Chloroquine Diphosphate Research Articles

A Polyoxometalate-Encapsulated Metal–Organic Framework Nanoplatform for Synergistic Photothermal–Chemotherapy and Anti-Inflammation of Ovarian Cancer

Photothermal therapy (PTT), as a noninvasive and local treatment, has emerged as a promising anti-tumor strategy with minimal damage to normal tissue under spatiotemporally controllable irradiation. However, the necrosis of cancer cells during PTT will induce an inflammatory reaction, which may motivate tumor regeneration and resistance to therapy. In this study, polyoxometalates and a chloroquine diphosphate (CQ) co-loaded metal-organic framework nanoplatform with hyaluronic acid coating was constructed for efficient ovarian cancer therapy and anti-inflammation. Our results demonstrated that this nanoplatform not only displayed considerable photothermal therapeutic capacity under 808 nm near-infrared laser, but also had an impressive anti-inflammatory capacity by scavenging reactive oxygen species in the tumor microenvironment. CQ with pH dependence was used for the deacidification of lysosomes and the inhibition of autophagy, cutting off a self-protection pathway induced by cell necrosis-autophagy, and achieving the synergistic treatment of tumors. Therefore, we combined the excellent properties of these materials to synthesize a nanoplatform and explored its therapeutic effects in various aspects. This work provides a promising novel prospect for PTT/anti-inflammation/anti-autophagy combinations for efficient ovarian cancer treatment through the fine tuning of material design.

Kinetics of Drug Molecule Interactions with a Newly Developed Nano-Gold-Modified Spike Protein Electrochemical Receptor Sensor.

In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic, and the spike protein has been reported to be an important drug target for anti-COVID-19 treatment. As such, in this study, we successfully developed a novel electrochemical receptor biosensor by immobilizing the SARS-CoV-2 spike protein and using AuNPs-HRP as an electrochemical signal amplification system. Moreover, the time-current method was used to quantify seven antiviral drug compounds, such as arbidol and chloroquine diphosphate. The results show that the spike protein and the drugs are linearly correlated within a certain concentration range and that the detection sensitivity of the sensor is extremely high. In the low concentration range of linear response, the kinetics of receptor–ligand interactions are similar to that of an enzymatic reaction. Among the investigated drug molecules, bromhexine exhibits the smallest Ka value, and thus, is most sensitively detected by the sensor. Hydroxychloroquine exhibits the largest Ka value. Molecular docking simulations of the spike protein with six small-molecule drugs show that residues of this protein, such as Asp, Trp, Asn, and Gln, form hydrogen bonds with the -OH or -NH2 groups on the branched chains of small-molecule drugs. The electrochemical receptor biosensor can directly quantify the interaction between the spike protein and drugs such as abidor and hydroxychloroquine and perform kinetic studies with a limit of detection 3.3 × 10−20 mol/L, which provides a new research method and idea for receptor–ligand interactions and pharmacodynamic evaluation.

Continuous removal of pharmaceutical drug chloroquine and Safranin-O dye from water using agar-graphene oxide hydrogel: Selective adsorption in batch and fixed-bed experiments

In this work, Chloroquine diphosphate, and the cationic dye Safranin-O were selectively removed from water using the agar-graphene oxide (A-GO) hydrogel, produced via simple one-step jellification process. The morphology of the A-GO biocomposite was characterized and batch experiments were performed, with adsorption isotherms satisfactorily fitting (R2 > 0.98) Sips (Safranin-O) and Freundlich (Chloroquine) isotherms. Driving force models and Fick's diffusion equation were applied to the modeling of kinetic data, and a satisfactory fit was obtained. Selective adsorption carried out in batch indicated that competitive adsorption occurs when both components are mixed in water solution - the adsorptive capacities dropped ∼10 mg g−1 for each component, remaining 41 mg g−1 for safranin-O and 31 mg g−1 for chloroquine. Fixed-bed breakthrough curves obtained in an adsorption column showed adsorption capacities over 63 mg g−1 and 100 mg g−1 for chloroquine and safranin-O, respectively, also exhibiting outstanding regenerative potentials. Overall, the biocomposite produced using graphene oxide proved to be a viable and eco-friendly alternative to continuously remove both contaminants from water.

