sedating H1 antagonist astemizole. A variety of linkers were investigated to conjugate the two agents into one molecule. Compounds 5–8 possessed improved in vitro activity against a CQ-resistant strain of Plasmodium falciparum, and examples 7 and 8 were active in vivo in mouse models of malaria.     

Synthesis and radical scavenging activity of phenol–imidazole conjugates

Novel hydroxylated benzylideneamino imidazole derivatives were synthesized and their radical scavenging activity was assessed against DPPH and hydroxyl radicals. In the DPPH assay, most of the synthesized compounds showed an IC₅₀ in the range 3.2 μM ⩽ IC₅₀ ⩽ 8.4 μM, lower than the reference compound trolox (IC₅₀ = 9.5 μM) or the parent aldehydes (5.4 μM ⩽ IC₅₀ ⩽ 11.6 μM). The activity depends mainly on the phenolic subunit (number and position of the hydroxyl groups) and the extent of conjugation with the imidazole ring. In the deoxyribose assay, all the compounds, including parent imidazoles and aldehydes, showed high activity against the hydroxyl radical and the ability to chelate iron ions. At 5 μM concentration, the compounds protected the deoxyribose from degradation by hydroxyl radical between 62% and 38%.     

O-Hydroxyl- or o-amino benzylamine-tacrine hybrids: Multifunctional biometals chelators,antioxidants, and inhibitors of cholinesterase activity and amyloid-β aggregation

In an effort to identify novel multifunctional drug candidates for the treatment of Alzheimer’s disease (AD), a series of hybrid molecules were synthesised by reacting N-(aminoalkyl)tacrine with salicylic aldehyde or derivatives of 2-aminobenzaldehyde. These compounds were then evaluated as multifunctional anti-Alzheimer’s disease agents. All of the hybrids are potential biometal chelators, and in addition, most of them were better antioxidants and inhibitors of cholinesterases and amyloid-β (Aβ) aggregation than the lead compound tacrine. Compound 7c has the potential to be a candidate for AD therapy: it is a much better inhibitor of acetylcholinesterase (AChE) than tacrine (IC₅₀: 0.55 nM vs 109 nM), has good biometal chelation ability, is able to inhibit Aβ aggregation and has moderate antioxidant activity (1.22 Trolox equivalents).     

Antitumour and antimalarial activity of artemisinin–acridine hybrids

Artemisinin–acridine hybrids were prepared and evaluated for their in vitro activity against tumour cell lines and a chloroquine sensitive strain of Plasmodium falciparum. They showed a 2–4-fold increase in activity against HL60, MDA-MB-231 and MCF-7 cells in comparison with dihydroartemisinin (DHA) and moderate antimalarial activity. Strong evidence that the compounds induce apoptosis in HL60 cells was obtained by flow cytometry, which indicated accumulation of cells in the G1 phase of the cell cycle.     

Novel tacrine–benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer’s Disease

Abstract

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ_1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.     

Novel aromatic–polyamine conjugates as cholinesterase inhibitors with notable selectivity toward butyrylcholinesterase

Three types of aromatic–polyamine conjugates (6a–6s) were designed, synthesized and evaluated as potential inhibitors for cholinesterases (ChEs). The results showed that anthraquinone–polyamine conjugates (AQPCs) exhibited the most potent acetylcholinesterase (AChE) inhibitory activity with IC₅₀ values from 1.50 to 11.13 μM. Anthracene–polyamine conjugates (APCs) showed a surprising selectivity (from 76- to 3125-fold) and were most potent at inhibiting butyrylcholinesterase (BChE), with IC₅₀ values from 0.016 to 0.657 μM. A Lineweaver–Burk plot and molecular modeling studies indicated that the representative compounds, 6l and 6k, targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of ChEs. Furthermore, APCs did not affect HepG2 cell viability at the concentration of 100 μM. Consequently, these polyamine conjugates could be thoroughly and systematically studied for the treatment of AD.     

