4-aminoquinoline Derivatives Research Articles

Physicochemical characteristics of the sorption of 4-aminoquinoline derivatives from water-acetonitrile solutions on nonpolar sorbents

Regularities of the retention of certain 4-aminoquinoline derivatives in the conditions of the reversed phase type of high performance liquid chromatography (HPLC) on octadecyl silica (ODS) and hypercrosslinked polystyrene (HCLPS) are studied. The correlation between the structure of aminoquinolines and their chromatographic retention is demonstrated.

A colorimetric sensor for pH utilizing a quinoline derivative

A simple sensor utilizing a simple aminoquinoline derivative (5-(quinolin-8-yliminol) pentanal, QYP) has been successfully developed for the naked-eye colorimetric assay of pH. The QYP compound presents strong solvatochromism due to the solute–solvent interaction, and it is sensitive to a pH change in the solution. The color of the solution changes from orange to colorless upon increasing the pH value, which is well consistent with the corresponding UV/vis absorbance variation. UV absorbance has a direct linear relationship with the pH values in the range of 4.0 to 8.0 in phosphate-buffered saline, and the corresponding color variation could be distinguished readily by the naked eye.

Palladium-Catalyzed Cascade Reactions of Isocyanides with Enaminones: Synthesis of 4-Aminoquinoline Derivatives

A method for palladium-catalyzed cascade reactions of isocyanides with enaminones has been developed. This methodology provides a direct approach to 4-aminoquinoline derivatives under mild conditions with up to 98% yields.

1218

Introduction: Hydroxychloroquine is a Aminoquinoline derivative which is widely used for treatment of malaria, rheumatoid arthritis and lupus besides many other autoimmune diseases. Though neutropenia is listed as a potential side effect, there is no reported case in the literature. We present a very rare presentation of hydroxychloroquine toxicity. CASE PRESENTATION 36 year old female presented with fever, malaise, chills and a lip rash for 3 days duration.Her past history included eosinophilic fasciitis being treated with methotrexate for 2 years which was stopped due to intolerence 3 weeks ago and she was started on hydroxychloroquine 300mg daily. Investigation revealed WBC 300,absolute neutrophil 0, Hg 13.1, Hct 39.2, platelets 51,000. Hydroxychloroquine was stopped and she was admitted in ICU for septic shock. She was started on Filgrastim and broad spectrum antibiotics for neutropenic fever. Her blood cultures were positive for methicillin sensitive Staphylococcus aureus which was treated with appropriate antibiotics.. On day 4 her count were 21,700 with absolute neutrophil 17,190. Filgrastim was then stopped. White blood count increased up to 44,100. She was afebrile from day 2 and her repeat cultures were negative. She was successfully treated and discharged to home on day 10 of hospital admission. Discussion: Hydroxychloroquine has relative safety profile with 0.73% incidence of neutropenia. Though there are some case reports of its use to treat neutropenia in some condition like Felty's syndrome(1), this is the first reported case of profound neutropenia to the best of our knowledge. This case illustrates the importance of anticipation and early recognition of its potential fatal side effect. REFERENCES: 1 Neutropenia in Felty's syndrome successfully treated with hydroxychloroquine. Mahévas M, Audia S, De Lastours V, Michel M, Bonotte B, Godeau B. Chloroquine cardiomyopathy - a review of the literature.Tönnesmann E, Kandolf R, Lewalter T.Immunopharmacol Immunotoxicol. 2013 Jun;35(3):434-42. doi: 10.3109/08923973.2013.780078. Epub 2013 May 1.12. Efficient and effective screening for hydroxychloroquine toxicity.Marmor MF.Am J Ophthalmol. 2013 Mar;155(3):413-4. doi: 10.1016/j.ajo.2012.10.020.

