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PubMed1999

Inoculum effect leads to overestimation of in vitro resistance for artemisinin derivatives and standard antimalarials: a Gambian field study.

Artemisinin (QHS) and its derivatives are new antimalarials which are effective against Plasmodium falciparum parasites resistant to chloroquine (CQ). As these drugs are introduced it is imperative that resistance is monitored. In this paper we demonstrate that the inoculum size used in in vitro testing influences the measured in vitro susceptibility to QHS and its derivative dihydroartemisinin (DHA) and to mefloquine (MEF) and CQ over the range of parasitaemias routinely used in testing with the WHO in vitro microtest. An increase in parasitaemia and/or haematocrit was accompanied by a decrease in the measured sensitivity of 2 laboratory lines. In the context of a field study testing in vitro susceptibility of parasite isolates from patients with uncomplicated malaria in Fajara, The Gambia we demonstrate that failure to control for inoculum size significantly overestimates the level of resistance to QHS and DHA as well as MEF, halofantrine (HAL) and quinine (QUIN). When controlling for the inoculum effect, cross-resistance was observed between QHS, MEF and HAL suggesting the presence of a multidrug resistance-like mechanism. These studies underline the importance of inoculum size in in vitro susceptibility testing.

Animals↗
PubMed2002

Identification and characterization of allophenylnorstatine-based inhibitors of plasmepsin II, an antimalarial target.

Plasmepsin II is a key enzyme in the life cycle of the Plasmodium parasites responsible for malaria, a disease that afflicts more than 300 million individuals annually. Since plasmepsin II inhibition leads to starvation of the parasite, it has been acknowledged as an important target for the development of new antimalarials. In this paper, we identify and characterize high-affinity inhibitors of plasmepsin II based upon the allophenylnorstatine scaffold. The best compound, KNI-727, inhibits plasmepsin II with a K(i) of 70 nM and a 22-fold selectivity with respect to the highly homologous human enzyme cathepsin D. KNI-727 binds to plasmepsin II in a process favored both enthalpically and entropically. At 25 degrees C, the binding enthalpy (DeltaH) is -4.4 kcal/mol and the entropic contribution (-TDeltaS) to the Gibbs energy is -5.56 kcal/mol. Structural stability measurements of plasmepsin II were also utilized to characterize inhibitor binding. High-sensitivity differential scanning calorimetry experiments performed in the absence of inhibitors indicate that, at pH 4.0, plasmepsin II undergoes thermal denaturation at 63.3 degrees C. The structural stability of the enzyme increases with inhibitor concentration in a manner for which the binding energetics of the inhibitor can quantitatively account. The effectiveness of the best compounds in killing the malaria parasite was validated by performing cytotoxicity assays in red blood cells infected with Plasmodium falciparum. EC50s ranging between 6 and 10 microM (3-6 microg/mL) were obtained. These experiments demonstrate the viability of the allophenylnorstatine scaffold in the design of powerful and selective plasmepsin inhibitors.

Amides↗
PubMed2004

Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines.

Quinone oxidoreductase 2 (QR2) purified from human red blood cells was recently shown to be a potential target of the quinoline antimalarial compounds [Graves et al., (2002) Mol. Pharmacol. 62, 1364]. QR2 catalyzes the two-electron reduction of menadione via the oxidation of N-alkylated or N-ribosylated nicotinamides. To investigate the mechanism and consequences of inhibition of QR2 by the quinolines further, we have used steady-state and transient-state kinetics to define the mechanism of QR2. Importantly, we have shown that QR2 when isolated from an overproducing strain of E. coli is kinetically equivalent to the enzyme from the native human red blood cell source. We observe ping-pong kinetics consistent with one substrate/inhibitor binding site that shows selectivity for the oxidation state of the FAD cofactor, suggesting that selective inhibition of the liver versus red blood cell forms of malaria may be possible. The reductant N-methyldihydronicotinamide and the inhibitor primaquine bind exclusively to the oxidized enzyme. In contrast, the inhibitors quinacrine and chloroquine bind exclusively to the reduced enzyme. The quinone substrate menadione, on the other hand, binds nonspecifically to both forms of the enzyme. Single-turnover kinetics of the reductive half-reaction are chemically and kinetically competent and confirm the inhibitor selectivity seen in the steady-state experiments. Our studies shed light on the possible in vivo potency of the quinolines and provide a foundation for future studies aimed at creating more potent QR2 inhibitors and at understanding the physiological significance of QR2.

Antimalarials↗
PubMedDate not supplied

Antimalarial activity of n(6)-substituted adenosine derivatives (part 2).

