ABSTRACT
Starting from the antimalarial drugs chloroquine and hydroxychloroquine, we conducted a structural optimization on the side chain of chloroquine by introducing amino substituted longer chains thus leading to a series of novel aminochloroquine derivatives. Anti-infectious effects against SARS-Cov2 spike glycoprotein as well as immunosuppressive and anti-inflammatory activities of the new compounds were evaluated. Distinguished immunosuppressive activities on the responses of T cell, B cell and macrophages upon mitogen and pathogenic signaling were manifested. Compounds 9-11 displayed the most promising inhibitory effects both on cellular proliferation and on the production of multiple pro-inflammatory cytokines, including IL-17, IFN-γ, IL-6, IL-1ß and TNF-α, which might be insightful in the pursuit of treatment for immune disorders and inflammatory diseases.
Subject(s)
Amines/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antiviral Agents/pharmacology , Chloroquine/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Amines/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , B-Lymphocytes/immunology , Cell Proliferation/drug effects , Chloroquine/chemical synthesis , Chloroquine/chemistry , Cytokines/metabolism , Dose-Response Relationship, Drug , Humans , Macrophages/drug effects , Macrophages/immunology , Microbial Sensitivity Tests , Molecular Structure , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
Malaria remains one of the deadliest infectious diseases worldwide and continues to infect hundreds of millions of individuals each year. Here we report the discovery and derivatization of a series of 2,6-dibenzylidenecyclohexanones targeting the chloroquine-sensitive 3D7 strain of Plasmodium falciparum . While the initial lead compound displayed significant toxicity in a human cell proliferation assay, we were able to identify a derivative with no detectable toxicity and sub-micromolar potency.
Subject(s)
Antimalarials/pharmacology , Chloroquine/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/chemical synthesis , Antimalarials/chemistry , Cell Proliferation/drug effects , Chloroquine/chemical synthesis , Chloroquine/chemistry , Dose-Response Relationship, Drug , Fibroblasts/drug effects , Humans , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Quinoline-based scaffolds have been the mainstay of antimalarial drugs, including many artemisinin combination therapies (ACTs), over the history of modern drug development. Although much progress has been made in the search for novel antimalarial scaffolds, it may be that quinolines will remain useful, especially if very potent compounds from this class are discovered. We report here the results of a structure-activity relationship (SAR) study assessing potential unsymmetrical bisquinoline antiplasmodial drug candidates using in vitro activity against intact parasites in cell culture. Many unsymmetrical bisquinolines were found to be highly potent against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. Further work to develop such compounds could focus on minimizing toxicities in order to find suitable candidates for clinical evaluation.
Subject(s)
Antimalarials/pharmacology , Chloroquine/chemistry , Chloroquine/pharmacology , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Chloroquine/analogs & derivatives , Chloroquine/chemical synthesis , Erythrocytes/drug effects , Erythrocytes/parasitology , Humans , Inhibitory Concentration 50 , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity RelationshipABSTRACT
The treatment of malaria, the most common parasitic disease worldwide and the third deadliest infection after HIV and tuberculosis, is currently compromised by the dramatic increase and diffusion of drug resistance among the various species of Plasmodium, especially P. falciparum (Pf). In this view, the development of new antiplasmodial agents that are able to act via innovative mechanisms of action, is crucial to ensure efficacious antimalarial treatments. In one of our previous communications, we described a novel class of compounds endowed with high antiplasmodial activity, characterized by a pharmacophore never described before as antiplasmodial and identified by their 4,4'-oxybisbenzoyl amide cores. Here, through a detailed structure-activity relationship (SAR) study, we thoroughly investigated the chemical features of the reported scaffolds and successfully built a novel antiplasmodial agent active on both chloroquine (CQ)-sensitive and CQ-resistant Pf strains in the low nanomolar range, without displaying cross-resistance. Moreover, we conducted an in silico pharmacophore mapping.
