4-aminoquinoline Derivatives Research Articles

Discovery of new 4-aminoquinoline derivatives containing an amine or hydroxamic acid terminal as multifunctional agents for the treatment of Alzheimer’s disease

Discovery of new 4-aminoquinoline derivatives containing an amine or hydroxamic acid terminal as multifunctional agents for the treatment of Alzheimer’s disease

Unveiling the 4-aminoquinoline derivatives as potent agents against pancreatic ductal adenocarcinoma (PDAC) cell lines

Common antimalarials such as artemisinins, chloroquine and their derivatives also possess potent anti-inflamantory, antiviral and anticancer properties. In the search for new therapeutics to combat difficult-to-treat pancreatic carcinomas, we unveiled that 4-aminoquinoline derivatives, with significant antiplasmodial properties and a great safety profile in vivo, have remarkable anticancer activity against pancreatic ductal adenocarcinoma (PDAC) and considerable efficacy in the xenograft model in vivo. The aim of the present study was to further investigate anticancer properties of these compounds in a drug-repurposing manner. The compounds showed profound cytotoxic effects at nanomolar to low micromolar concentration in 2D cultured cells (in vitro) and in the zebrafish PDAC xenograft model (in vivo). A deeper insight into their mechanisms of cytotoxic action showed these compounds induce apoptosis while increasing reactive oxygen species levels along with autophagy inhibition. Additional investigation of the autophagy modulation proved that tested quinoline derivatives cause P62 and LC3-II accumulation in PDAC cells alongside lysosomal alkalinization. Further, in vivo toxicity studies in the zebrafish model showed low toxicity without developmental side effects of the investigated 4-aminoquinolines, while the applied compounds effectively inhibited tumor growth and prevented the metastasis of xenografted pancreatic cells. Taken together, these results highlight the 4-aminoquinolines as privileged structures that ought to be investigated further for potential application in pancreatic carcinoma treatment.

Lewis Acid Mediated Synthesis of 4-Aminoquinoline Derivatives from 2-Aminobenzonitriles and Activated Alkynes via Aza-Michael and Annulation Reactions

AbstractAn efficient methodology for the synthesis of highly diverse 4-aminoquinoline derivatives from activated alkynes and 2-aminobenzonitriles mediated by Lewis acid is described. The reaction proceeds via sequential aza-Michael addition/intramolecular annulation to afford highly substituted 4-aminoquinolines in good yields. The reaction is operationally simple and has high atom-economy with broad substrate scope. The post synthetic application of the reaction provides 4H-benzo[de][1,6]naphthyridines.

Degradation of hydroxychloroquine in aqueous solutions under electron beam treatment

Abstract Hydroxychloroquine (HCQ), a 4-amino quinoline derivative, has antimalarial and anti-inflammatory activity and was most recently proposed in the treatment of SARS-COVID-19. Its pharmacokinetics and toxic side effects necessitate the monitoring of its presence in the environment and its removal from wastewater. In this study, HCQ was removed from an aqueous solution with a removal efficiency of between 80% and 90% under electron beam (EB) irradiation. The degradation of HCQ was propagated by reactions involving both the hydroxyl radical and aqueous electron. The degradation was observed to follow a pseudo-first-order kinetic reaction. The applied radiation dose, pH, and initial HCQ concentration were influential in the degradation efficiency under EB irradiation. Acidic and alkaline pH favored the removal of HCQ under EB irradiation. Even though the initial HCQ was successfully degraded, it was not completely mineralized. The TOC and chemical oxygen demand (COD) remained at a relatively stable level following EB irradiation of the aqueous solutions. This is attributed to the formation of other organic compounds that were not degraded under the investigated experimental conditions.

Analysis of the interaction of antimalarial agents with Plasmodium falciparum glutathione reductase through molecular mechanical calculations.