Aminoquinoline Derivatives as HCV Inhibitors

Aminoquinoline Derivatives as HCV Inhibitors Jean-Francois Brazeau and Gerard Rosse* Structure Guided Chemistry, Dart Neuroscience LLC, 7473 Lusk Boulevard, San Diego, California 92121, United States Adjunct Associate Professor, Department of Pharmacology and Physiology, College of Medicine, Drexel University, New College Building, 245 North 15th Street, Philadelphia, Pennsylvania 19102, United States

Synthesis, antimalarial-, and antibacterial activity evaluation of some new 4-aminoquinoline derivatives

Some new 4-aminoquinoline derivatives were synthesized, characterized by their analytical and spectral data (IR, 1HNMR, 13CNMR and MS), and screened for in vitro antimalarial activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7). Results clearly reveal that all the synthesized compounds possess in vitro antimalarial activity at the tested dose which, however, was considerably less than that of the standard reference drug, chloroquine. From results, it could be assumed that the presence of an aromatic bulky group with optimal lipophilicity at 1,3-thiazinan-4-one ring system might be an important requirement for the antimalarial activity of synthesized compounds, 6a–g. In addition to the evaluation of antimalarial activity, the synthesized compounds were also screened for antibacterial activity against six different strains of Gram-positive (Bacillus subtilis, Bacillus cereus, and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae). All the compounds at the tested doses were found to be active against all the tested organisms, but were less active as compared to the standard drug, ofloxacin. Results of antibacterial study indicate that aromatic bulky substituents have greater contributing effect than the aliphatic non-bulky group toward the antibacterial activity of the prepared 4-aminoquinoline derivatives.

A Parallel Design Study to Assess the Bioequivalence of Generic and Branded Hydroxychloroquine Sulfate Tablets in Healthy Volunteers

Hydroxychloroquine (HCQ) is a racemic 4-aminoquinoline derivative that was first introduced as an antimalarial, and subsequently applied to the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Information on the pharmacokinetics of HCQ in healthy volunteers, especially in a Chinese population is limited, and this study was conducted to provide support for a generic product to obtain marketing authorization in China.The aim of the present study was to compare the pharmacokinetics and assess bioequivalence of a new generic test and the branded reference hydroxychloroquine sulfate tablets in healthy volunteers.This was a parallel, open-label, randomized, single-dose, 1-period fasting study. 54 healthy subjects were randomly assigned (1:1) to receive 200 mg hydroxychloroquine sulfate tablets of the test or the reference formulation. 15 blood samples were collected and whole blood concentrations of HCQ were determined by a validated liquid chromatography-isotopic dilution mass spectrometry method. Log-transformed Cmax and AUC0-24 values were used to test for bioequivalence. The 2 formulations were considered bioequivalent if 90% confidence intervals (CIs) for the log-transformed ratios of Cmax and AUC0-24 were within the predetermined bioequivalence range of 80-125%. Tolerability was evaluated throughout the study by vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and interviews with the subjects about adverse events.54 healthy subjects were enrolled and completed the study (mean [SD] age, height, body weight, and BMI were 23.9 [2.4] years, 168.9 [5.0] cm, 61.3 [5.4] kg, and 21.5 [1.7] kg/m2), 27 subjects per group. No formulation or sequence effects were observed. The mean values of Cmax and AUC0-24 for the test and reference formulations of HCQ (197.6 and 199.0 ng/mL, 2460.1 and 2468.3 ng/mL/h) were not significantly different. The 90% CIs of the ratios of Cmax and AUC0-24 were 99.3% (98.1-102.1%), 99.7% (98.9-101.4%), respectively. 4 subjects (7.41%) experienced a total of 4 mild AEs (headache and microscopic hematuria, 1 each; and increase in plasma triglycerides, 2).The results of this study suggest that the test and reference hydroxychloroquine sulfate tablets are bioequivalent. Both formulations were generally well tolerated.

Synthesis and antitumor activity of novel 4-aminoquinoline derivatives

A series of novel 4-aminoquinoline derivatives were synthesized as antitumor agents by reacting 4-chloroquinoline with the corresponding mono/dialkyl amines. The cytotoxicity of these compounds was evaluated in vitro against HCT-116, A549, DU-145, HepG2, and LN229 cell lines. The results showed that most of the synthesized compounds displayed excellent cytotoxicity, and 5,7-dimethoxy-2-phenyl-N-propylquinoline-4-amine (6a) displayed the most potent cytotoxicity against HCT-116 cells. Furthermore, 6a could decrease VEGF protein expression. The synthesis and antitumor activity of 4-aminoquinoline derivatives have been described.