Subject(s)
Antimalarials/chemical synthesis , Chloroquine/analogs & derivatives , Chloroquine/chemical synthesis , Malaria/drug therapy , Plasmodium falciparum/drug effects , Amines/chemistry , Animals , Antimalarials/pharmacology , Chloroquine/pharmacology , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Resistance , Humans , Kidney/drug effects , Microbial Viability , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Anti-malaria drugs chloroquine and amodiaquine and their metabolites were synthesized to incorporate 13 C and 15 N starting from U-13 C-labeled benzene to give M + 7 isotopomers. Chloroquine and its metabolites were prepared from 7-chloro-1,2,3,4-tetrahydroquinolin-4-one through an aryl substitution with the corresponding amines; and the amodiaquine and its metabolites were prepared from 4,7-dichloroquinoline in a similar fashion.
Subject(s)
Amodiaquine/chemical synthesis , Amodiaquine/metabolism , Chloroquine/chemical synthesis , Chloroquine/metabolism , Amodiaquine/chemistry , Chemistry Techniques, Synthetic , Chloroquine/chemistry , Isotope Labeling , RadiochemistryABSTRACT
In a focused exploration, we designed, synthesized, and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity (in vitro 50% inhibitory concentration, 56.98 nM for strain 3D7 and 97.76 nM for strain K1; selectivity index in vivo [up to at a dose of 12.5 mg/kg of body weight], 3,510) as a new lead antimalarial agent. Other compounds (compounds 6b, 6d, 7d, 7h, 8c, 8d, 9a, and 9c) also showed moderate activity against a CQ-sensitive strain (3D7) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum Furthermore, we carried out docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of all in-house data sets (168 molecules) of chiral CQ analogues to explain the structure-activity relationships (SAR). Our new findings specify the significance of the H-bond interaction with the side chain of heme for biological activity. In addition, the 3D-QSAR study against the 3D7 strain indicated the favorable and unfavorable sites of CQ analogues for incorporating steric, hydrophobic, and electropositive groups to improve the antimalarial activity.
Subject(s)
Antimalarials/chemical synthesis , Chloroquine/analogs & derivatives , Heme/chemistry , Malaria/drug therapy , Piperazines/chemistry , Plasmodium falciparum/drug effects , Animals , Antimalarials/pharmacology , Chlorocebus aethiops , Chloroquine/chemical synthesis , Chloroquine/pharmacology , Drug Design , Drug Resistance/drug effects , Erythrocytes/drug effects , Erythrocytes/parasitology , Hemeproteins/antagonists & inhibitors , Hemeproteins/biosynthesis , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Malaria/mortality , Malaria/parasitology , Mice , Molecular Docking Simulation , Parasitic Sensitivity Tests , Plasmodium falciparum/growth & development , Plasmodium falciparum/metabolism , Plasmodium yoelii/drug effects , Plasmodium yoelii/growth & development , Plasmodium yoelii/metabolism , Static Electricity , Stereoisomerism , Structure-Activity Relationship , Survival Analysis , Vero CellsABSTRACT
It is well established that chloroquine, a quinoline antimalarial, inhibits hemozoin formation in the malaria parasite. Counterintuitively, this archetypal antimalarial is also used in the treatment of diseases in which hemozoin biocrystallization does not play a role. Hence, we decided to investigate whether chloroquine possesses binding targets other than Fe(III) protoporphyrin IX in blood stage Plasmodium falciparum parasites and whether these are related to sites of accumulation within the parasite other than the digestive vacuole. A 7-nitrobenz-2-oxa-1,3-diazole (NBD)-labeled fluorescent derivative of chloroquine, especially sensitive to regions outside the digestive vacuole and retaining the antiplasmodial pharmacophore, was synthesized to investigate subcellular localization in the parasite. Super-resolution microscopy revealed association with membranes including the parasite plasma membrane, the endoplasmic reticulum, and possibly also the mitochondrion. A drug-labeled affinity matrix was then prepared to capture protein binding targets of chloroquine. SDS-PAGE revealed a single prominent band between 200 and 250 kDa from the membrane-associated fraction. Subsequent proteomic analysis revealed that this band corresponded to P. falciparum multidrug resistance-associated protein (PfMRP1). Intrigued by this finding, we demonstrated pull-down of PfMRP1 by matrices labeled with Cinchona alkaloids quinine and quinidine. While PfMRP1 has been implicated in resistance to quinolines and other antimalarials, this is the first time that these drugs have been found to bind directly to this protein. Based on previous reports, PfMRP1, the only prominent protein found to bind to quinolines in this work, is likely to modulate the activity of these antimalarials in P. falciparum rather than act as a drug target.