Malaria remains a significant global health challenge with emerging resistance to current treatments. Plasmodium falciparum glutathione reductase (PfGR) plays a critical role in the defense mechanisms of malaria parasites against oxidative stress. In this study, we investigate the potential of targeting PfGR with conventional antimalarials and dual drugs combining aminoquinoline derivatives with GR inhibitors, which reveal promising interactions between PfGR and studied drugs. The naphthoquinone Atovaquone demonstrated particularly high affinity and potential dual-mode binding with the enzyme active site and cavity. Furthermore, dual drugs exhibit enhanced binding affinity, suggesting their efficacy in inhibiting PfGR, where the aliphatic ester bond (linker) is essential for effective binding with the enzyme's active site. Overall, this research provides important insights into the interactions between antimalarial agents and PfGR and encourages further exploration of its role in the mechanisms of action of antimalarials, including dual drugs, to enhance antiparasitic efficacy. The drugs were tested as PfGR potential inhibitors via molecular docking on AutoDock 4, which was performed based on the preoptimized structures in HF/3-21G-PCM level of theory on ORCA 5. Drug-receptor systems with the most promising binding affinities were then studied with a molecular dynamic's simulation on AMBER 16. The molecular dynamics simulations were performed with a 100ns NPT ensemble employing GAFF2 forcefield in the temperature of 310K, integration time step of 2fs, and non-bond cutoff distance of 6.0Å.

4-Aminoquinoline derivatives as potent inhibitors of pancreatic cancer: Synthesis, evaluation and docking studies.

Herein we describe synthesis and evaluation of 4-aminoquinoline derivatives as anticancer agents. By using Friedlander type condensation and cyclization reactions, the new compounds were synthesized in one-pot from commercially available anthranilonitriles and substituted acetophenones in excellent yields. All the new compounds were purified, fully characterized, and evaluated for in vitro anticancer activity against different cancer cell lines HeLa (human cervical carcinoma), MIA PaCa-2 (pancreatic cancer), PANC-1(pancreatic cancer), SK-N-SH (neuroblastoma), and DU145 (prostate cancer). Compound 3g was found to be the most potent derivative among all the tested compounds against five cancer cell lines, with 50 % inhibition concentration, IC50 of 3.85±0.16, 3.75±0.32, 3.8 ± 0.13, 4.29±0.56, and 5.13±0.78 μM, respectively, with the lowest IC50 value in MIA PaCa-2 cancer cells. The exact mechanism of action of 3g was therefore investigated in MIA-PaCa-2 cells. The results show that 3g induces dose-dependent cell cycle arrest during the G2/M phase. Furthermore, downregulation of the expression of cell cycle marker proteins, such as that of cyclin B1 and Cdc25C, was found to be the reason for the termination of the G2/M phase. Furthermore, docking analysis of the promising compounds 3f, 3g, 3i, and 3j revealed the most efficient molecular interactions with the target protein cyclooxygenase-2 (PDB ID: 1CX2). Overall, 3 g could prove to be an effective agent for treating pancreatic cancer.

Preparation of a novel cadmium-containing coordination polymer and catalytic application in the synthesis of N-alkylated aminoquinoline derivatives via the borrowing hydrogen approach.

Herein, we report an efficient and straightforward approach for the synthesis of N-alkylated aminoquinoline derivatives by recyclable Cd-containing coordination polymer-catalyzed reactions of aminoquinolines with primary alcohols via the borrowing hydrogen strategy. In this work, a new type of coordination polymer [Cd(CIA)(phen)2(H2O)]n was successfully designed and fabricated. The molecular structure was corroborated by single-crystal X-ray diffraction and fully characterized by PXRD, FT-IR, TGA, and XPS. Importantly, this polymer revealed high catalytic activity for the N-alkylation reaction of 2-aminoquinoline and 8-aminoquinoline with inexpensive and low-toxicity alcohols as alkylating agents in excellent yields up to 95%. Interestingly, the present synthetic protocol was successfully applied for the gram-level synthesis of several biologically active compounds. In addition, several control reactions were carried out to investigate the possible mechanisms of this transformation. Finally, recycling experiments indicated that the cadmium coordination polymer showed good recovery performance for borrowing hydrogen reactions.

Aerobic Dehydrogenative Aromatization in the Preparation of 4-Aminoquinoline Derivatives by Synergistic Pd/Cu Catalysis.

The 4-aminoquinoline moiety is widely present in various bioactive compounds and marketed drugs, while the preparation of this target structure relies heavily on the amination of 4-chloroquinolines. Herein, an atom and step economic procedure was developed based on an aerobic dehydrogenative aromatization strategy. Unlike the well-known palladium-catalyzed dehydrogenative aromatization of cyclohexanones with amines, synergistic Pd/Cu catalysis is crucial for 2,3-dihydroquinolin-4(1H)-one type of substrates. Under the optimized conditions, a range of aromatic/aliphatic amines and 2,3-dihydroquinolin-4(1H)-ones were coupled to give the corresponding 4-aminoquinoline products in moderate to high yields, and the application of the current methodology for the preparation and late-stage diversification of marketed drugs was also demonstrated.