Synthesis and evaluation of hybrid drugs for a potential HIV/AIDS-malaria combination therapy

Malaria and HIV are among the most important global health problems of our time and together are responsible for approximately 3 million deaths annually. These two diseases overlap in many regions of the world including sub-Saharan Africa, Southeast Asia and South America, leading to a higher risk of co-infection. In this study, we generated and characterized hybrid molecules to target Plasmodium falciparum and HIV simultaneously for a potential HIV/malaria combination therapy. Hybrid molecules were synthesized by the covalent fusion of azidothymidine (AZT) with dihydroartemisinin (DHA), a tetraoxane or a 4-aminoquinoline derivative; and the small library was tested for antiviral and antimalarial activity. Our data suggests that compound 7 is the most potent molecule in vitro, with antiplasmodial activity comparable to that of DHA (IC50=26nM, SI>3000), a moderate activity against HIV (IC50=2.9μM; SI>35) and not toxic to HeLa cells at concentrations used in the assay (CC50>100μM). Pharmacokinetics studies further revealed that compound 7 is metabolically unstable and is cleaved via O-dealkylation. These studies account for the lack of in vivo efficacy of compound 7 against the CQ-sensitive Plasmodium berghei N strain in mice, when administered orally at 20mg/kg.

Novel 4-Aminoquinoline Analogs Highly Active against the Blood and Sexual Stages of Plasmodium In Vivo and In Vitro

New drugs to treat malaria must act rapidly and be highly potent against asexual blood stages, well tolerated, and affordable to residents of regions of endemicity. This was the case with chloroquine (CQ), a 4-aminoquinoline drug used for the prevention and treatment of malaria. However, since the 1960s, Plasmodium falciparum resistance to this drug has spread globally, and more recently, emerging resistance to CQ by Plasmodium vivax threatens the health of 70 to 320 million people annually. Despite the emergence of CQ resistance, synthetic quinoline derivatives remain validated leads for new drug discovery, especially if they are effective against CQ-resistant strains of malaria. In this study, we investigated the activities of two novel 4-aminoquinoline derivatives, TDR 58845, N(1)-(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine, and TDR 58846, N(1)-(7-chloro-quinolin-4-yl)-2,N(2),N(2)-trimethylpropane-1,2-diamine and found them to be active against P. falciparum in vitro and Plasmodium berghei in vivo. The P. falciparum clones and isolates tested were susceptible to TDR 58845 and TDR 58846 (50% inhibitory concentrations [IC(50)s] ranging from 5.52 to 89.8 nM), including the CQ-resistant reference clone W2 and two multidrug-resistant parasites recently isolated from Thailand and Cambodia. Moreover, these 4-aminoquinolines were active against early and late P. falciparum gametocyte stages and cured BALB/c mice infected with P. berghei. TDR 58845 and TDR 58846 at 40 mg/kg were sufficient to cure mice, and total doses of 480 mg/kg of body weight were well tolerated. Our findings suggest these novel 4-aminoquinolines should be considered for development as potent antimalarials that can be used in combination to treat multidrug-resistant P. falciparum and P. vivax.

The Ca2+-ATPase (SERCA1) Is Inhibited by 4-Aminoquinoline Derivatives through Interference with Catalytic Activation by Ca2+, Whereas the ATPase E2 State Remains Functional

Several clotrimazole (CLT) and 4-aminoquinoline derivatives were synthesized and found to exhibit in vitro antiplasmodial activity with IC(50) ranging from nm to μm values. We report here that some of these compounds produce inhibition of rabbit sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1) with IC(50) values in the μm range. The highest affinity for the Ca(2+)-ATPase was observed with NF1442 (N-((3-chlorophenyl)(4-((4-(7-chloroquinolin-4-yl)piperazin-1-yl)methyl)phenyl)methyl)-7-chloro-4-aminoquinoline) and NF1058 (N-((3-chlorophenyl)(4-(pyrrolidin-1-ylmethyl)phenyl)methyl)-7-chloro-4-aminoquinoline),yielding IC(50) values of 1.3 and 8.0 μm as demonstrated by measurements of steady state ATPase activity as well as single cycle charge transfer. Characterization of sequential reactions comprising the ATPase catalytic and transport cycle then demonstrated that NF1058, and similarly CLT, interferes with the mechanism of Ca(2+) binding and Ca(2+)-dependent enzyme activation (E(2) to E(1)·Ca(2) transition) required for formation of phosphorylated intermediate by ATP utilization. On the other hand, Ca(2+) independent phosphoenzyme formation by utilization of P(i) (i.e. reverse of the hydrolytic reaction in the absence of Ca(2+)) was not inhibited by NF1058 or CLT. Comparative experiments showed that the high affinity inhibitor thapsigargin interferes not only with Ca(2+) binding and phosphoenzyme formation with ATP but also with phosphoenzyme formation by utilization of P(i) even though this reaction does not require Ca(2+). It is concluded that NF1058 and CLT inhibit SERCA by stabilization of an E(2) state that, as opposed to that obtained with thapsigargin, retains the functional ability to form E(2)-P by reacting with P(i).