Subject(s)
4-Chloro-7-nitrobenzofurazan/analogs & derivatives , 4-Chloro-7-nitrobenzofurazan/metabolism , Chloroquine/analogs & derivatives , Chloroquine/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Protozoan Proteins/metabolism , 4-Chloro-7-nitrobenzofurazan/chemical synthesis , 4-Chloro-7-nitrobenzofurazan/pharmacology , Antimalarials/chemical synthesis , Antimalarials/metabolism , Antimalarials/pharmacology , Chloroquine/chemical synthesis , Chloroquine/pharmacology , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/metabolism , Fluorescent Dyes/pharmacology , Mass Spectrometry , Microscopy, Confocal , Plasmodium falciparum/chemistry , Plasmodium falciparum/drug effects , Protein Binding , Proteomics/methodsABSTRACT
Chloroquine-containing 2-(dimethylamino)ethyl methacrylate copolymers (PDCs) are synthesized by reversible addition-fragmentation chain-transfer polymerization. Systematic evaluation is performed to test the hypothesis that presence of chloroquine (CQ) in the PDC structure will improve miRNA delivery due to enhanced endosomal escape while simultaneously contribute to anticancer activity of PDC/miRNA polyplexes through inhibition of cancer cell migration. The results show that miRNA delivery efficiency is dependent both on the molecular weight and CQ. The best performing PDC/miRNA polyplexes show effective endosomal escape of miRNA. PDC polyplexes with therapeutic miR-210 show promising anticancer activity in human breast cancer cells. PDC/miRNA polyplexes show excellent ability to inhibit migration of cancer cells. Overall, this study supports the use of PDC as a promising polymeric drug platform for use in combination anti-metastatic and anticancer miRNA therapeutic strategies.
Subject(s)
Breast Neoplasms/classification , Breast Neoplasms/therapy , Methacrylates/pharmacology , MicroRNAs/genetics , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Chloroquine/chemical synthesis , Chloroquine/chemistry , Chloroquine/pharmacology , Endocytosis/drug effects , Endosomes/drug effects , Female , Genetic Vectors/drug effects , Humans , Methacrylates/chemical synthesis , Methacrylates/chemistry , MicroRNAs/chemistry , MicroRNAs/pharmacology , Polymers/chemical synthesis , Polymers/chemistry , Polymers/pharmacology , TransfectionABSTRACT
A novel series of cinnamoylated chloroquine hybrid analogues were synthesized and evaluated as antimalarial agents. The trans cinnamic acid derivatives (3-8) were synthesized by utilizing substituted aldehydes and malanoic acid in DMF catalysed by DABCO. The final cinnamoylated chloroquine analogues (9-14) were synthesized by utilizing DCC coupling reagent. The amido chloroquine (17) was prepared from acid (16) and compound 2 in benzene using SOCl2 as chlorinating agent. The corresponding ester (15) was prepared from 2-hydroxy acetophenone and 2-bromoacetates in actonitrile in presence of K2CO3 as base followed by basic hydrolysis. The preparation of amide based chloroquine-chalcone analogues (18-22), were obtained by the combination of amido chloroquine (17) and aldehydes in 10% aq. KOH in methanol at room temperature. Further we prepared epichlorohydrin based chloroquine-chalcone analogues (25-28), by reacting the epoxide (24a, 24b and 24c) with 2 and methelenedioxy aniline. In vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant strain K1 of P. falciparum and in vitro cytotoxicity of compounds using VERO cell line was carried out. The synthesized molecules showed significant in vitro antimalarial activity especially against CQ resistant strain (K1). Among tested compounds, 13, 9 and 10 were found to be the most potent compounds of the series with IC50 value of 44.06, 48.04 and 59.37 nM against chloroquine resistant K1 strain.
