Signal-On Detection of Dopamine and Tyrosinase Using Tris(hydroxypropyl)phosphine as a New Lucigenin Chemiluminescence Coreactant.

Dopamine (DA) is a very imperative neurotransmitter in our body, since it contributes to several physiological processes in our body, for example, memory, feeling, cognition, cardiovascular diseases, and hormone secretion. Meanwhile, tyrosinase is a critical biomarker for several dangerous skin diseases, including vitiligo and melanoma cancer. Most of the reported chemiluminescent (CL) methods for monitoring DA and tyrosinase are signal-off biosensors. Herein, we introduce a new chemiluminescent "signal-on" system, lucigenin-tris(hydroxypropyl)phosphine (THPP), for the selective determination of DA and tyrosinase. THPP is well known as a versatile and highly water-soluble sulfhydryl-reducing compound that is more highly stable against air oxidation than common disulfide reductants. By employing THPP for the first time as an efficient lucigenin coreactant, the lucigenin-THPP system has shown a high CL response (approximately 16-fold) compared to the lucigenin-H2O2 classical CL system. Surprisingly, DA can remarkably boost the CL intensity of the lucigenin-THPP CL system. Additionally, tyrosinase can efficiently catalyze the conversion of tyramine to DA. Therefore, lucigenin-THPP was employed as an ultrasensitive and selective signal-on CL system for the quantification of DA, tyrosinase, and THPP. The linear ranges for the quantification of DA, tyrosinase, and THPP were 50-1000 nM, 0.2-50 µg/mL, and 0.1-800 µM, respectively. LODs for DA and tyrosinase were estimated to be 24 nM and 0.18 µg/mL, respectively. Additionally, the CL system has been successfully employed for the detection of tyrosinase in human serum samples and the assay of DA in human serum samples as well as in dopamine injection ampules with excellent obtained recoveries.

Cryo-EM structure of P-glycoprotein bound to triple elacridar inhibitor molecules.

P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. This mechanism is particularly problematic in cancer cells, where it diminishes the therapeutic efficacy of anticancer drugs. P-gp inhibitors, such as elacridar, have been developed to circumvent the decrease in drug efficacy due to P-gp efflux. An earlier study reported the cryo-EM structure of human P-gp-Fab (MRK-16) complex bound by two elacridar molecules, at a resolution of 3.6 Å. In this study, we have obtained a higher resolution (2.5 Å) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules. This finding, which exposes a larger space for compound-binding sites than previously acknowledged, has significant implications for the development of more selective inhibitors and enhances our understanding of the compound recognition mechanism of P-gp.

First-in-Human Evaluation of [18F]FDOPA Produced by Organo-Photoredox Reactions.

Photoredox is a powerful synthetic tool in organic chemistry and has been widely used in various fields, including nuclear medicine and molecular imaging. In particular, acridinium-based organophotoredox radiolabeling has significantly impacted the production and discovery of positron emission tomography (PET) agents. Despite their extensive use in preclinical research, no PET agents synthesized by acridinium photoredox labeling have been tested in humans. [18F]FDOPA is clinically used for tumor diagnosis and the evaluation of neuropsychiatric disorders, but its application is limited by complex synthesis methods, the need for expensive modules, and/or the high cost of consumable materials/cassettes. In this report, we integrated a photoredox labeling unit with an automated module and produced [18F]FDOPA for human study. This research not only represents the first human study of a PET agent generated by acridinium-based organophotoredox reactions but also demonstrates the safety of this novel labeling method, serving as a milestone/reference for the clinical translation of other PET agents generated by this technique in the future.

Acridinedione-phthalimide conjugates: Intramolecular electron transfer and singlet oxygen generation studies for optical and photodynamic therapy applications.