We have investigated the in vitro antimalarial activity of a new series of adenosine derivatives. The results show that N(6)-(1-naphthylmethyl)-5'-deoxy-5'-(amido)adenosines as well as N(6)-(4-phenylbenzyl)-5'-deoxy-5'-(amido)adenosines display significant activity against the malaria-causing parasites, with the sterically demanding bisubstituted species reported being active in most cases in the low-micromolar range. The novel compounds with unusual substitution pattern were obtained applying an efficient convergent polymer-assisted solution-phase (cPASP) synthesis protocol. Thus, we were able to prepare a series of substituted derivatives in parallel that would have been difficult to synthesize by standard techniques. The scope and limitations of the synthetic methodology are discussed.

Adenosine↗
PubMedDate not supplied

3D QSAR investigations on antimalarial naphthylisoquinoline alkaloids by comparative molecular similarity indices analysis (CoMSIA), based on different alignment approaches.

3D QSAR models based on the CoMSIA descriptor fields were established using a diverse data set of 53 antimalarial biaryl compounds (tested in vitro against a chloroquine-resistant strain of Plasmodium falciparum), consisting mainly of naphthylisoquinoline alkaloids, but also including phenylanthraquinone structures and naphthylindenes. For the alignment, two commercially available automated approaches, FLEXS and GASP, were compared; initially none of them succeeded in treating the important phenomenon of axial chirality correctly, but after some manual refinement of the alignments initially obtained, the best overall model, based on a modified FLEXS alignment, showed a q(2) (cross-validated r(2)) of 0.818 (eight components), using only the hydrophobic and the H-bond donor and acceptor fields. Using a test set of five compounds the model showed a squared multiple correlation coefficient for the test set (predictive r(2)) of 0.578. The analysis of the 3D contour maps permitted interesting conclusions about the effects of particular functional groups on the biological activity and will now guide the design of novel, hopefully even more active compounds.

Algorithms↗
PubMedDate not supplied

The role of charge distribution on the antimalarial activity of artemisinin analogues.

In this work the calculated nuclear quadrupole coupling constants (NQCC; chi) of 17O in artemisinin and some of its derivatives and the effects of charge density due to the nature of ligands on NQCC of 17O were investigated. All calculations were performed at the HF/3-21G level using the Gaussian 98 program. The results show that the O-O linkage has a characteristic role in the antimalarial activity of artemisinin. In addition, various substitutions on C4 change the charge density on these oxygens and consequently change the pharmaceutical effect of artemisinin. Our results suggest that due to a larger charge density on O1, the heme iron approaches the endoperoxide moiety at the O1 position with preference to the O2 position.

Alkylation↗
PubMedDate not supplied

Quantum pharmacological analysis of structure-activity relationships for mefloquine antimalarial drugs using optimal transformations.

Optimal nonlinear transformations provided by alternating conditional expectations (ACE) method are used to study the relationship between electronic structure and antimalarial activity of mefloquine and its substituted derivatives. The electronic structure of these molecules is featured by atomic net charges evaluated on the basis of CNDO/2 molecular orbital calculations. A comparison to multiple linear regression (MLR) and partial least squares (PLS) method is also included. The results show that ACE can be a useful and well-suited technique for establishing QSAR and predicting the pharmacological activity of compounds.

Algorithms↗
PubMedDate not supplied

A QSAR study of the antimalarial activity of some synthetic 1,2,4-trioxanes.

The antimalarial activity of a series of synthetic 1,2,4-trioxanes is correlated with molecular structure by using a pharmacophore search method (CATALYST). The technique is shown to have predictive accuracy and confirms that docking between an active trioxane and the receptor, heme, is the crucial step for drug action.

Animals↗
PubMed1995

Synthesis and activity of some antimalarial bisquinolines.

A new type of bisquinoline antimalarial, in which the basic side chain of chloroquine is retained, has been evaluated. Nine bisamides were prepared from aliphatic diacids with 6-amino- and 8-amino-((4-(diethylamino)-1-methylbutyl)amino)quinoline, and screened against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. The resistance indices for all compounds were lower than for chloroquine. The position of attachment and length of the linker chain markedly affected activity. The most active (IC50 = 120 nM against the chloroquine-resistant FAC8 strain) was the -(O)C(CH2)4C(O)- linked 8-amino compound.

Animals↗
PubMed2000

Syntheses and antimalarial activities of 10-substituted deoxoartemisinins.

Two series of 10-substituted deoxoartemisinin derivatives have been synthesized. The first employed the reaction of dihydroartemisinin acetate with several silyl enol ethers in the presence of titanium tetrachloride. The second utilized the reaction of 10-(2-oxoethyl)deoxoartemisinin with several Grignard reagents. The in vitro antimalarial activities of both series were determined against two drug-resistant clones of P. falciparum. The activities of 13 beta and 15 beta were 5-7 times greater than that of artemisinin.

Animals↗
PubMed1995

Synthesis and antimalarial activities of several fluorinated artemisinin derivatives.

The carbonyl groups in several artemisinin derivatives were converted into geminal difluorinated compounds on treatment with diethylaminosulfur trifluoride. A number of other mono- and polyfluorinated artemisinin derivatives were prepared. Their in vitro antimalarial activities were all equal to or greater than the nonfluorinated analogs or precursors.