Subject(s)
Antimalarials/pharmacology , Chloroquine/pharmacology , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Chlorocebus aethiops , Chloroquine/chemical synthesis , Chloroquine/chemistry , Dose-Response Relationship, Drug , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Vero CellsABSTRACT
Zika virus (ZIKV), an emerging Flavivirus, was recently associated with severe neurological complications and congenital diseases. Therefore, development of antiviral agents capable of inhibiting ZIKV replication is urgent. Chloroquine is a molecule with a confirmed safety history for use with pregnant women, and has been found to exhibit anti-ZIKV activity at concentrations around 10 µM. This suggests that modifications to the chloroquine structure could be promising for obtaining more effective anti-ZIKV agents. Here, we report the ability of a series of N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives to inhibit ZIKV replication in vitro. We have found that the quinoline derivative, N-(2-((5-nitrofuran-2-yl)methylimino)ethyl)-7-chloroquinolin-4-amine, 40, was the most potent compound within this series, reducing ZIKV replication by 72% at 10 µM. Compound 40 exhibits an EC50 value of 0.8 ± 0.07 µM, compared to that of chloroquine of 12 ± 3.2 µM. Good activities were also obtained for other compounds, including those with aryl groups = phenyl, 4-fluorophenyl, 4-nitrophenyl, 2,6-dimethoxyphenyl, 3-pyridinyl and 5-nitrothien-2-yl. Syntheses of these quinoline derivatives have been obtained both by thermal and ultrasonic means. The ultrasonic method produced comparable yields to the thermal (reflux) method in very much shorter times 30-180 s compared to 30-180 min reactions times. These results indicate that this group of compounds is a good follow-up point for the potential discovery of new drugs against the Zika disease.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Chloroquine/chemical synthesis , Chloroquine/pharmacology , Temperature , Ultrasonic Waves , Zika Virus/drug effects , Animals , Antiviral Agents/chemistry , Chlorocebus aethiops , Chloroquine/chemistry , Chloroquine/toxicity , Vero Cells , Virus Replication/drug effects , Zika Virus/physiologyABSTRACT
The synthesis and characterization of twenty new pentamethylcyclopentadienyl-rhodium and iridium complexes containing N^N and N^O-chelating chloroquine analogue ligands are described. The in vitro antimalarial activity of the new ligands as well as the complexes was evaluated against the chloroquine sensitive (CQS) NF54 and the chloroquine resistant (CQR) Dd2 strains of Plasmodium falciparum. The antimalarial activity was found to be good to moderate; although all complexes are less active than artesunate, some of the ligands and complexes showed better activity than chloroquine (CQ). In particular, rhodium complexes were found to be considerably more active than iridium complexes against the CQS NF54 strain. Salicylaldimine Schiff base ligands having electron-withdrawing groups (F, Cl, Br, I and NO2) in para position of the salicyl moiety and their rhodium complexes showed good antiplasmodial activity against both the CQS-NF54 and the CQR-Dd2 strains. The crystal structures of (η(5)-pentamethylcyclopentadienyl){N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)} chlororhodium(III) chloride and (η(5)-pentamethylcyclopentadienyl){(4-chloro-2-(((2-((7-chloroquinolin-4-yl)amino)ethyl)imino)methyl)phenolate)}chlororhodium(III) chloride are reported. The crystallization of the amino-pyridyl complex (η(5)-pentamethylcyclopentadienyl){(N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)}chloroiridium(III) chloride in acetone resulted in the formation of the imino-pyridyl derivative (η(5)-pentamethylcyclopentadienyl){(N1-(7-chloroquinolin-4-yl)-N2-(pyridin-2-ylmethylene)ethane-1,2-diamine)}chloroiridium(III) chloride, the crystal structure of which is also reported.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Chloroquine/analogs & derivatives , Chloroquine/pharmacology , Iridium/chemistry , Organometallic Compounds/chemistry , Rhodium/chemistry , Antimalarials/chemical synthesis , Chemistry Techniques, Synthetic , Chloroquine/chemical synthesis , Chloroquine/chemistry , Drug Resistance/drug effects , Ligands , Models, Molecular , Molecular Conformation , Plasmodium falciparum/drug effectsABSTRACT
