quinine and Malaria

Discovery and development of antimalarial drugs have long been dominated by single-target therapy. Continuous effort has been made to explore and identify different targets in malaria parasite crucial for the malaria treatment. The single-target drug therapy was initially successful, but it was later supplanted by combination therapy with multiple drugs to overcome drug resistance. Emergence of resistant strains even against the combination therapy has warranted a review of current antimalarial pharmacotherapy. This has led to the development of the new concept of covalent biotherapy, in which two or more pharmacophores are chemically bound to produce hybrid antimalarial drugs with multi-target functionalities. Herein, the review initially details the current pharmacotherapy for malaria as well as the conventional and novel targets of importance identified in the malaria parasite. Then, the rationale of multi-targeted therapy for malaria, approaches taken to develop the multi-target antimalarial hybrids, and the examples of hybrid molecules are comprehensively enumerated and discussed.

Topics: Animals; Antimalarials; Artemisinins; Drug Discovery; Drug Resistance; Humans; Malaria; Molecular Structure; Paclitaxel; Quinolines

Quinoline-containing compounds, such as quinine and chloroquine, have a long-standing history as potent antimalarial agents. However, the increasing resistance of the Plasmodium parasite against these drugs and the lack of licensed malaria vaccines have forced chemists to develop synthetic strategies toward novel biologically active molecules. A strategy that has attracted considerable attention in current medicinal chemistry is based on the conjugation of two biologically active molecules into one hybrid compound. Since quinolines are considered to be privileged antimalarial building blocks, the synthesis of quinoline-containing antimalarial hybrids has been elaborated extensively in recent years. This review provides a literature overview of antimalarial hybrid molecules containing a quinoline core, covering publications between 2009 and 2014.

Topics: Animals; Antimalarials; Drug Discovery; Humans; Malaria; Plasmodium; Quinolines

Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC

Topics: Amino Alcohols; Animals; Antimalarials; Cell Line; Cricetulus; Dose-Response Relationship, Drug; Drug Design; Ether-A-Go-Go Potassium Channels; Female; Humans; Malaria; Mice; Mice, Inbred BALB C; Microsomes, Liver; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Quinolines; Structure-Activity Relationship

Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

Topics: Acridones; Animals; Antimalarials; Disease Models, Animal; Drug Discovery; Hep G2 Cells; Humans; Malaria; Mice; Plasmodium; Species Specificity; Structure-Activity Relationship

Sulphonamides and carboxamides have shown large number of pharmacological properties against different types of diseases among which is malaria. Twenty four new carboxamide derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for their in silico and in vitro antimalarial and antioxidant properties. The substituted benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in vitro antimalarial studies showed that all synthesized compounds had antimalarial property. Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08 μM respectively comparable with chloroquine 0.06 μM. Compound 7c was the most potent antioxidant agent with IC

Topics: Antimalarials; Dose-Response Relationship, Drug; Malaria; Molecular Docking Simulation; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship; Sulfonamides

N-tert-Butyl isoquine (4) (GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.

Topics: Aminoquinolines; Amodiaquine; Animals; Antimalarials; Benzylamines; Cytochrome P-450 Enzyme Inhibitors; Dogs; Drug Evaluation, Preclinical; Drug Resistance; Female; Haplorhini; Heme; Humans; Malaria; Mice; Models, Molecular; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; Rats; Structure-Activity Relationship

On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.