We reported herein the synthesis, characterization of hybrid conjugates composed of phthalimide (Phth) and acridine-1,8-diones (Acr) for optical and medical applications. For the synthetic procedure, a three-step synthetic strategy has been utilized. The optical properties of the examined 1,8-acridinedione-phthalimide connected molecules (AcrPhth 1-5) have been examined utilizing various spectroscopic techniques, e.g., steady-state absorption and fluorescence, and time-correlated single photon counting. The steady-state absorption studies showed that AcrPhth 1-5 absorbs the light in the UV and visible region. The fluorescence studies of AcrPhth 1-5 exhibited significant fluorescence quenching compared to the acridinedione control compounds (Acr 1-5) suggesting the occurrence of electron-transfer reactions from the electron donating acridinedione moiety (Acr) to the electron accepting phthalimide moiety (Phth). The rate and efficiency of the electron-transfer reactions were determined from the fluorescence lifetime measurements indicating the fast electron-transfer processes of the covalently connected AcrPhth 1-5 conjugates. Computational studies supported the intramolecular electron-transfer reaction of AcrPhth conjugates using ab initio B3LYP/6-311G methods. In the optimized structures, the HOMO was found to be entirely located on the Acr entity, while the LUMO was found to be entirely on the Phth entity. Further, the synthesized compounds were tested as photosensitizers for generating the singlet oxygen species, which is a key factor in the photodynamic therapy (PDT) applications. The nanosecond laser flash measurements enable us to detect the triplet-excited states of examined Acr and AcrPhth conjugates, determining the triplet quantum yields, and direct detecting the singlet oxygen in an accurate way. From this observation, the singlet quantum yields were found to be in the range of 0.12-0.27 (for Acr 1-5) and 0.07-0.19 (for AcrPhth 1-5 conjugates). The molecular docking studies revealed that compound AcrPhth 2 exhibited high binding affinity with for key genes (p53, TOP2B, p38, and EGFR) suggesting its potential as a targeted anticancer therapy.

Chromenone: An emerging scaffold in anti-Alzheimer drug discovery.

Alzheimer's disease (AD) presents a growing global health concern. In recent decades, natural and synthetic chromenone have emerged as promising drug candidates due to their multi-target potential. Natural chromenone, quercetin, scopoletin, esculetin, coumestrol, umbelliferone, bergapten, and methoxsalen (xanthotoxin), and synthetic chromenone hybrids comprising structures like acridine, 4-aminophenyl, 3-arylcoumarins, quinoline, 1,3,4-oxadiazole, 1,2,3-triazole, and tacrine, have been explored for their potential to combat AD. Key reactions used for synthesis of chromenone hybrids include Perkin and Pechmann condensation. The activity of chromenone hybrids has been reported against several drug targets, including AChE, BuChE, BACE-1, and MAO-A/B. This review comprehensively explores natural, semisynthetic, and synthetic chromenone, elucidating their synthetic routes, possible mode of action/drug targets and structure-activity relationships (SAR). The acquired knowledge provides valuable insights for the development of new chromenone hybrids against AD.

Innovative N-Acridine Thiosemicarbazones and Their Zn(II) Complexes Transmetallate with Cu(II): Redox Activity and Suppression of Detrimental Oxy-Myoglobin Oxidation.

The coordination chemistry and electrochemistry of novel N-acridine thiosemicarbazones (NATs) were investigated along with their redox activity, antiproliferative efficacy, transmetalation, and dissociation properties. The ability of NAT Fe(III) complexes to inhibit detrimental oxy-myoglobin (oxy-Mb) oxidation was also examined. The NATs act as tridentate ligands with a 2:1 L/Zn(II) complex crystal structure, revealing a distorted octahedral geometry, where both ligands bind Zn(II) in a meridional conformation. The NAT Fe(III) complexes exhibited fully reversible one-electron FeIII/II couples with more positive potentials than the Fe(III) complexes of a related clinically trialed thiosemicarbazone (e.g., [Fe(DpC)2]+) due to the electron-donating capacity of acridine. Surprisingly, the NAT-Zn(II) complexes showed generally greater or similar antiproliferative activity than their ligands, Cu(II), or Fe(III) complexes. This may be explained by (1) formation of a highly lipophilic Zn(II) complex that acts as a chaperone to promote cellular uptake and (2) the capacity of the Zn(II) complex to dissociate or undergo transmetalation to the redox-active Cu(II) complex. Of the NAT-Fe(III) complexes, [Fe(AOBP)2]+ demonstrated a significant (p < 0.0001) improvement in preventing oxy-Mb oxidation than the Fe(III) complex of the clinically trialed thiosemicarbazone, DpC. This article advances our understanding of NAT coordination chemistry, electrochemistry, and the intriguing biological activity of their complexes.

Synthesis of 9-(substituted phenoxycarbonyl)-10-methylacridinium trifluoromethanesulfonates: Effects of the leaving group on chemiluminescent properties.