Eight new ruthenium and five new osmium p-cymene half-sandwich complexes have been synthesized, characterized and evaluated for antimalarial activity. All complexes contain ligands that are based on a 4-chloroquinoline framework related to the antimalarial drug chloroquine. Ligands HL(1-8) are salicylaldimine derivatives, where HL(1) = N-(2-((2-hydroxyphenyl)methylimino)ethyl)-7-chloroquinolin-4-amine, and HL(2-8) contain non-hydrogen substituents in the 3-position of the salicylaldimine ring, viz. F, Cl, Br, I, NO2, OMe and (t)Bu for HL(2-8), respectively. Ligand HL(9) is also a salicylaldimine-containing ligand with substitutions in both 3- and 5-positions of the salicylaldimine moiety, i.e. N-(2-((2-hydroxy-3,5-di-tert-butylphenyl)methyl-imino)ethyl)-7-chloroquinolin-4-amine, while HL(10) is N-(2-((1-methyl-1H-imidazol-2-yl)methylamino)ethyl)-7-chloroquinolin-4-amine) The half sandwich metal complexes that have been investigated are [Ru(η(6)-cym)(L(1-8))Cl] (Ru-1-Ru-8, cym = p-cymene), [Os(η(6)-cym)(L(1-3,5,7))Cl] (Os-1-Os-3, Os-5, and Os-7), [M(η(6)-cym)(HL(9))Cl2] (M = Ru, Ru-HL(9); M = Os, Os-HL(9)) and [M(η(6)-cym)(L(10))Cl]Cl (M = Ru, Ru-10; M = Os, Os-10). In complexes Ru-1-Ru-8 and Ru-10, Os-1-Os-3, Os-5 and Os-7 and Os-10, the ligands were found to coordinate as bidentate N,O- and N,N-chelates, while in complexes Ru-HL(9) and Os-HL(9), monodentate coordination of the ligands through the quinoline nitrogen was established. The antimalarial activity of the new ligands and complexes was evaluated against chloroquine sensitive (NF54 and D10) and chloroquine resistant (Dd2) Plasmodium falciparum malaria parasite strains. Coordination of ruthenium and osmium arene moieties to the ligands resulted in lower antiplasmodial activities relative to the free ligands, but the resistance index is better for the ruthenium complexes compared to chloroquine. Overall, osmium complexes appeared to be less active than the corresponding ruthenium complexes.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Chloroquine/analogs & derivatives , Chloroquine/pharmacology , Osmium Compounds/chemical synthesis , Osmium Compounds/pharmacology , Ruthenium Compounds/chemical synthesis , Ruthenium Compounds/pharmacology , Animals , Chloroquine/chemical synthesis , Ligands , Models, Molecular , Molecular Structure , Plasmodium falciparum/drug effects , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2â nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7â nm) strains of P.â falciparum. Several compounds were found to have good inhibitory activity against ß-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2â µm.
Subject(s)
Aminoquinolines/chemistry , Antimalarials/chemical synthesis , Chloroquine/chemistry , Drug Design , Ferrous Compounds/chemistry , Aminoquinolines/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Chloroquine/chemical synthesis , Chloroquine/pharmacology , Crystallography, X-Ray , Drug Resistance/drug effects , Ferrous Compounds/pharmacology , Hemeproteins/antagonists & inhibitors , Hemeproteins/metabolism , Inhibitory Concentration 50 , Metallocenes , Microbial Sensitivity Tests , Molecular Conformation , Octoxynol , Plasmodium falciparum/drug effects , Plasmodium falciparum/metabolism , Polyethylene Glycols/chemistry , Protein Binding , Structure-Activity RelationshipABSTRACT
Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.