Topics: Aminoquinolines; Amodiaquine; Animals; Antimalarials; Cell Survival; Chloroquine; Dogs; Drug Resistance; Female; Haplorhini; Hepatocytes; Humans; In Vitro Techniques; Malaria; Male; Mice; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; Rats; Rats, Wistar; Structure-Activity Relationship

A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds has been assayed for inhibition of the carbonic anhydrase (CA, EC 4.2.1.1) from the malaria parasite Plasmodium falciparum (pfCA). Low micromolar and submicromolar in vitro inhibitors were detected, whereas several compounds showed ex vivo anti-P. falciparum activity, in cell cultures. One derivative, that is, 4-(3,4-dichlorophenylureido)thioureido-benzenesulfonamide was an effective in vitro pfCA inhibitor (K(I) of 0.18 microM), inhibited the ex vivo growth of P. falciparum with an IC(50) of 1 microM, and was also effective as an antimalarial agent in mice infected with P. berghei, an animal model of human malaria infection, with an ID(50) of 10 mg/kg (chloroquine as standard showed an ID(50) of 5 mg/kg). By inhibiting the first step of pyrimidine nucleotide biosyntheses, that is, the CA-mediated carbamoylphosphate biosynthesis, sulfonamide inhibitors of the protozoan CAs may have potential for the development of novel therapies of human malaria.

Topics: Animals; Antimalarials; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Chemistry, Pharmaceutical; Drug Design; Humans; Inhibitory Concentration 50; Kinetics; Malaria; Mice; Plasmodium berghei; Plasmodium falciparum; Pyrimidines; Sulfonamides

On the basis of earlier reported quantitative structure-activity relationship studies, a series of 9beta-16-(arylalkyl)-10-deoxoartemisinins were proposed for synthesis. Several of the new compounds 7 and 10-14 were synthesized employing the key synthetic intermediate 23. In a second approach, the natural product (+)-artemisinic acid was utilized as an acceptor for conjugate addition, and the resultant homologated acids were subjected to singlet oxygenation and acid treatment to provide artemisinin analogues. Under a new approach, we developed a one step reaction for the interconversion of artemisinin 1 into artemisitene 22 that did not employ selenium-based reagents and found that 2-arylethyliodides would undergo facile radical-induced conjugate addition to the exomethylene lactone of 22 in good yield. The lactone carbonyls were removed sequentially by diisobutylaluminum hydride reduction followed directly by a second reduction (BF(3)-etherate/Et(3)SiH) to afford the desired corresponding pyrans. Six additional halogen-substituted aromatic side chains were installed via 22 furnishing the bioassay candidates 15-20. The analogues were examined for in vitro antimalarial activity in the W-2 and D-6 clones of Plasmodium falciparum and were additionally tested in vivo in Plasmodium berghei- and/or Plasmodium yoelii-infected mice. Several of the compounds emerged as highly potent orally active candidates without obvious toxicity. Of these, two were chosen for pharmacokinetic evaluation, 14 and 17.

Topics: Administration, Oral; Animals; Antimalarials; Artemisinins; Drug Evaluation, Preclinical; Drug Resistance; Injections, Intravenous; Malaria; Mice; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Stereoisomerism; Structure-Activity Relationship

A new series of hydrolytically stable and water-soluble dihydroartemisinin derivatives with optically active side chains was prepared as potential antimalarial agents. This was an effort to prepare compounds with activity superior to that of artelinic acid and to examine the impact of the stereospecificity of the introduced alkyl side chain on biological properties. The ester derivatives (6a-d) possess superior in vitro activity to artemisinin, artemether, and arteether against two strains of Plasmodium falciparum (D-6 and W-2); however, conversion of the esters to their corresponding acids drastically reduces their antimalarial activity. None of the new acids possess in vitro antimalarial activity superior to that of artelinic acid. Although there appears to be limited stereospecificity for antimalarial activity among the acids (7a-d) tested, significant differences in antimalarial activity was seen among the esters.

Topics: Animals; Artemisinins; Chemical Phenomena; Chemistry; Malaria; Mice; Molecular Structure; Plasmodium falciparum; Sesquiterpenes; Solubility; Stereoisomerism; Structure-Activity Relationship; Water

A quantitative structure-activity relationship has been formulated for 646 antimalarials acting against P. berghei in mice. The equation developed has 14 terms, 9 of which are indicator variables. The correlation coefficient for the QSAR is 0.898 and the standard deviation is 0.309. The antimalarials are all arylcarbinols of the type X-ArCHOHCH2NR1R2. Sixty different aryl structures, including a variety of heterocyles, are contained in the study. The most important determinate of activity is found to be the electron-withdrawing ability of the substituents X; the hydrophobic character of X and R plays less important roles. Suggestions for more potent analogues are made and the lack of activity of about 100 additional analogues is also considered.