Various 9-(substituted phenoxycarbonyl)-10-methylacridinium trifluoromethanesulfonates possessing electron-withdrawing substituents have been synthesized. The effect of substituents on the stability of the acridinium esters (AEs) at various temperatures in different buffers and the chemiluminescent properties have been examined. There was little correlation between the chemiluminescent properties of AEs and the pKa values of their associated phenols, but the steric effects of the ortho-substituents in the phenoxy group, as well as their electron-withdrawing natures, seem to play an important role in determining the properties. In general, when two identical substituents are present in the 2- and 6-positions, the compound is significantly more stable than when only a single substituent is present, presumably because of greater steric hindrance from the second group. The exception is the 2,6-difluorophenyl ester, which is less stable than the 2-fluorophenyl ester, presumably because the fluoro group is small. Addition of a third electron-withdrawing substituent at the 4-position, where it has no steric influence, typically increases susceptibility to decomposition. The presence of a nitro group has a significant destabilizing effect on AEs. Of the AEs studied, the 4-chlorophenyl ester showed the greatest chemiluminescent yield, while the 2-iodo-6-(trifluoromethyl)phenyl ester group showed the greatest stability in low pH buffers.

Facile and Novel Synthetic Approach, Molecular Docking, Molecular Dynamics, and Drug-Likeness Evaluation of 9-Substituted Acridine Derivatives as Dual Anticancer and Antimicrobial Agents.

In the present study, numerous acridine derivatives A1-A20 were synthesized via aromatic nucleophilic substitution (SNAr) reaction of 9-chloroacridine with carbonyl hydrazides, amines, or phenolic derivatives depending upon facile, novel, and eco-friendly approaches (Microwave and ultrasonication assisted synthesis). The structures of the new compounds were elucidated using spectroscopic methods. The title products were assessed for their antimicrobial, antioxidant, and antiproliferative activities using numerous assays. Promisingly, the investigated compounds mainstream revealed promising antibacterial and anticancer activities. Thereafter, the investigated compounds' expected mode of action was debated by using an array of in silico studies. Compounds A2 and A3 were the most promising antimicrobial agents, while compounds A2, A5, and A7 revealed the most cytotoxic activities. Accordingly, RMSD, RMSF, Rg, and SASA analyses of compounds A2 and A3 were performed, and MMPBSA was calculated. Lastly, the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analyses of the novel acridine derivatives were investigated. The tested compounds' existing screening results afford an inspiring basis leading to developing new compelling antimicrobial and anticancer agents based on the acridine scaffold.

A Novel Tetrahydroacridine Derivative with Potent Acetylcholinesterase Inhibitory Properties and Dissociative Capability against Aß42 Fibrils Confirmed by In Vitro Studies.

Alzheimer's disease (AD) is one of the most common causes of dementia, accounting for more than 60% of all cases. It is a neurodegenerative disease in which symptoms such as a decline in memory, thinking, learning, and organizing skills develop gradually over many years and eventually become more severe. To date, there is no effective treatment for the cause of Alzheimer's disease, and the existing pharmacological options primarily help manage symptoms. Treatment is mainly based on acetylcholinesterase (AChE) inhibitors such as donepezil, rivastigmine, and galantamine, which exhibit numerous adverse cardiovascular and gastrointestinal effects due to excessive stimulation of peripheral cholinergic activity involving muscarinic receptors. Therefore, in addition to the obvious drugs that act on the cause of the disease, new drugs based on AChE inhibition that show the fewest side effects are needed. One potential drug could be a new compound under study, tetrahydroacridine derivative (CHDA), which showed significant potential to inhibit the AChE enzyme in previous in vitro studies. The present study shows that while having very potent AChE inhibitory properties, CHDA is a compound with low toxicity to nerve cell culture and living organisms. In addition, it exhibits dissociative activity against amyloid ß fibrils, which is extremely important for applications in Alzheimer's disease therapy.

A Bis(Acridino)-Crown Ether for Recognizing Oligoamines in Spermine Biosynthesis.