Subject(s)
Antimalarials/pharmacology , Chloroquine/pharmacology , Drug Resistance/drug effects , Plasmodium falciparum/drug effects , Protozoan Proteins/antagonists & inhibitors , Antimalarials/chemical synthesis , Chloroquine/analogs & derivatives , Chloroquine/chemical synthesis , Dose-Response Relationship, Drug , Drug Resistance/genetics , Gene Expression , Halogenation , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Parasitic Sensitivity Tests , Plasmodium falciparum/genetics , Plasmodium falciparum/metabolism , Polymorphism, Genetic , Protozoan Proteins/genetics , Protozoan Proteins/metabolismABSTRACT
The synthesis and spectroscopic characterization of nine π-arene piano-stool ruthenium (II) complexes with aromatic dinitrogen chelating ligands or containing chloroquine (CQ), are described in this study: [Ru(η(6)-C10H14)(phen)Cl]PF6 (1), [Ru(η(6)-C10H14)(dphphen)Cl]PF6 (2), [Ru(η(6)-C10H14)(bipy)Cl]PF6 (3), [Ru(η(6)-C10H14)(dmebipy)Cl]PF6 (4) and [Ru(η(6)-C10H14)(bdutbipy)Cl]PF6 (5), [Ru(η(6)-C10H14)(phen)CQ](PF6)2 (6), [Ru(η(6)-C10H14)(dphphen)CQ](PF6)2 (7), [Ru(η(6)-C10H14)(bipy)CQ](PF6)2 (8), [Ru(η(6)-C10H14)(dmebipy)CQ](PF6)2 (9): [1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,2'-bipyridine (bipy), 5,5'-dimethyl-2,2'-bipyridine (dmebipy), and 4,4'-di-t-butyl-2,2'-bipyridine (dbutbipy)]. The solid state structures of five ruthenium complexes (1-5) were determined by X-ray crystallography. Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru(II)/Ru(III) couple in each case. Their interactions with DNA and BSA, and activity against four cell lines (L929, A549, MDA-MB-231 and MCF-7) were evaluated. Compounds 2, 6 through 9, interact with DNA which was comparable to the one observed for free chloroquine. The results of fluorescence titration revealed that these complexes strongly quenched the intrinsic fluorescence of BSA following a static quenching procedure. Binding constants (Kb) and the number of binding sites (n~1) were calculated using modified Stern-Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated and subsequently the values of ΔH and ΔS were also calculated, which revealed that hydrophobic and electrostatic interactions play a major role in the BSA-complex association. The MTT assay results indicated that complexes 2, 5 and 7 showed cytostatic effects at appreciably lower concentrations than those needed for cisplatin, chloroquine and doxorubicin.
Subject(s)
Antineoplastic Agents/pharmacology , Chelating Agents/pharmacology , Chloroquine/pharmacology , Coordination Complexes/pharmacology , DNA/chemistry , Ruthenium/chemistry , Serum Albumin, Bovine/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Binding Sites , Breast Neoplasms , Cattle , Cell Line, Tumor , Chelating Agents/chemical synthesis , Chelating Agents/chemistry , Chloroquine/chemical synthesis , Chloroquine/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Electrochemical Techniques , Female , Humans , Intercalating Agents/chemical synthesis , Intercalating Agents/chemistry , Intercalating Agents/pharmacology , Lung Neoplasms , Mice , Molecular Structure , Proton Magnetic Resonance Spectroscopy , ThermodynamicsABSTRACT
In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. Thus, a series of N-acylated analogues were synthesized, and their activities against blood- and liver-stage Plasmodiumâ spp. were assessed along with their in vitro cytotoxicities. Although the new N-acylated analogues were found to be somewhat less active and more cytotoxic than their N-cinnamoylated counterparts, they equally displayed nanomolar activities in vitro against blood-stage drug-sensitive and drug-resistant P.â falciparum, and significant in vitro liver-stage activity against P.â berghei. Therefore, it is demonstrated that simple N-acylated surrogates of classical antimalarial drugs are promising dual-stage antimalarial leads.