Polymeric Conjugates of Selected Aminoquinoline Derivatives as Potential Drug Adjuvants in Cancer Chemotherapy

In the chemotherapy of cancerous diseases, the clinical co-administration of an active anti-tumor drug with other compounds acting as potentiating agents or adjuvants has demonstrated considerable merits in comparison with single-drug administration. Selected members of the 4- and 8-aminoquinoline-based class of antimalarials, such as chloroquine and hydroxychloroquine, have been identified as providers of such adjuvant effects in combination with certain standard antitumor drugs, although no significant clinical experiences have as yet been reported. The here described project aims at the synthesis of water-soluble macromolecular carriers to which selected aminoquinolines are bioreversibly conjugated together with cytotoxic drug species exemplified by a diaminoplatinum(II) complex and by the organoiron compound, ferrocene, the latter being a relative newcomer to the family of organometallic antineoplastic agents. As most medicinal agents differ from each other by their pharmacokinetic path and, therefore, experience different rates and degree of body distribution and organ accumulation, the simultaneous availability of two or more mutually potentiating drug species can best be achieved if a common transport vehicle, such as a multifunctional carrier polymer of the type synthesized in this study, is utilized for this purpose. The conjugates and co-conjugates, isolated by conventional methods as water-soluble solids, are compositionally characterized by NMR-spectroscopic and microanalytical techniques.

Synthesis of new 4-aminoquinolines and quinoline–acridine hybrids as antimalarial agents

Despite emergence of resistance to CQ and other 4-aminoquinoline drugs in most of the endemic regions, research findings provide considerable support that there is still significant potential to discover new affordable, safe, and efficacious 4-aminoquinoline antimalarials. In present study, new side chain modified 4-aminoquinoline derivatives and quinoline–acridine hybrids were synthesized and evaluated in vitro against NF 54 strain of Plasmodium falciparum. Among the evaluated compounds, compound 17 (MIC = 0.125 μg/mL) was equipotent to standard drug CQ (MIC = 0.125 μg/mL) and compound 21 (MIC = 0.031 μg/mL) was four times more potent than CQ. Compound 17 showed the curative response to all the treated swiss mice infected with CQ-resistant N-67 strain of Plasmodium yoelii at the doses 50 mg/kg and 25 mg/kg for four days by intraperitoneal route and was found to be orally active at the dose of 100 mg/kg for four days. The promising antimalarial potency of compound 17 highlights the significance of exploring the privileged 4-aminoquinoline class for new antimalarials.

ChemInform Abstract: Compounds with Positive Inotropic Activity. Part 3. Synthesis of 4- Aminoquinoline Derivatives as Potential Positive Inotropic Agents.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

4-Aminoquinoline derived antimalarials: Synthesis, antiplasmodial activity and heme polymerization inhibition studies

A new series of 4-aminoquinoline derivatives have been synthesized and found to be active against both susceptible and resistant strains of Plasmodium falciparum in vitro. Compound 1-[3-(7-chloro-quinolin-4-ylamino)-propyl]-3-cyclopropyl-thiourea ( 7) exhibited superior in vitro activity against resistant strains of P. falciparum as compared to chloroquine (CQ). All the compounds showed resistance factor between 0.59 and 4.31 as against 5.05 for CQ. Spectroscopic studies suggested that this class of compounds act on heme polymerization target.