Oligoamines in cellular metabolism carry extremely diverse biological functions (i.e., regulating Ca2+-influx, neuronal nitric oxide synthase, membrane potential, Na+, K+-ATPase activity in synaptosomes, etc.). Furthermore, they also act as longevity agents and have a determinative role in autophagy, cell growth, proliferation, and death, while oligoamines dysregulation is a key in a variety of cancers. However, many of their mechanisms of actions have just begun to be understood. In addition to the numerous biosensing methods, only a very few simple small molecule-based tests are available for their selective but reversible tracking or fluorescent labeling. Motivated by this, we present herein a new fluorescent bis(acridino)-crown ether as a sensor molecule for biogenic oligoamines. The sensor molecule can selectively distinguish oligoamines from aliphatic mono- and diamino-analogues, while showing a reversible 1:2 (host:guest) complexation with a stepwise binding process accompanied by a turn-on fluorescence response. Both computational simulations on molecular docking and regression methods on titration experiments were carried out to reveal the oligoamine-recognition properties of the sensor molecule. The new fluorescent chemosensor molecule has a high potential for molecular-level functional studies on the oligoamine systems in cell processes (cellular uptake, transport, progression in cancers, etc.).

Design, Synthesis, and Characterization of Novel Thiazolidine-2,4-Dione-Acridine Hybrids as Antitumor Agents.

This study focuses on the synthesis and structural characterization of new compounds that integrate thiazolidine-2,4-dione, acridine moiety, and an acetamide linker, aiming to leverage the synergistic effects of these pharmacophores for enhanced therapeutic potential. The newly designed molecules were efficiently synthesized through a multi-step process and subsequently transformed into their hydrochloride salts. Comprehensive spectroscopic techniques, including nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), infrared (IR) spectroscopy, and elemental analysis, were employed to determine the molecular structures of the synthesized compounds. Biological evaluations were conducted to assess the therapeutic potential of the new compounds. The influence of these derivatives on the metabolic activity of various cancer cell lines was assessed, with IC50 values determined via MTT assays. An in-depth analysis of the structure-activity relationship (SAR) revealed intriguing insights into their cytotoxic profiles. Compounds with electron-withdrawing groups generally exhibited lower IC50 values, indicating higher potency. The presence of the methoxy group at the linking phenyl ring modulated both the potency and selectivity of the compounds. The variation in the acridine core at the nitrogen atom of the thiazolidine-2,4-dione core significantly affects the activity against cancer cell lines, with the acridin-9-yl substituent enhancing the compounds' antiproliferative activity. Furthermore, compounds in their hydrochloride salt forms demonstrated better activity against cancer cell lines compared to their free base forms. Compounds 12c·2HCl (IC50 = 5.4 ± 2.4 µM), 13d (IC50 = 4.9 ± 2.9 µM), and 12f·2HCl (IC50 = 4.98 ± 2.9 µM) demonstrated excellent activity against the HCT116 cancer cell line, and compound 7d·2HCl (IC50 = 4.55 ± 0.35 µM) demonstrated excellent activity against the HeLa cancer cell line. Notably, only a few tested compounds, including 7e·2HCl (IC50 = 11.00 ± 2.2 µM), 7f (IC50 = 11.54 ± 2.06 µM), and 7f·2HCl (IC50 = 9.82 ± 1.92 µM), showed activity against pancreatic PATU cells. This type of cancer has a very high mortality due to asymptomatic early stages, the occurrence of metastases, and frequent resistance to chemotherapy. Four derivatives, namely, 7e·2HCl, 12d·2HCl, 13c·HCl, and 13d, were tested for their interaction properties with BSA using fluorescence spectroscopic studies. The values for the quenching constant (Ksv) ranged from 9.59 × 104 to 10.74 × 104 M-1, indicating a good affinity to the BSA protein.

Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 µM) with pyrimidone compound 5 (GSK-3ß: IC50 = 3 µM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3ß (GSK-3ß). The optimal compound 18a possessed potent dual AChE/GSK-3ß inhibition (AChE: IC50 = 0.047 ± 0.002 µM, GSK-3ß: IC50 = 0.930 ± 0.080 µM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 µM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.

A systematic computational study of acridine derivatives through conceptual density functional theory.