Subject(s)
Antimalarials/chemistry , Cinnamates/chemistry , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Cell Survival/drug effects , Chloroquine/analogs & derivatives , Chloroquine/chemical synthesis , Chloroquine/pharmacology , Hep G2 Cells , Humans , Life Cycle Stages/drug effects , Plasmodium berghei/drug effects , Plasmodium berghei/growth & development , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Quinacrine/analogs & derivatives , Quinacrine/chemical synthesis , Quinacrine/pharmacology , Structure-Activity RelationshipABSTRACT
BACKGROUND: Malaria still has significant impacts on the world; particularly in Africa, South America and Asia where spread over several millions of people and is one of the major causes of death. When chloroquine diphosphate (CQDP) lost its efficiency as a first-line anti-malarial drug, this was a major setback in the effective control of malaria. Currently, malaria is treated with a combination of two or more drugs with different modes of action to provide an adequate cure rate and delay the development of resistance. Clearly, a new effective and non-toxic anti-malarial drug is urgently needed. METHODS: All metal-chloroquine (CQ) and metal-CQDP complexes were synthesized under N(2) using Schlenk techniques. Their interactions with haematin and the inhibition of ß-haematin formation were examined, in both aqueous medium and near water/n-octanol interfaces at pH 5. The anti-malarial activities of these metal- CQ and metal-CQDP complexes were evaluated in vitro against two strains, the CQ-susceptible strain (CQS) 3D7 and the CQ-resistant strain (CQR) W2. RESULTS: The previously synthesized Au(CQ)(Cl) (1), Au(CQ)(TaTg) (2), Pt(CQDP)(2)Cl(2) (3), Pt(CQDP)(2)I(2) (4), Pd(CQ)(2)Cl(2) (5) and the new one Pd(CQDP)(2)I(2) (6) showed better anti-malarial activity than CQ, against the CQS strain; moreover, complexes 2, 3 and 4 were very active against CQR strain. These complexes (1-6) interacted with haem and inhibited ß-haematin formation both in aqueous medium and near water/n-octanol interfaces at pH 5 to a greater extent than chloroquine diphosphate (CQDP) and other known metal-based anti-malarial agents. CONCLUSIONS: The high anti-malarial activity displayed for these metal-CQ and metal-CQDP complexes (1-6) could be attributable to their effective interaction with haem and the inhibition of ß-haematin formation in both aqueous medium and near water/n-octanol interfaces at pH 5.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Chloroquine/analogs & derivatives , Chloroquine/pharmacology , Metals/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/chemical synthesis , Chloroquine/chemical synthesis , Parasitic Sensitivity TestsABSTRACT
In this investigation, we describe a new approach to chiral synthesis of chloroquine and its analogues. All tested compounds displayed potent activity against chloroquine sensitive as well as chloroquine resistant strains of Plasmodium falciparum in vitro and Plasmodium yoelii in vivo. Compounds S-13 b, S-13c, S-13 d and S-13 i displayed excellent in vitro antimalarial activity with an IC50 value of 56.82, 60.41, 21.82 and 7.94 nM, respectively, in the case of resistant strain. Furthermore, compounds S-13a, S-13c and S-13 d showed in vivo suppression of 100% parasitaemia on day 4 in the mouse model against Plasmodium yoelii when administered orally. These results underscore the application of synthetic methodology and need for further lead optimization.
Subject(s)
Antimalarials/chemistry , Antimalarials/therapeutic use , Chloroquine/analogs & derivatives , Chloroquine/therapeutic use , Malaria/drug therapy , Plasmodium falciparum/drug effects , Plasmodium yoelii/drug effects , Aminoquinolines/chemical synthesis , Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Aminoquinolines/therapeutic use , Animals , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Chlorocebus aethiops , Chloroquine/chemical synthesis , Chloroquine/pharmacology , Mice , Vero CellsABSTRACT
A series of 1H-1,2,3-triazole-tethered isatin-7-chloroquinoline and 3-hydroxy-indole-7-chloroquinoline conjugates have been synthesized and evaluated for their antimalarial activity against chloroquine-resistant W2 strain of Plasmodium falciparum. The most potent of the test compound with an optimum combination of 3-hydroxy-indole ring and a n-butyl linker displayed an IC50 value of 69 nM.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Hydrazines/chemical synthesis , Hydrazines/pharmacology , Plasmodium falciparum/drug effects , Quinolines/chemical synthesis , Quinolines/pharmacology , Antimalarials/chemistry , Chloroquine/chemical synthesis , Chloroquine/chemistry , Chloroquine/pharmacology , Drug Resistance , Hydrazines/chemistry , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Isatin/chemical synthesis , Isatin/chemistry , Isatin/pharmacology , Quinolines/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cell lines: MKN-28, Caco-2, and MCF-7. All compounds display anti-proliferative activity in the micromolar range against the three cell lines tested, and most of them were more active than their parent drug, chloroquine, against all cell lines tested. Hence, N-cinnamoyl-chloroquine analogues are a good start towards development of affordable antitumor leads.