Evaluation of the biological activity of different 4-aminoquinolines for the development of new drugs against painful and inflammatory disorders

The potential biological properties of four 4-aminoquinoline derivatives (1–4) have been previously demonstrated. However, the evaluation of important aspects of their toxicity, anti-inflammatory, and antinociceptive activities has not been described. Here, we report other pharmacological properties of 1–4 using classic in vivo models of pain and inflammation. Preliminary toxicity tests revealed the narrow therapeutic window of the compounds, and the doses for biological tests were chosen after median lethal dose (LD50) determination. Then, the formalin-induced nociception test was used for screening. The antinociceptive and anti-inflammatory potentials were observed only in the inflammatory phase among 1–3 at the highest administered dose (50 mg/kg, p.o.). This response pattern was confirmed for all compounds in the acute inflammation model of zymosan-induced peritonitis. The intriguing lack of activity in the first phase of the formalin test led us to explore other pathways through other methods. The derivatives exhibited antinociceptive activity in peripheral and central components of pain in different patterns among models. In the acetic acid-induced writhing test, oral pretreatment with 1 and 2 significantly reduced painful behavior. Glutamate-mediated nociceptive induction was attenuated by 1 and 3. Under thermal stimulation, all compounds produced antinociception in the hot plate test in mice, confirming a centrally mediated action. Moreover, 1–3 at antinociceptive and anti-inflammatory doses did not affect the motor performance in mice in the rotarod test, thus validating the data. This work is the first report of these activities for 1–3. Because they are chloroquine analogs, these compounds represent ideal prototypes of antinociceptive and anti-inflammatory drugs that are able to induce peripheral and central effects on pain and inflammation pathways. Further studies are needed for pharmacodynamic characterizations.

Evaluation of synthetic aminoquinoline derivatives as urease inhibitors: in vitro, in silico and kinetic studies.

Background: Quinoline and acyl thiourea scaffolds have major chemical significance in medicinal chemistry. Quinoline-based acyl thiourea derivatives may potentially target the urease enzyme. Materials & methods: Quinoline-based acyl thiourea derivatives 1-26 were synthesized and tested for urease inhibitory activity. Results: 19 derivatives (1-19) showed enhanced urease enzyme inhibitory potential (IC50=1.19-18.92μM) compared with standard thiourea (IC50=19.53±0.032μM), whereas compounds 20-26 were inactive. Compounds with OCH3, OC2H5, Br and CH3 on the aryl ring showed significantly greater inhibitory potential than compounds with hydrocarbon chains of varying length. Molecular docking studies were conducted to investigate ligand interactions with the enzyme's active site. Conclusion: The identified hits can serve as potential leads against the drug target urease in advanced studies.

Paper-based fluorescent sensors from quinoline ligands for distance-based quantification of Zn2+

A series of aminoquinoline derivatives with different N-alkyl substituents were synthesized and used in the development of paper-based fluorescent sensors. In aqueous solutions, the quinoline ligands show strong green fluorescence selectively upon binding to Zn2+ that is clearly observed by naked eyes under blacklight illumination. The paper-based sensors were prepared by depositing the amidoquinoline derivatives in wax-printed channels on filter paper. Developing of Zn2+ samples, deposited below the ligand spots, with an aqueous buffer solution creates green fluorescent lines suitable for distance measurement. The ligands with a tertiary amino group showed better-defined fluorescent lines than those of ligands containing primary and secondary amino groups. The length of the fluorescent lines increases linearly with the amounts of Zn2+ in the range of 2.5–80 nmol that can be easily determined by naked-eye observation or an image processing software. The increase in hydrophobicity of the ligands results in a wider dynamic concentration range of the detection. The paper-based sensor can accurately and conveniently quantify Zn2+ in drinking water, dietary supplement, and fertilizer samples.

Synthesis of Azuleno[2,1-b]quinolones and Quinolines via Brønsted Acid-Catalyzed Cyclization of 2-Arylaminoazulenes.

Quinolone and quinoline derivatives are frequently found as substructures in pharmaceutically active compounds. In this paper, we describe a procedure for the synthesis of azuleno[2,1-b]quinolones and quinolines from 2-arylaminoazulene derivatives, which are readily prepared via the aromatic nucleophilic substitution reaction of a 2-chloroazulene derivative with several arylamines. The synthesis of azuleno[2,1-b]quinolones was established by the Brønsted acid-catalyzed intramolecular cyclization of 2-arylaminoazulene derivatives bearing two ester groups at the five-membered ring. The halogenative aromatization of azuleno[2,1-b]quinolones with POCl3 yielded azuleno[2,1-b]quinolines with a chlorine substituent at the pyridine moiety. The aromatic nucleophilic substitution reaction of azuleno[2,1-b]quinolines bearing chlorine substituent with secondary amines was also investigated to afford the aminoquinoline derivatives. These synthetic methodologies reported in this paper should be valuable in the development of new pharmaceuticals based on the azulene skeleton.