Copper (I)-Chloroquine Complexes: Interactions with DNA and Ferriprotoporphyrin, Inhibition of β-Hematin Formation and Relation to Antimalarial Activity

A new Cu(I)-chloroquine (CQ) complex [Cu(CQ)(PPh3)2]NO3 (1) was synthesized and characterized, and its mechanism of action studied concomitant with the previously reported complex [Cu(CQ)2]Cl (2). These copper (I) coordination compounds can be considered as potential antimalarial agents because they show better inhibition of the CQ-resistant strain in in vitro studies than CQ alone. In comparison with other metal-CQ complexes, only the gold complex was similar to (1), i.e., more active than CQ against both CQ-susceptible (3D7) and CQ-resistant strains (W2). These two copper (I)-compounds also demonstrated higher antiplasmodial activity against W2 than other copper complexes reported to date. This suggests that the incorporation of the copper metal center enhanced the biological activity of CQ. To better understand their significant growth inhibition of the Plasmodium falciparum parasite, the interaction with two essential molecular targets for the survival and proliferation of the malarial parasite were studied. These were the ferriprotoporphyrin group and the DNA, both important targets for current antimalarial drugs at the asexual erythrocytic stages. Both compounds (1,2) exhibited significant interactions with these targets. In particular, interactions with the DNA were dominated by the intercalator properties of the CQ ligand but may have also been affected by the presence of copper. Overall, these compounds were better parasitic inhibitors than chloroquine diphosphate (CQDP) alone or other previously reported metal-CQ complexes such as platinum, ruthenium and gold.

Green-emission nitrogen-doped carbon quantum dots from alkaline N-methyl-2-pyrrolidinone for determination of β-galactosidase and its inhibitors.

Anew fluorescence method was established for sensitive detection of β-galactosidase (β-gal) activity in spiked human serum and screeningof inhibitor. Nitrogen-doped carbon quantum dots (N-CQDs) were prepared by solvothermal polymerization of N-methyl-2-pyrrolidinone in an alkaline condition. The colloidal N-CQDs exhibit good water solubility, stability, and emit bright green fluorescence with a maximum emission peak at 528nm upon excitation at 420nm. β-gal specifically catalyzes the decomposition of its substrate P-nitrophenyl-β-D-galactopyranoside into 4-nitrophenol, whose absorption spectrum overlaps well with the excitation spectrum of the N-CQDs. As a result, the fluorescence of the N-CQDs is remarkably quenched by 4-nitrophenol via an inner filter effect. The sensing platform presents a linear response range for β-gal activity from 0.05 to 3.0 U·L-1 with a low limit of detection of 0.023 U·L-1. An acceptable precision is obtained with a relative standard deviation (RSD) of 3.1% for 1.0 U·L-1 β-gal (n = 11). The method was applied to determine β-gal in spiked human serums with recoveries in the range 96.3-104.7%. The methodwas employed to evaluate inhibitor screening with D-galactal and chloroquine diphosphate as models.

Rhenium(I) derivatives of aminoquinoline and imidazolopiperidine-based ligands: Synthesis, in vitro and in silico biological evaluation against Plasmodium falciparum

A small library of aminoquinoline and imidazolopiperidine (IMP)-based ligands, containing the 1,2,3-triazole moiety, and their corresponding tricarbonyl rhenium complexes were synthesised and their inhibitory activities evaluated against the chloroquine-sensitive (CQS) and multidrug-resistant (MDR) strains (NF54 and K1, respectively) of P. falciparum. The quinoline-based compounds (L1, L2, ReL1, and ReL2) were at least six-fold more potent than their IMP-based counterparts (L3, L4, ReL3, and ReL4) against both strains of P. falciparum, with the most promising compound (L1) displaying activity comparable to chloroquine diphosphate (CQDP) in the MDR strain. Additionally, all of the synthesised compounds have resistance indices less than CQDP. To gain insight into a possible mechanism of action, in silico hemozoin docking simulations were performed. These studies proposed that the tested compounds may act via hemozoin inhibition, as the new aminoquinoline-derivatives, with the exception of complex ReL2 (binding affinity: −12.62 kcal/mol), showed higher binding affinities than the reference drug chloroquine (CQ, −13.56 kcal/mol). Furthermore, the ligands exhibited superior binding affinity relative to their corresponding Re(I) complexes, which is reflected in their antiplasmodial activity.