A detailed computational analysis of acridine derivatives viz. acridone, 9-amino acridine hydrochloride hydrate, proflavin, acridine orange and acridine yellow is done in terms of conceptual density functional theory (CDFT). CDFT-based global descriptors-ionization potential, electron affinity, HOMO-LUMO gap, hardness, softness, electronegativity and electrophilicity index of acridine derivatives for ground state as well as excited state are estimated with the help of different hybrid functionals B3LYP/6-31G (d, p), B3LYP/6-311G (d, p), B3LYP/DGDZVP and B3LYP/LANL2DZ. Acridine derivatives show higher values of ionization potential and electron affinity in excited state as compared to ground state, indicating that these compounds are willing to accept electrons in excited state rather than donating electron. Acridone shows the maximum HOMO-LUMO energy gap in ground and excited state which implies that one-way electron transfer is most feasible with this compound. Our computed results emphasize the pronounced electron acceptor behaviour of the acridine derivatives in the excited state which has already been experimentally verified. It is observed that the trend in the computed values of the descriptors is not much improved on refinement of the basis set.

Synthesis, structure elucidation, and chemiluminescent activity of new 9-substituted 10-(ω-(succinimidyloxycarbonyl)alkyl)acridinium esters.

Several new acridinium esters 2-9 having their central acridinium ring bearing a 9-(2,5-dimethylphenoxycarbonyl), 9-(2,6-bis(trifluoromethyl)phenoxycarbonyl) or 9-(2,6-dinitrophenoxycarbonyl) group, and a 10-methyl, 10-(3-(succinimidyloxycarbonyl)propyl), 10-(5-(succinimidyloxycarbonyl)pentyl), or 10-(10-(succinimidyloxycarbonyl)decyl) group, have been synthesized and their chemiluminescent properties have been tested. The 2,5-dimethylphenyl acridinium esters emit light slowly (glow) when treated with alkaline hydrogen peroxide, while the 2,6-dinitrophenyl and 2,6-bis(trifluoromethyl)phenyl esters emit light rapidly (flash). The substituent at the 10 position affects the hydrolytic stabilities of the compounds.

Brønsted Acid Promoted Facile Synthesis of Benzoacridines from Aromatic Aldehydes and N-Phenyl Naphthylamines.

A facile method for the rapid synthesis of benzoacridines has been described. This protocol promoted by p-toluenesulfonic acid starts from aromatic aldehydes and N-phenyl naphthylamines, affording a variety of benzoacridines in 30-90 % yields under metal-free conditions. The present approach involves a cascade of condensation, Friedel-Crafts alkylation, annulation and dehydroaromatization in one pot.

Novel 3,9-Disubstituted Acridines with Strong Inhibition Activity against Topoisomerase I: Synthesis, Biological Evaluation and Molecular Docking Study.

A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives 17a-17j, in a moderate yield. The principles of cheminformatics and computational chemistry were applied in order to study the relationship between the physicochemical properties of the 3,9-disubstituted acridines and their biological activity at a cellular and molecular level. The selected 3,9-disubstituted acridine derivatives were studied in the presence of DNA using spectroscopic (UV-Vis, circular dichroism, and thermal denaturation) and electrophoretic (nuclease activity, relaxation and unwinding assays for topoisomerase I and decatenation assay for topoisomerase IIα) methods. Binding constants (2.81-9.03 × 104 M-1) were calculated for the derivatives from the results of the absorption titration spectra. The derivatives were found to have caused the inhibition of both topoisomerase I and topoisomerase IIα. Molecular docking simulations suggested a different way in which the acridines 17a-17j can interact with topoisomerase I versus topoisomerase IIα. A strong correlation between the lipophilicity of the derivatives and their ability to stabilize the intercalation complex was identified for all of the studied agents. Acridines 17a-17j were also subjected to in vitro screening conducted by the Developmental Therapeutic Program of the National Cancer Institute (NCI) against a panel of 60 cancer cell lines. The strongest biological activity was displayed by aniline acridine 17a (MCF7-GI50 18.6 nM) and N,N-dimethylaniline acridine 17b (SR-GI50 38.0 nM). The relationship between the cytostatic activity of the most active substances (derivatives 17a, 17b, and 17e-17h) and their values of KB, LogP, ΔS°, and δ was also investigated. Due to the fact that a significant correlation was only found in the case of charge density, δ, it is possible to assume that the cytostatic effect might be dependent upon the structural specificity of the acridine derivatives.

Solvent Effect on the Chemiluminescence of Acridinium Thioester: A Computational Study.