Animals↗
PubMed1995

In vitro antimalarial activity of chalcones and their derivatives.

A series of chalcones and their derivatives have been synthesized and identified as novel potential antimalarials using both molecular modeling and in vitro testing against the intact parasite. A large number of chalcones and their derivatives were prepared using one-step Claisen-Schmidt condensations of aldehydes with methyl ketones. These condensates were screened in vitro against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and shown to be active at concentrations in the nanomolar range. The most active chalcone derivative, 1-(2,5-dichlorophenyl)-3-(4-quinolinyl)-2-propen-1-one (7), had an IC50 value of 200 nM against both a chloroquine-resistant strain (W2) and a chloroquine-sensitive strain (D6). The resistance indexes for all compounds were substantially lower than for chloroquine, suggesting that this series will be active against chloroquine-resistant malaria. Structure-activity relationships (SAR) of the chalcones in the context of a homology-based model structure of the malaria trophozoite cysteine protease, the most likely target enzyme, are presented.

Animals↗
PubMed1995

Structure-activity relationships of the antimalarial agent artemisinin. 2. Effect of heteroatom substitution at O-11: synthesis and bioassay of N-alkyl-11-aza-9-desmethylartemisinins.

A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found in some cases to be more active than artemisinin. A comparison of the in vitro testing methods of Milhous and Makler was conducted and gave similar relative antimalarial activities for these artemisinin analogs. Log P values were determined for most of the compounds, but no apparent correlation between log P and in vitro activity was found.

Animals↗
PubMed1995

Syntheses and antimalarial activities of N-substituted 11-azaartemisinins.

A two-step reaction sequence between artemisinin and methanolic ammonia followed by treatment with Amberlyst 15 yielded 11-azaartemisinin in 65% yield. Substituting a variety of primary alkyl- and heteroaromatic amines for ammonia in the reaction sequence yields N-substituted 11-azaartemisinins in similar or greater yield. When Amberlyst 15 is replaced by a mixture of sulfuric acid/silica gel, both 11-azaartemisinin and the expected metabolite, 10-azadesoxyartemisinin, are formed in 45% and 15% yields, respectively. In vitro and in vivo test data for a number of novel N-substituted 11-azaartemisinins, against drug-resistant strains of Plasmodium falciparum, show they possess antimalarial activities equal to or greater than that of artemisinin. The most active derivative, N-(2'-acetaldehydo)-11-azaartemisinin, 17, was 26 times more active in vitro and 4 times more active in vivo than artemisinin.

Animals↗
PubMed1992

Synthesis and antimalarial properties of 1-imino derivatives of 7-chloro-3-substituted-3,4-dihydro-1,9(2H,10H)-acridinediones and related structures.

To improve upon the activity and properties of the 3-aryl-7-chloro-3,4- dihydro-1,9(2H,10H)-acridinediones, a variety of 1-[(alkylamino)alkylene]imino derivatives (3) were prepared and shown to be highly active antimalarial agents in both rodents and primates. Among structural modifications prepared, including N10-alkyl and C2-substituted analogs, removal of the C9 oxygen, and introduction of an imino side chain at C9, the imines of the N10-H acridinediones were the most active compounds obtained. The [3-(N,N- dimethylamino)propyl]imino derivative of 7-chloro-3-(2,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)- acridinedione (9aa) proved to be highly active in advanced studies in primates.

Acridines↗
PubMed1991

Antimalarial polyamine analogues.

A series of novel tetraamines of the general formula RNH(CH2)xNH(CH2)yNH(CH2)xNHR was synthesized and examined for activity against growth of Plasmodium falciparum in vitro. Within the series, dibenzyl analogues (R = benzyl) were found to be the most effective growth inhibitors, with IC50 values of about 10(-6) M. Further modifications of the tetraamine provided the optimum chain length for antimalarial activity of y = 7, x = 3. Compound 8 (MDL 27,695) with the structure y = 7, x = 3, R = benzyl, in combination with the ornithine decarboxylase inhibitor alpha-(difluoromethyl)ornithine, resulted in radical cures when tested against experimental Plasmodium berghei infections in mice. The structure-activity relationships of the series are discussed.

Animals↗
PubMed1991

Synthesis and antimalarial activity of 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate derivatives.

A series of 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate derivatives has been synthesized and evaluated for antimalarial activity in vitro against the human malaria parasite, Plasmodium falciparum (Vietnam Smith strain, chloroquine-resistant at the R3 level). The most active compounds, 2-aziridinyl-1,4-naphthoquinon-5-yl p-ethylbenzenesulfonate (13), 2-aziridinyl-1,4-naphthoquinon-5-yl p-tert-butylbenzenesulfonate (48), and 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (5) produced 50% inhibition of the growth of P. falciparum at 9.6 x 10(-8), 2.4 x 10(-8), and 8.8 x 10(-8) M, respectively.

Animals↗