Synthesis and Antimalarial Activity Assay of <i>C</i>- Arylcalix[4]pyrogallolarenes Using Heme Polymerization Inhibition Activity (HPIA) Method

Malaria is one of the most devastating and widespread tropical parasitic diseases in developing countries with high prevalence. Furthermore, antimalarial drug resistance results in a global resurgence of malaria. Thus there is an urgent need to find new and active antimalarial agents. In this work, we reported the synthesis of C-arylcalix[4]pyrogallolarenes and their in vitro activity assay as new antimalarial agent candidates. The C-arylcalix[4]pyrogallolarenes were prepared in high yields through a condensation reaction between pyrogallol and aromatic aldehydes (i.e., benzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, and 2-chlorobenzaldehyde) under acidic conditions. The antimalarial activity of C-arylcalix[4]pyrogallolarenes was tested using the Heme Polymerization Inhibition Activity (HPIA) method with chloroquine diphosphate as the positive control. The heme polymerization inhibitory activity was reflected from the IC50 values in which the IC50 values were obtained from probit analysis using IBM SPSS statistics 25 software. The result showed that the IC50 values of C-arycalix[4]pyrogallolarene derivatives were in a range of 0.238–1.268 mg/mL, which were lower than chloroquine diphosphate (IC50 = 2.788 mg/mL). This finding reveals that the C-arylcalix[4]pyrogallolarenes are potential antimalarial agents to be developed in the future.

Synthesis of <i>N</i>-Phenylpyrazoline Derivative from 4-Chlorobenzaldehyde and 4-Chloroacetophenone and its Activity as an Antimalarial Agent

This study was aimed to synthesize N-phenylpyrazoline derivative and evaluate its antimalarial activity. The pyrazoline was synthesized from chalcone derivative through a cyclo- condensation reaction. Moreover, chalcone derivative was prepared from 4-chlorobenzaldehyde and 4-chloroacetophenone through Claisen-Schmidt condensation. The structure elucidation of the products was performed by FTIR, GC-MS, 1H- and 13C-NMR spectrometers. The antimalarial assay was conducted by inhibition of heme polymerization. The chalcone was obtained as a white solid in 83% yield, while N-phenylpyrazoline derivative was obtained as brown solid in 70% yield. The IC50 values of chalcone and N-phenylpyrazoline derivatives as well as a positive control (chloroquine diphosphate) were 98.66, 20.83, and 3.54 mg/mL, respectively. The results showed that both chalcone and N-phenylpyrazoline derivatives had lower antimalarial activity than the positive control. Molecular docking studies were also performed to explain the mode of action of chalcone and N-phenyl pyrazoline as antimalarial agent.

Chemistry of glycol nucleic acid (GNA): Synthesis, photophysical characterization and insight into the biological activity of phenanthrenyl GNA constituents

The knowledge pertaining to the chemistry and biological activity of glycol nucleic acid (GNA) components, like nucleosides and nucleotides, is still very limited. Herein we report on the preparation of the uracil nucleoside (1) and nucleotide ester GNA (2). The compounds are functionalised with a luminescent phenanthrenyl group. In DMSO, 1 and 2 are brightly fluorescent, with emission maxima at 390 nm, nanosecond decay times (0.6 and 0.75 ns, respectively), and quantum yields of ca. 0.2. In the solid phase, they show excimeric emission, with maxima at 495 nm (1) and 432 nm (2), and decay times of 3.7 ns (1) and 2.9 ns (2). The anticancer activity of the GNA components, as well as gemcitabine hydrochloride, used as a reference drug, were examined in vitro against human cancer HeLa and Ishikawa cells, as well as against normal L929 cells, using a battery of biochemical assays. Furthermore, biodistribution imaging studies were carried out in HeLa cells, with luminescence confocal microscopy, which showed that the compounds localized mainly in the lipophilic cellular compartments. Nucleoside (1) and nucleotide ester (2) features two different anticancer activity profiles. At 24 h of treatment, the nucleoside acts mainly as a toxin and induces necrosis in HeLa cells, whereas the nucleotide ester exhibits pro-apoptotic activity. At longer treatment times (72 h), the nucleoside and the reference, gemcitabine hydrochloride, featured almost identical signs of anticancer activity, such as S-phase cell cycle arrest, proliferation inhibition, and apoptosis induction. In view of this data, one can hypothesize that despite the structural differences, the newly obtained phenanthrenyl GNA nucleoside (1) and gemcitabine may share a common mechanism of anticancer activity in HeLa cancer cells. The GNA components were also examined as antiplasmodial agents against Plasmodium falciparum, in vitro. Nucleoside (1) was found to be more potent than nucleotide (2), displaying activity in the low micromolar range. Furthermore, both phenanthrene derivatives were found to display resistance indices at least 9-fold lower than chloroquine diphosphate (CQDP).