Comparison of the antiplasmodial and falcipain-2 inhibitory activity of β-amino alcohol thiolactone-chalcone and isatin-chalcone hybrids

The synthesis and biological evaluation of two novel series of natural-product-like hybrids based on the chalcone, thiolactone and isatin scaffolds is herein described. Results for a 36-member β-amino alcohol triazole library showed that the thiolactone-chalcones, with IC₅₀s ranging from 0.68 to 6.08 μM, were more active against W2 strain Plasmodium falciparum than the isatin-chalcones with IC₅₀s of 14.9 μM or less. Also of interest is falcipain-2 inhibitory activity displayed by the latter, whereas the thiolactone-chalcones lacked enzyme inhibitory activity.     

What do we measure with luminol-, lucigenin- and penicillin-amplified chemiluminescence? 1. Investigations with hydrogen peroxide and sodium hypochlorite

Evidence is provided that the amplifiers luminol and lucigenin react with different reactive oxygen species (ROS), depending on the ROS-generating system used. H₂O₂ is used to produce calibration curves for luminol- and lucigenin-amplified chemiluminescence. With this chemiluminescence generator we characterized the specificity and sensitivity of luminol- and lucigenin-amplified chemiluminescence and also studied penicillin G, a known enhancer of luminol-amplified chemiluminescence. The combination of luminol and lucigenin in reciprocally changing concentrations is effective in an additive manner, but the weak amplifier penicillin increases luminol-amplified chemiluminescence distinctly more than in an additive manner in different combinations. Lucigenin-amplified chemiluminescence is increased by penicillin at about 1% of the optimum concentration of penicillin; increasing concentrations of penicillin are less and less effective. On the other hand, low lucigenin concentrations enhance penicillin-amplified chemiluminescence at optimum penicillin concentrations more than in an additive manner. Fe²⁺ does not alter luminol-, lucigenin- or penicillin-amplified chemiluminescence. Co²⁺ increases luminol-amplified chemiluminescence by a factor of 100. Lucigenin- and penicillin-amplified chemiluminescence are minimally enhanced by Co²⁺. Cu²⁺ enhances luminol-amplified chemiluminescence with increasing concentrations by a factor of 1000. Lucigenin-amplified chemiluminescence increases also by the factor of 1000, but the concentration–reaction curve is not as steep. NaOCl enhances H₂O₂/Fe²⁺-driven luminol-amplified chemiluminescence in a concentration-dependent manner by a factor of 10⁴ (in the highest concentration of 10 mmol/L) and lucigenin amplified chemiluminescence only by a factor of about 25. Catalase (CAT) abolishes luminol-, lucigenin- and penicillin-amplified chemiluminescence completely, whereas superoxide dismutase (SOD) has no effect on luminol- or penicillin-amplified chemiluminescence, but enhances lucigenin-amplified chemiluminescence five-fold increasingly with increasing SOD activity. © 1998 John Wiley & Sons, Ltd.     

Synthesis,topoisomerase I and II inhibitory activity,cytotoxicity, and structure–activity relationship study of hydroxylated 2,4-diphenyl-6-aryl pyridines

A new series of 2,4-diphenyl-6-aryl pyridines containing hydroxyl group(s) at the ortho, meta, or para position of the phenyl ring were synthesized, and evaluated for topoisomerase I and II inhibitory activity and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Structure–activity relationship study revealed that the substitution of hydroxyl group(s) increased topoisomerase I and II inhibitory activity in the order of meta > para > ortho position. Substitution of hydroxyl group on the para position showed better cytotoxicity.     

Design,synthesis and neuroprotective evaluation of novel tacrine–benzothiazole hybrids as multi-targeted compounds against Alzheimer’s disease