Chemiluminescent labelling, which is one of the promising procedures of modern immunodiagnostics, is increasingly carried out using acridinium derivatives, an oxidant, and an alkaline aqueous environment. However, the efficiency of the chemiluminescence of luminol or acridinium esters is higher in non-aqueous solvents such as dimethyl sulfoxide or acetonitrile. Therefore, the search for a new environment for the chemiluminescence reaction, especially the one characterized by a higher quantum yield of chemiluminescence, is one of the aims of current research. Using computational methods (DFT and TD DFT with PCM model of solvent), we examined thermodynamic and kinetic data concerning the chemiluminescence and competitive dark pathways. Our results suggest that better characteristics of the chemiluminescence reaction of acridinium thioester are observed in nonpolar solvents, such as methylcyclohexane, n-hexane and n-pentane, than in aqueous media used so far. Further experimental verification is necessary to confirm the possible application of proposed nonpolar solvents in chemiluminescent labelling and hence in immunodiagnostics.

New Polymerizable Tetraaza Macrocycle Containing Two Acridine Units for Selective Fluorescence Sensing of Metal Ions.

A new fluorescent bis(acridino)-macrocycle containing two allyl groups was synthesized and photophysically studied. Studies were carried out on metal ion recognition and selectivity-influencing effects including the determination of the relevant thermodynamic constants as logK and pKa. The proposed sensor molecule is recommended for the development of Zn2+-selective optochemical analyzers based on covalently immobilized ionophores as it has a unique pH-independent metal ion recognition ability, which is not influenced by anions and other potentially occurring metal ions in biological samples.

Synthesis, computational study and biological evaluation of 9-acridinyl and 1-coumarinyl-1,2,3-triazole-4-yl derivatives as topoisomerase II inhibitors.

Topoisomerase (IIB) inhibitors have been involved in the therapies of tumour progression and have become a major focus for the development of anticancer agents. New three-component hybridised ligands, 1,4-disubstituted-1,2,3-triazoles (8-17), were synthesised via a 1,3-dipolar cycloaddition reaction of 9-azidoacridine/3-azidocoumarin with N/O-propargyl small molecules under click reaction conditions. Cancer cell growth inhibition of the synthesised triazoles was tested against human cell-lines in the NCI-60-cell-panel, and the most active compounds tested against topoisomerase (IIB)-enzymes. The acridinyl ligands (8-10) revealed 60-97% cell growth inhibition in six cancer cell-panels. Cell-cycle analysis of MCF7 and DU-145 cells treated with the active acridinyl ligands exhibited cell-cycle arrest at G2/M phase and proapoptotic activity. In addition, compound 8 displayed greater inhibitory activity against topoisomerase (IIB) (IC50 0.52 µM) compared with doxorubicin (IC50 0.83 µM). Molecular dynamics simulation studies showed the acridine-triazole-pyrimidine hybrid pharmacophore was optimal with respect to protein-ligand interaction and fit within the binding site, with optimal orientation to allow for intercalation with the DNA bases (DG13, DC14, and DT9).

Novel Cyclopentaquinoline and Acridine Analogs as Multifunctional, Potent Drug Candidates in Alzheimer's Disease.

A series of new cyclopentaquinoline derivatives with 9-acridinecarboxylic acid and a different alkyl chain length were synthesized, and their ability to inhibit cholinesterases was evaluated. All designed compounds, except derivative 3f, exhibited a selectivity for butyrylcholinesterase (BuChE) with IC50 values ranging from 103 to 539 nM. The 3b derivative revealed the highest inhibitory activity towards BuChE (IC50 = 103.73 nM) and a suitable activity against AChE (IC50 = 272.33 nM). The 3f derivative was the most active compound to AChE (IC50 = 113.34 nM) with satisfactory activity towards BuChE (IC50 = 203.52 nM). The potential hepatotoxic effect was evaluated for both 3b and 3f compounds. The 3b and 3f potential antioxidant activity was measured using the ORAC-FL method. The 3b and 3f derivatives revealed a significantly higher antioxidant potency, respectively 35 and 25 higher than tacrine. Theoretical, physicochemical, and pharmacokinetic properties were calculated using ACD Labs Percepta software. Molecular modeling and kinetic study were used to reveal the mechanism of cholinesterase inhibition in the most potent compounds: 3b and 3f.