Trifluridine induces HUVECs senescence by inhibiting mTOR-dependent autophagy

Trifluridine, a key component of trifluridine/tipiracil, is a potential anti-cancer drug that can act effectively on refractory metastatic colorectal cancer. Chemotherapy is important for cancer treatment, but its adverse effects limit its use. Long-term side-effects caused by the drug used during chemotherapy are closely related to the accumulation of cellular senescence. However, the relationship between trifluridine and normal cell aging remains unclear. The purpose of this study is to evaluate whether trifluridine can induce the senescence of human umbilical vein endothelial cells and to explore the possible mechanism. Human umbilical vein endothelial cells were treated with trifluridine, senescence levels were measured via senescence-related acidic β-galactosidase staining and senescence-associated secretory phenotype levels respectively. Autophagy was assessed by the protein levels of LC3II/LC3I and p62, and LC3 fusion was detected by fluorescence microscopy. Chloroquine diphosphate salt and rapamycin were used to detect the effect of trifluridine on autophagy flux and mTOR signaling pathway. Trifluridine increased the expression of senescence-associated acidic β-galactosidase and senescence-related secretory phenotype mRNA levels in cells. In addition, also trifluridine induced cellular senescence by inhibiting autophagy and was closely related to the activation of the mTOR signaling pathway, therefore, we believe that trifluridine may be an effective mTOR activator. The findings also provide a new strategy for establishing autophagy or aging models, as well as a new theoretical basis for the use of trifluridine in clinical treatment.

Nicorandil alleviates cardiac remodeling and dysfunction post -infarction by up-regulating the nucleolin/autophagy axis

ObjectiveThe present study aimed to investigate whether the drug nicorandil can improve cardiac remodeling after myocardial infarction (MI) and the underlying mechanisms. MethodsMouse MI was established by the ligation of the left anterior descending coronary artery and H9C2 cells were cultured to investigate the underlying molecular mechanisms. The degree of myocardial collagen (Col) deposition was evaluated by Masson's staining. The expressions of nucleolin, autophagy and myocardial remodeling-associated genes were measured by Western blotting, qPCR, and immunofluorescence. The apoptosis of myocardial tissue cells and H9C2 cells were detected by TUNEL staining and flow cytometry, respectively. Autophagosomes were observed by transmission electron microscopy. ResultsTreatment with nicorandil mitigated left ventricular enlargement, improved the capacity of myocardial diastolic-contractility, decreased cardiomyocyte apoptosis, and inhibited myocardial fibrosis development post-MI. Nicorandil up-regulated the expression of nucleolin, promoted autophagic flux, and decreased the expressions of TGF-β1 and phosphorylated Smad2/3, while enhanced the expression of BMP-7 and phosphorylated Smad1 in myocardium. Nicorandil decreased apoptosis and promoted autophagic flux in H2O2-treated H9C2 cells. Autophagy inhibitors 3-methyladenine (3MA) and chloroquine diphosphate salt (CDS) alleviated the effects of nicorandil on apoptosis. Knockdown of nucleolin decreased the effects of nicorandil on apoptosis and nicorandil-promoted autophagic flux of cardiomyocytes treated with H2O2. ConclusionsTreatment with nicorandil alleviated myocardial remodeling post-MI through up-regulating the expression of nucleolin, and subsequently promoting autophagy, followed by regulating TGF-β/Smad signaling pathway.