Alzheimer’s disease (AD) is a multifactorial disorder with several target proteins contributing to its etiology. In search for multifunctional anti-AD drug candidates, taking into account that the acetylcholinesterase (AChE) and beta-amyloid (Aβ) aggregation are particularly important targets for inhibition, the tacrine and benzothiazole (BTA) moieties were conjugated with suitable linkers in a novel series of hybrids. The designed compounds (7a–7e) were synthesized and in vitro as well as in ex vivo evaluated for their capacity for the inhibition of acetylcholinesterase (AChE) and Aβ self-induced aggregation, and also for the protection of neuronal cells death (SHSY-5Y cells, AD and MCI cybrids). All the tacrine–BTA hybrids displayed high in vitro activities, namely with IC₅₀ values in the low micromolar to sub-micromolar concentration range towards the inhibition of AChE, and high percentages of inhibition of the self-induced Aβ aggregation. Among them, compound 7a, with the shortest linker, presented the best inhibitory activity of AChE (IC₅₀ = 0.34 μM), while the highest activity as anti-Aβ₄₂ self-aggregation, was evidenced for compound 7b (61.3%, at 50 μM. The docking studies demonstrated that all compounds are able to interact with both catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Our results show that compounds 7d and 7e improved cell viability in cells treated with Aβ₄₂ peptide. Overall, these multi-targeted hybrid compounds appear as promising lead compounds for the treatment of Alzheimer’s disease.     

Synthesis of new conjugated coumarin–benzimidazole hybrids and their anticancer activity

A series of novel coumarin–benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2-yl)-7-(substituted amino)-2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized compounds were screened for in vitro antitumor activity against preliminary 60 tumor cell lines panel assay. A significant inhibition for cancer cells was observed with compound 8 (more than 50% inhibition) compared with other compounds and active known drug 5-fluorouracil (in some cell lines) as positive control. Compound 8 displayed appreciable anticancer activities against leukemia, colon cancer and breast cancer cell lines.     

Tacrine–propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer’s disease

Abstract

A series of tacrine–propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer’s disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC₅₀ values of 51.3 and 77.6?nM; 3b: IC₅₀ values of 11.2 and 83.5?nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.     

Monoterpenoids and Triterpenoids from Pterocephalus hookeri with NF-κB inhibitory activity

In this study, we isolated two new monoterpenoids hookerinoids A and B (1 and 2; rare arranged nonglycosidic bis-iridoids) and hookerinoid C (3; a novel norursane-type triterpenoid) in addition to two known compounds, 11,12-epoxy-2,6-dihydroxy-24-norursa-1,4-dien-3-on-2-on-(28 → 13)-olide (4) and rivularicin (5), from Pterocephalus hookeri. The structures of 1–3 were established using one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution electrospray ionisation mass spectrometry. All compounds were isolated from this plant for the first time. Bis-iridoids isolated from P. hookeri possessed secoiridoid/iridoid subtype skeletons. Therefore, bis-iridoids can be considered chemotaxonomic markers of P. hookeri. The origins of the new compounds (1–3) were postulated and their inhibitory activities on a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway were assayed; 1 and 2 showed obvious activity in inhibiting NF-κB.     

Antileishmanial activity of new thiophene–indole hybrids: Design,synthesis, biological and cytotoxic evaluation,and chemometric studies

In the present work, thirty-two hybrid compounds containing cycloalka[b]thiophene and indole moieties (TN5, TN5 1–7, TN6, TN6 1–7, TN7, TN7 1–7, TN8, TN8 1–7) were designed, synthesized and evaluated for their cytotoxic and antileishmanial activity against Leishmania amazonensis promastigotes. More than half of the compounds (18 compounds) exhibited significant antileishmanial activity (IC₅₀ lower than 10.0 μg/L), showing better performance than the reference drugs (tri- and penta-valent antimonials). The most active compounds were TN8-7, TN6-1 and TN7 with respective IC₅₀ values of 2.1, 2.3 and 3.2 μg/mL. Demonstrating that all of the compounds were less toxic than the reference drugs, even at the highest evaluated concentration (400 μg/mL), no compound tested presented human erythrocyte cytotoxicity. Compound TN8-7’s effectiveness against a trivalent antimony-resistant culture was demonstrated. It was observed that TN8-7’s antileishmanial activity is associated with DNA fragmentation of L. amazonensis promastigotes. Chemometric studies (CPCA, PCA, and PLS) highlight intrinsic solubility/lipophilicity, and compound size and shape as closely related to activity. Our results suggest that hybrid cycloalka[b]thiophene–indole derivatives may be considered as lead compounds for further development of new drugs for the treatment of leishmaniasis.