Toxicological effects of hydroxychloroquine sulfate and chloroquine diphosphate substances on the early-life stages of fish in the COVID-19 pandemic context.

Hydroxychloroquine sulfate (HCQ) and chloroquine diphosphate (CQ) have been used at increased rates to treat COVID-19 but can constitute a potential environmental risk. The objective was to evaluate the toxicity of sublethal concentrations of HCQ and CQ in zebrafish embryos/larvae. The 50% lethal concentrations (LC50) of HCQ and CQ at 96 h post-fertilization (hpf) were calculated by testing various concentrations on 2,160 embryos. The LC50 obtained were 560 and 800 µM for HCQ and CQ, respectively. Next, the embryotoxicity assay was performed, where 1,200 embryos were subjected to sublethal concentrations of HCQ and CQ. The hatching and heart rates were recorded. After euthanasia, photomicrographs of all larvae were taken to measure the total length, pericardial and yolk sac areas. The embryos exposed to sublethal concentrations of HCQ and CQ showed delayed hatching at 72 hpf, as well as an increase in the heart rate, larger pericardial and yolk sac areas, and body malformations at 96 hpf. The findings show that HCQ and CQ are toxic to fish in the early development phases. Understanding the mechanisms of toxicity will help extrapolate the effects of 4-aminoquinoline derivatives when they reach the aquatic environment in the context of the COVID-19 pandemic.

Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer's disease

The most successful therapeutic strategy in the treatment of Alzheimer's disease (AD) is directed toward increasing levels of the neurotransmitter acetylcholine (ACh) by inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes responsible for its hydrolysis. In this paper, we extended our study on 4-aminoquinolines as human cholinesterase inhibitors on twenty-six new 4-aminoquinolines containing an n-octylamino spacer on C(4) and different substituents on the terminal amino group. We evaluated the potency of new derivatives to act as multi-targeted ligands by determining their inhibition potency towards human AChE and BChE, ability to chelate biometals Fe, Cu and Zn, ability to inhibit the action of β-secretase 1 (BACE1) and their antioxidant capacity. All of the tested derivatives were very potent inhibitors of human AChE and BChE with inhibition constants (Ki) ranging from 0.0023 to 1.6 μM. Most of the compounds were estimated to be able to cross the blood-brain barrier (BBB) by passive transport and were nontoxic to human neuronal, kidney and liver cells in concentrations in which they inhibit cholinesterases. Generally, newly synthesised compounds were weak reductants compared to standard antioxidants, but all possessed a certain amount of antioxidant activity compared to tacrine. Of the eleven most potent cholinesterase inhibitors, eight compounds also inhibited BACE1 activity at 10–18%. Based on our overall results, compounds 8 with 3-fluorobenzyl, 11 with 3-chlorobenzyl and 17 with 3-metoxy benzyl substituents on the terminal amino group stood out as the most promising for the treatment of AD; they strongly inhibited AChE and BChE, were non-toxic on HepG2, HEK293 and SH-SY5Y cells, had the potential to cross the BBB and possessed the ability to chelate biometals and/or inhibit the activity of BACE1 within a range close to the therapeutically desired degree of inhibition.

DBU-Catalyzed Efficient One-Pot Three-Component Synthesis of Aminoquinoline Derivatives via Betti Reaction in Polar Medium and Antidiabetic Activity of the Products

DBU-Catalyzed Efficient One-Pot Three-Component Synthesis of Aminoquinoline Derivatives via Betti Reaction in Polar Medium and Antidiabetic Activity of the Products

Construction of Chiral Cyclobutanone-Fused 4-Aminoquinolines via Sequential Chiral Phosphoric Acid and Palladium Catalysis.

A one-pot catalytic asymmetric route to novel chiral quaternary-carbon-containing cyclobutanone-fused 4-aminoquinoline derivatives in good to high yields and enantioselectivities is described. This process consists of a chiral phosphoric acid-catalyzed desymmetric carbonyl-amine condensation of prochiral cyclobutane-1,3-diones with 2-halogenated anilines and a Pd-catalyzed coupling reaction of the chiral enaminone intermediates with isocyanides.