Investigation of Chloroquine Resinate Feasibility and In Vitro Taste Masking Evaluation for Pediatric Formulations.

In this study, chloroquine resinates were prepared at a 1:1 (w:w) drug-to-resin ratio using the batch method with polacrilex (PC), sodium polystyrene sulfonate (SPS), and polacrilin potassium (PP) ion exchange resins (IER). The influence of drug/resin ratio and pH of the medium on drug loading efficiency was explored. UV-VIS spectrophotometric analysis showed that SPS resin had high loading efficiency for chloroquine diphosphate (CLP), above 89%, regardless of the pH. PP resin was more effective at pH 5.0 (90.68%) than at pH 1.0 (2.09%), and PC resin had only 27.63% of CLP loading efficiency. CLP complexation with IER yielded amorphous mixtures according to results from differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD), thus indicating drug-resin interaction. The taste masking efficiency was evaluated with in vitro methods using an adapted dissolution test and an electronic tongue system. During dissolution tests, SPS released only 1.0% of CLP after 300 s, while PP released over 10% after 90 s in simulated saliva solution. The electronic tongue distinguished the samples containing CLP, resins, and resinates by using multidimensional projection techniques that indicated an effective drug taste masking. In an accelerated stability study, the drug contents did not decrease in chloroquine resinates, and there was no physical degradation of the resinates after 60 days. Using chloroquine resinates therefore represents a novel way to evaluate taste masking in vitro which is relevant for the early formulation development process.

Antimalarial Activity of Ethanol Extract of Kelakai Leaves (Stenochlaena palustris) to Parasitemia and Splenomegaly in BALB/c Mice Infected with Plasmodium berghei ANKA

Introduction: Malaria is one of global health problems. Splenomegaly is one of malaria symptoms. Antimalarial drug resistance had been reported. Alternative treatment is by using traditional medicinal plants such as kelakai (Stenochlaena palustris). Kelakai contains alkaloid and flavonoid which had been reported to have antimalarial activity. The aim of this study was to discover antimalarial activity of ethanol extract of kelakai leaves to parasitemia and splenomegaly of Plasmodium berghei ANKA in infected BALB/c mice.Methods: This study was based on a modified Peter test using BALB/c mice infected with P. berghei ANKA treated with ethanol extract of kelakai leaves, with chloroquine diphosphate as a positive control. The negative control was P. berghei ANKA infected mice without any additional treatment. Administration of ethanol extract of kelakai leaves was performed for 4 days with a serial doses of 100, 10, and 1 mg/kg body weight. The positive control was given chloroquine diphosphate 20 mg/kg body weight. Parasitemia was observed daily prior to the calculation of the percentage of parasite growth and parasite growth inhibition. At the end of the test, the mice were sacrificed and spleens were isolated to measure their sizes. Probit analysis was performed to obtain ED50 to find the effect of extract in parasite killing by 50%. Spearman test was performed to analyze the correlation of doses of extract and splenomegaly.Results: Parasitemia growth inhibition was directly proportional to the dose. Higher parasitemia inhibition was obtained at higher doses and vice versa. Result of probit analysis showed an ED50 was 77.05 mg/kg body weight. Statistical analysis resulted in insignificant correlation between doses and splenomegaly p = 1.0 (significancy < 0.05).Conclusion: Ethanol extract of kelakai leaves possessed good antimalarial activity and there was no correlation between extract doses and splenomegaly in Plasmodium berghei ANKA-infected mice.

The Effect of Andrographis paniculata Nees on Oxidative Stress and Parasitemia Levels of Plasmodium berghei Infected Rats