Synthesis and anti-prion activity evaluation of aminoquinoline analogues

Transmissible spongiform encephalopathies form a group of neurodegenerative diseases that affect humans and other mammals. They occur when the native prion protein is converted into an infectious isoform, the scrapie PrP, which aggregates, leading to neurodegeneration. Although several compounds were evaluated for their ability to inhibit this conversion, there is no effective therapy for such diseases. Previous studies have shown that antimalarial compounds, such as quinolines, possess anti-scrapie activity. Here, we report the synthesis and evaluate the effect of aminoquinoline derivatives on the aggregation of a prion peptide. Our results show that 4-amino-7-chloroquinoline and N-(7-chloro-4-quinolinyl)-1,2-ethanediamine inhibit the aggregation significantly. Therefore, such aminoquinolines might be considered as candidates for the further development of therapeutics to prevent the development of prion diseases.

Synthesis and Biological Activity of Some 2‐(2’‐(Substituted Phenyl‐4‐thiazolidinone‐3‐yl)‐1’3’‐isoxazol‐4‐yl)aminoquinoline Derivatives

Quinoline a heterocyclic nucleus, played a pivotal role in the development of different medicinal agents and in the field of agrochemicals. Several 2‐(2’‐substituted phenyl‐4‐thiazolidinon‐3‐yl)‐1’3’‐isoxazol‐4‐yl) amino‐quinoline IV(a-k) have been prepared 2‐(substituted arylideneimino‐1’3’‐isoxazol‐4’‐yl) aminoquinoline III(a-k) and tested for their antimicrobial and antifungal activity against different microorganism. The structure of compound III(a-k) and IV(a-k) have confirmed on the basis of their elemental and spectral analysis such as IR, 1H NMR and Mass spectrometry.

A 4-aminoquinoline derivative that markedly sensitizes tumor cell killing by Akt inhibitors with a minimum cytotoxicity to non-cancer cells

The purpose of this study was to evaluate the enhancement value of chloroquine analogs when used in combination with Akt inhibitors on the MDA-MB468, MDA-MB231 and MCF7 human breast cancer cell lines. The result showed that the combination of certain chloroquine analogs and Akt inhibitors are highly effective. In particular, the chloroquine analog N′-(7-fluoro-quinolin-4-yl)-N,N-dimethyl-ethane-1,2-diamine (compound 5) was highly effective in sensitizing cancer cell killing when combined with either Akt inhibitor 8 (1-{1-[4-(7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)-benzyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one) or 9 ([4-(2-chloro-4a,10a-dihydro-phenoxazin-10-yl)-butyl]-diethyl-amine hydrochloride). Importantly, the enhancement of chloroquine analogs 5 on cell killing by Akt inhibitors 8 and 9 was cancer-specific. Thus, this combinational approach is highly promising in controlling tumors with a minimum side effect. Structural analysis of effective and ineffective chloroquine analogs suggests that the 4-aminoquinoline scaffold and lateral side chain of dimethylamino functionality play an important role for the enhancement of cell killing by Akt inhibitors.

Aminoquinoline derivatives with antiproliferative activity against melanoma cell line

The synthesis of a novel series of aminoquinoline derivatives 1a–p and their antiproliferative activities against A375 human melanoma cell line were described. Most compounds showed superior antiproliferative activities to Sorafenib as a reference compound. Among them, quinolinyloxymethylphenyl compounds 1k and 1l exhibited potent activities (IC 50 = 0.77 and 0.79 μM, respectively) and excellent selectivity against melanoma and fibroblast cell lines.

Design, synthesis and in vitro antitumor activity of 4-aminoquinoline and 4-aminoquinazoline derivatives targeting EGFR tyrosine kinase

Two series of new 6-alkoxy-4-substituted-aminoquinazolines (2– 4f) and their bioisoteric quinoline congeners (5– 7c) were designed and synthesized. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors. The newly synthesized compounds were tested in vitro on human breast carcinoma cell line (MCF-7) in which EGFR is highly expressed. Most of the tested compounds exploited potent antitumor activity with IC 50 values in the nanomolar range in particular compound 3b which displayed the highest activity among the tested compounds with IC 50 equal to 0.13 nmol.