Topics: Animals; Antimalarials; Ethanolamines; Malaria; Mice; Models, Biological; Phenanthrenes; Plasmodium berghei; Pyridines; Quinolines; Structure-Activity Relationship

As part of the search for new antimalarial drugs, a screening program was developed using sensitive and chlorguanide triazine (CGT, cycloguanil) resistant strains of the folate-requiring bacteria, Streptococcus faecium durans, Lactobacillus casei, and Pediococcus cerevisiae. The activities of 40 compounds have been studied against these strains and Escherichia coli. Observations have been made on the points of 50% growth inhibition, the fold increase of resistance shown to each compound by the resistant strains as compared with the parent sensitive strains, and the reversal of growth inhibition by folic acid with S. faecium and L. casei by folinic acid with P. cerevisiae and by p-aminobenzoic acid with E. coli. Comparisons have been made of the activities of the test compounds with those of the standard antimalarial antifoltes, CGT and pyrimethamine (PM), and the antibacterial results have been compared with the activities of the compounds against Plasmodium berghei infections in the mouse and against human malaria infections where data are available. Of the 17 compounds reversed by folates, five had patterns of activity similar to CGT and PM in that they were most active against S. faecium and nine compounds exhibited a different pattern, being highly active against all four test bacteria. This suggests that these latter compounds either have different pharmacokinetic properties or have additional modes of action. The three CGT-resistant organisms responded to antifolates in different ways. S. faecium (R) and P. cerevisiae (R) strains were cross resistant to 4,6-diaminotriazines, 2,4-diaminopyrimidines, 2,4-diaminoquinazolines, and active 2,4-diaminopteridines. L. casei (R) was cross resistant to the triazines but was collaterally sensitive to all the other antifolates. Most of the compounds not reversed by folates were much less inhibitory for the test organisms; they were most active against L. casei. In general, their growth inhibitory concentrations varied less for the four test organisms and the responses of the sensitive and CGTR strains were similar. However, there was some cross resistance to five compounds and some collateral sensitivity to five others. Comparison of the bacteriological data with the activities of the compounds against Plasmodium berghei in the mouse showed little correlation between the two test systems; each appears to provide independent and useful information.

Topics: Animals; Antimalarials; Bacteria; Drug Resistance, Microbial; Escherichia coli; Folic Acid; Folic Acid Antagonists; Malaria; Mice; Plasmodium berghei; Triazines

Nine alpha-dibutylaminomethylbenzo[h]quinoline-4-methanols were synthesized from the corresponding 1-amino-naphthalenes by the following sequence: 1-aminonaphthalene leads to 1H-benz[g]indole-2,3-dione leads to benzo[h]quinoline-4-carboxylic acid leads to acid chloride leads to bromomethyl ketone leads to epoxide leads to benzo[h]quinoline-4-methanol. Several acid chlorides substituted in the 3 position reacted incompletely with ethereal diazomethane but were efficiently converted, without isolation of the intermediates, to the bromomethyl ketones by reaction with ethoxymagnesium diethylmalonate, bromination, hydrolysis, and decarboxylation. Several compounds prepared, especially alpha-dibutylaminomethyl-2-(2',4'-dimethylphenyl)-3-methyl-6-chlorobenzo[h]quinoline-4-methanol, showed significant antimalarial activity against Plasmodium berghei in infected mice but were moderately phototoxic.

Topics: Animals; Antimalarials; Malaria; Mice; Photosensitivity Disorders; Plasmodium berghei; Quinolines