Background: During malaria infection, oxidative stress arises due to the high metabolic rate of the multiplying parasite within the erythrocyte. Malondialdehyde (MDA), a product of lipid peroxidation and glutathione (GSH) has been suggested as a biomarker of oxidative stress. The Ethyl acetate (EA) fraction from the ethanol extract of Andrographis paniculata was shown to inhibit Plasmodium berghei in vivo. However, the antimalarial mechanism of the EA fraction, specifically on oxidative stress has not been investigated previously. Therefore, this study aimed to investigate the effects of the EA fraction on parasitemia levels, GSH and MDA levels of P. berghei infected rats. Methods: Female Wistar rats infected with P. berghei were divided into three groups. Group one received no treatment (negative control), group two was treated with 1.4 mg/200 g body weight of chloroquine diphosphate as positive control, and group three was treated with the EA fraction at a dose equal to andrographolide 3.5 mg/200 g body weight. The treatments lasted for four days (day 0 to day 3) and parasitemia was observed from day 0 to day 4. Rats were sacrificed and blood taken intracardially on day 4 after parasitemia observation. GSH was measured using an ELISA reader at a wavelength of 415 nm. MDA was observed via spectrophotometry at a wavelength of 532 nm. Results: The EA fraction at a dose equal to andrographolide 3.5 mg/200 g body weight was able to inhibit parasite growth by 81.97±9.14%. The GSH levels of the negative control, positive control and EA fraction treated group were 139.30±75.93 μMol/mL, 81.06±53.26 μMol/mL and 105.71±76.00 μMol/mL, respectively. Furthermore, the MDA level of negative control, positive control and EA fraction treated group were 11.18±0.70 nMol mL, 8.81±1.26 nMol/mL and 9.40±0.74 nMol/mL, respectively. No significant differences were detected between treatment groups regarding their GSH levels. Additionally, there was a significant difference in MDA levels between the negative control and positive control groups; as well as a significant difference between the negative control and the EA treated group. However, no significant difference in MDA levels between the EA fraction treated group and positive control group. Interestingly, a correlation was found between parasite growth inhibition and MDA levels among groups (p<0.05). Conclusion: The EA fraction of A. paniculata significantly decreased MDA levels which correlated significantly with parasitemia levels of P. berghei infected rats. The antimalarial activity of the EA fraction may have been correlated with oxidative stress mechanisms and this correlation could be explained in part by the decreased production of MDA.

Hemoglobin Variants Influence Plasmodium Falciparum Sexual Differentiation

It has long been recognized that individuals who express variations of the hemoglobin-A (HbA) protein experience less severe malaria disease. As malaria remains to be one of the most significant infectious diseases in history, this human adaptation has led to the persistence of HbA variants (HbVARs) in the population. The intricate lifecycle of the parasite which causes the most cases of clinical malaria, Plasmodium falciparum, relies on both asexual and sexual reproductive cycles, with host to vector transmission reliant on sexual stage gametocyte formation. Multiple epidemiological studies have shown that HbVARs may influence gametocyte production during P. falciparum infection, with greater gametocyte numbers reported in individuals with hemoglobin variant containing erythrocytes (Hb VAR-Ery) when compared to hemoglobin A containing erythrocytes (Hb A-Ery). Here we provide experimental support for these studies by showing significantly higher sexual differentiation rates among parasites grown in Hb S containing erythrocytes (Hb S-Ery) obtained from sickle cell patients than those differentiated in Hb A-Ery (p=0.038). Because the digestion of hemoglobin is such an integral part of the intraerythrocytic cycle, we then sought to determine whether there was a difference between the hydrolysis efficiencies of HbA and other hemoglobin variants (HbVAR). By using a prominent recombinant P. falciparum hemoglobinase we found the hydrolysis efficiency of HbA to be significantly (p=0.0058) more efficient after 24 hours compared to a HbVAR sample containing mixed amounts of HbA, HbF, and HbS. To further determine whether there is a link between hemoglobin digestion efficiency and sexual differentiation, we therapeutically inhibited the hemoglobin digestion and hemozoin formation process in a culture of P. falciparum using sub-optimal doses of chloroquine diphosphate. We found a significant difference (p<0.001) among gametocyte conversion rates between treated and non-treated cultures, as well as a moderate negative correlation between hemozoin formation and gametocyte conversion rate (Pearson r=0.72, p=0.008). Gene expression analysis also revealed patterns of expression that were consistent with increased gametocytogenesis. We conclude that hemoglobin type plays a significant role in the process of sexual conversion in P. falciparum. Though further studies should be completed in order to confirm these results, these findings may suggest hemoglobin digestion efficiency as a causative factor for sexual differentiation. As individuals with hemoglobinopathies make up approximately 7% of the global population, and malaria infection rates have been shown to differ depending on these genetic dynamics, these findings may support the creation of targeted initiatives to reduce transmission specifically in areas where there is a high percentage of hemoglobinopathy carriage. DisclosuresNo relevant conflicts of interest to declare.