Metal-free [2 + 2] and [4 + 2] cycloadditions ofN-aryl-substituted ynamides to construct functionalized aminocyclobutenes and 4-aminoquinolines

Metal-free [2 + 2] and [4 + 2] self-cycloadditions ofN-aryl-substituted ynamides provide various valuable functionalized aminocyclobutenes and 4-aminoquinoline derivatives.

4-Aminoquinolines as Antimalarial Agents: Review of A Medicinal Chemistry Perspective

Abstract: Malaria is a potentially fatal parasitic disease brought on by five Plasmodium species, including Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi. The fast emergence of P. falciparum resistance to currently available treatments has increased health concerns in developing countries. The growth in resistance emphasizes the need for a novel, secure, and cost-effective antimalarial drug that can treat malaria resistant to multiple antimalarial drugs. Therefore, it has become crucial to create new therapeutic approaches to deal with the rise of parasites resistant to artemisinin. For the treatment of P. falciparum malaria in children living in areas with moderate to high transmission, as established by WHO, the malaria vaccine RTS, S has been authorized. The WHO recommends that governments consider this immunization against a human parasite when deciding the optimum subnational combination of measures for maximum impact. The current research synthesizes numerous 4-aminoquinoline derivatives successfully treating malaria and its diverse etiological species. Additionally crucial to the management and prevention of malaria are antibiotics. Effective and well-tolerated antimalarial medications include tetracycline and chloramphenicol, chloroquine, primaquine, pamaquine, and artemisinins are some of the drugs used to treat malaria; however, numerous new compounds have proven to be even more efficient. This review, based on literature reports, will give medicinal chemists ideas for new malaria drugs to develop. In addition, this review will help search for new antimalarial drug leads in the future.

Side effects of long-term treatment with chloroquine for rheumatoid arthritis - a review of the literature

Background: Chloroquine is a 4-aminoquinoline derivative. Initially the substance was used as an antimalarial drug, but now chloroquine is also used to treat connective tissue diseases. It is a widely used drug in rheumatological diseases, especially in rheumatoid arthritis and systemic lupus erythematosus. A number of side effects have been reported in the public literature among patients using this drug. This article reviews side effects during long-term treatment of patients with rheumatoid arthritis. Materials and methods: A review of the literature available in the PubMed database was performed, using the key words: "Chloroquin" ; "Chloroquin rheumatoid" ; "Chloroquin toxicity" ; "Chloroquine" ; "Chloroquine rheumatoid" ; "Chloroquine toxicity". Results: Chloroquine is a quinine derivative, originally used in the prevention and treatment of malaria. It is now being successfully used to treat patients with certain connective tissue diseases, including rheumatoid arthritis. A number of publications have described various side effects of this drug. Serious and major problems arise from the drug's toxicity with long-term use, such as in the treatment of rheumatoid arthritis. Long-term use of the drug results in retinopathy and cardiotoxicity (conduction disturbances, cardiomyopathy). The available literature also mentions neuromyotoxicity which is rarely reported by patients. Conclusion: Long-term use of chloroquine carries serious side effects. The main complications of long-term use of the drug affect the visual, cardiovascular and nervous systems. The use of chloroquine in patients with rheumatoid arthritis should emphasize the need for accurate dosing and periodic cardiovascular, ophthalmologic and neurologic monitoring.

Design, synthesis and biological evaluation of 4-aminoquinoline derivatives as receptor-interacting protein kinase 2 (RIPK2) inhibitors

Receptor-interacting protein kinase 2 (RIPK2) is an essential protein kinase mediating signal transduction by NOD1 and NOD2, which play an important role in regulating immune signalling. In this study, we designed and synthesised a novel series of 4-aminoquinoline-based derivatives as RIPK2 inhibitors. In vitro, compound 14 exhibited high affinity (IC50 = 5.1 ± 1.6 nM) and excellent selectivity to RIPK2 showing in a dendrogram view of the human kinome phylogenetic tree. Bearing favourable lipophilicity and eligible lipophilic ligand efficiency (LipE), compound 14 was selected to investigate cellular anti-inflammatory effect and was identified as a potent inhibitor to reduce the secretion of MDP-induced TNF-α with a dose-dependent manner. Moreover, compound 14 showed moderate stability in human liver microsome. Given these promising results, compound 14 could serve as a favourable inhibitor of RIPK2 for further physiological and biochemical research so as to be used in therapeutic treatment.