Synthesis, characterization, docking study and biological evaluation of new chalcone, pyrazoline, and pyrimidine derivatives as potent antimalarial compounds

Malaria is a protozoan disease caused by a unicellular parasite named Plasmodium (Phylum- Apicomplexa). World Health Organization has estimated roughly fifty percent of the world’s community lives under the continuing threat of malaria. The focus of drug discovery has increased towards valuable structures known as chalcones, pyrazoline, and pyrimidine due to their extensive bioactivity in malaria treatment. In this study, four chalcone derivatives (1–4) have been synthesized via the Claisen-Schmidt condensation. New compounds of 12 pyrazolines (1–4)Ai-iii and eight pyrimidines, (1–4)Bi-ii derivatives have also been synthesized via a ring-closing reaction of the chalcones. All the synthesized compounds were characterized and tested against malaria. The results showed that compound 1Aiii exhibited significant antiproliferative effects against 3D7 and RKL9 with 3D7 = 2.1 μg/mL, IC80 3D7 = 8 μg/mL, and IC50 RKL9 when exposed to compared to the reference anticancer drug, CQ Chloroquine diphosphate, and Artemisinin. The molecular docking analysis showed that compounds 1, 1Aiii and 1Bi had entered the PfATP4 receptor pocket and had been stuck with the amino acids in a high affinity of binding.

O-24 A CASE SERIES OF CHLOROQUINE MONOTHERAPY TO INDUCE BIOCHEMICAL REMISSION IN PATIENTS WITH RELAPSED AUTOIMMUNE HEPATITIS

Azathioprine (AZA) and prednisone (PD) are the standard treatment (ST) for the onset or relapse of autoimmune hepatitis (AIH). Antimalarials were effective for maintenance of remission of AIH after immunosuppression withdrawal. Our aim is to describe a series of patients who relapsed after antimalarial withdrawal and achieved biochemical remission after reintroduction of chloroquine in monotherapy. Eight patients received chloroquine diphosphate (DCQ) 250mg/d or hydroxichloroquine (HCQ) 400-800mg/d in monotherapy for biochemical remission after relapse. The schedule is described below: histological remission (HR) with ST → ST withdrawal and antimalarial use for maintenance of remission for 1-3y → antimalarial withdrawal → relapse of AIH → reintroduction of antimalarial instead of ST, at the request of patient due to corticosteroids side effects (SE). Four out of 8 patients underwent liver biopsy to evaluate HR after at least 18mo of biochemical remission. Mean age at diagnosis of AIH of 36.2 ± 20.4y; 6 type-1, 2 anti-SLA/LP (5 reactive in 7 tested); 3 with cirrhosis at diagnosis. Mean doses of AZA/PD at HR were, respectively, 84.4 ± 18.6 and 9.4 ± 2.2mg/d. Mean interval between antimalarial withdrawal and relapse was 20.5 ± 34.1mo. Mean ALT at relapse was 139.7 ± 54.2 U/L. Three patients received DCQ and 5 HCQ. During HCQ intake 1 patient needed further adjustment of drug to 800 mg/d for 15 days due to worsening of ALT from 130 to 246 U/L, with subsequent reduction to the initial dose. Seven patients achieved biochemical remission, in a mean time of 14.2 ± 19.9mo; 3/4 had histological remission. The drug was well tolerated and there were no serious SE. CQ monotherapy was safe and effective for induction of remission in this subgroup of AIH. This finding raises arguments to include this drug as an option for treatment of AIH, not necessarily in monotherapy.

Dependence of Viscosity and Diffusion on β-Cyclodextrin and Chloroquine Diphosphate Interactions

Mutual diffusion coefficients of chloroquine diphosphate (CDP) in aqueous solutions both without and with β-cyclodextrin (β-CD) were measured at concentrations from (0.0000 to 0.0100) mol dm−3 and 298.15 K, using the Taylor dispersion technique. Ternary mutual diffusion coefficients (Dik) measured by the same technique are reported for aqueous CDP + β-CD solutions at 298.15 K. The presence of β CD led to relevant changes in the diffusion process, as showed by nonzero values of the cross-diffusion coefficients, D12 and D21. β-CD concentration gradients produced significant co-current coupled flows of CDP. In addition, the effects of β-CD on the transport of CDP are assessed by comparing the binary diffusion coefficient of aqueous CDP solutions with the main diffusion coefficient (D11) measured for ternary {CDP(1) + β-CD(2)} solutions. These observations are supported by viscosity analysis. All data allow to have a better interpretation on the effect of cyclodextrin on the transport behavior of CDP.

Investigation of molecular interactions insight into some biologically active amino acids and aqueous solutions of an anti-malarial drug by physicochemical and theoretical approach

Herein we have made a comprehensive analysis of the mode of interactions between the L-Alanine/L-Valine and Chloroquine diphosphate in aqueous solution. Evaluation of different Physico-chemical parameters like density, viscosity, refractive index, conductance study (at three different temperatures), and surface tension (at 298.15 K) at atmospheric pressure have used to help in the gathering of knowledge about the existence of plausible intermolecular interactions in the ternary (Drug + Water + Amino acid) solution. Furthermore, apparent molar volume, limiting apparent molar volume, viscosity B-coefficient, and molar refraction, limiting molar refraction all support the idea that the leading solute–solvent interaction is influenced by the solute concentration and temperature. In addition, in aqueous Chloroquine diphosphate, both amino acids showed structure-breaking activities. The system's Gibbs free energy change was measured, suggesting its spontaneity. The 1H NMR spectroscopy results showed significance changes in the shifting of aromatic protons of CDP and protons of amino acids indicating that a strong interaction (hydrophobic-hydrophobic) takes place among them which is further supported by our theoretical observations. L-Valine-Drug interactions were found to be more predominating over L-Alanine-Drug interactions, according to both experiment and theory. Models for mixtures of drug molecules and amino acids could be developed using the experimental and correlated results.

Positive effect of hydroxychloroquine on lipid profiles of patients with rheumatoid arthritis: A Veterans Affair cohort.

Despite remarkable improvements in rheumatoid arthritis (RA) treatment, there is evidence indicating that the mortality gap between patients with RA and the general population is not closing. The increase in mortality rates in patients with RA is predominantly due to cardiovascular disease (CVD). Literature suggests that important links exist between RA inflammation and atherosclerosis in CVD. Dyslipidemia is a well-known risk factor of atherosclerosis. Previous studies have suggested that antimalarials, chloroquine diphosphate, and hydroxychloroquine (HCQ), used in the treatment of autoimmune diseases, have a beneficial effect on the lipid levels. However, the studies had small sample sizes. We analyzed a Veterans Affair RA cohort of 2,925 patients to characterize the effect of 4 months' use of HCQ on the lipid levels. Data for this cohort were obtained from the department of Veterans Affairs administrative database. Individuals (age ≥18 years) with a diagnosis of RA (ICD-9 code) at 2 or more outpatient visits from 1999 to 2009 were identified. Only the patients with at least 1 lipid level measured at 120-180 days before staring HCQ were included. Lipids levels on pre- and poststart dates of HCQ (120-180 days) were compared using student's t-test and adjusted for age, sex, race, C-reactive protein (CRP), and statin use with multivariable regression (analysis of variance/analysis of covariance) for the change in different lipid levels. To give equal weightage to covariables, we conducted an analysis of marginal means for race in each lipid level. All analyses were performed using STATA 11. After adjusting for sex, age, race, statin use, and post CRP values >10 mg/dL using a linear regression, the factor driving the change in the different lipid levels was race (p values for total cholesterol, 0.006; low-density lipoprotein, 0.09; non-high-density lipoprotein [HDL], 0.03; atherogenic index, 0.08; and HDL, 0.17). When considering race individually using marginal means analysis, the race in the subgroup "others" was more influential. Our results suggest that sex and race influences the HCQ effect on the lipid profiles in patients with RA. Use of HCQ in males is found to be associated with positive changes in the lipid profiles independent from the use of statins. There is a suggestion that whites and African Americans might be less susceptible to HCQ effect on lipid profiles than other races.