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Biomedical subjects

M L Go

Publications and source records attributed to M L Go.

At least 19 recordsLinked to original sources
PubMed2005

Chalcones: an update on cytotoxic and chemoprotective properties.

Chalcone is a unique template that is associated with several biological activities. In this review, an update of the cytotoxic and chemoprotective activities of chalcones is provided. Cytotoxicity against tumour cell lines may be the result of disruption of the cell cycle, inhibition of angiogenesis, interference with p53-MDM2 interaction, mitochondrial uncoupling or induction of apoptosis. Structural requirements for cytotoxic activity vary according to the mechanisms of action. For anti-mitotic activity, the presence of methoxy substituents, alpha-methylation of the enone moiety and the presence of 2' oxygenated substituents are favourable features. Conformational restraint of the chalcone template generally leads to a decrease in cytotoxic activity. Chemoprotection by chalcones may be a consequence of their antioxidant properties, mediated via inhibition or induction of metabolic enzymes, by an anti-invasive effect or a reduction in nitric oxide production. Hydroxyl and prenyl substituents are associated with antioxidant properties and induction of quinone reductase activities. The thiol reactivity of chalcones is likely to contribute to both cytotoxic and chemoprotective properties of these compounds.

Animals↗
PubMed2001

Antimalarial alkoxylated and hydroxylated chalcones [corrected]: structure-activity relationship analysis.

Chalcones with 2',3',4'-trimethoxy, 2',4'-dimethoxy, 4'-methoxy, 4'-ethoxy, 2',4'-dihydroxy, and 4'-hydroxy groups on ring B were synthesized and evaluated in vitro against Plasmodium falciparum (K1) in a [3H] hypoxanthine uptake assay. The other ring A was quinoline, pyridine, naphthalene, or phenyl rings with electron-donating or electron-withdrawing substituents of varying lipophilicities. Trimethoxy 6 and 27, dimethoxy 7, 8, 29, and methoxy 31 analogues had good in vitro activities (IC(50) < 5 microM). 3-Quinolinyl ring A derivatives were well represented among the active compounds. Hydroxylated chalcones were less active than the corresponding alkoxylated analogues. When evaluated in vivo, 8 and 208 were comparable to chloroquine in extending the lifespan of infected mice. Multivariate data analysis showed that in vitro activity was mainly determined by the properties of ring B. Quantitative structure-activity relationship models with satisfactory predictive ability were obtained for various B ring chalcones using projections to latent structures. A model with good predictability was proposed for 19 active chalcones. Size and hydrophobicity were identified as critical parameters.

Animals↗
PubMed2001

Halofantrine-phospholipid interactions: monolayer studies.

The antimalarial agent halofantrine penetrates dipalmitolylphosphatidylcholine (DPPC) monolayers resulting in an increase in surface pressure and an expansion in area occupied by the lipid components of the monolayer. This phenomenon is observed at concentrations (0.05-0.2 microm) of halofantrine that have no surface activity. Penetration increases with drug concentration and is greatest at low initial surface pressures of the monolayer. A critical surface pressure of the DPPC monolayer has been determined from constant area and constant pressure conditions. The magnitude of these values support the hypothesis that halofantrine readily penetrates the DPPC monolayers. The presence of cholesterol in the DPPC monolayer hampers penetration and a lower critical surface pressure is obtained under such conditions. Even then, a slower rate of penetration is observed only in monolayers maintained at high initial surface pressures (10, 15 mN/m), corresponding to the liquid condensed phase of the monolayer, and not at low surface pressures (2.5, 5.0 mN/m). These results help to give a better understanding of the dynamics of the halofantrine-phospholipid interaction as well as the pharmacodynamic character of the drug.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2000

Caffeine and nicotinamide enhances the aqueous solubility of the antimalarial agent halofantrine.

The aqueous solubility of the antimalarial agent halofantrine in phosphate buffers pH 5.9 and 7.0 (ionic strength 0.08) is increased by the addition of caffeine and nicotinamide. Solubility is increased to a greater extent in the presence of caffeine (12.5-125 mM) than nicotinamide (125 mM -2.0 M). The greatest increase in solubility was observed at pH 5.9 where the basal solubility of halofantrine rose from 0.91 to 435 microM when 125 mM caffeine was added. Phase solubility studies support the formation of a 1:1 complex between caffeine and halofantrine which is characterised by a K(1:1) constant of 2.75x10(3) M(-1) (pH 5.9). A less stable 1:1 complex is formed at pH 7.0 (K(1:1)=6.37x10(3) M(-1)). Differential scanning calorimetry of solid mixtures of caffeine and halofantrine showed the absence of the endotherms of the two drugs and the appearance of a distinct endotherm (with a smaller enthalpy) characteristic of the complex. An analysis of the 1H-NMR spectra of mixtures of caffeine and halofantrine revealed perturbations in the chemical shifts of the methyl group and proton at positions 4 and 8 of caffeine, and a change in splitting pattern of the H(9) proton of the phenanthrene ring in halofantrine.

Antimalarials↗
PubMed2000

Study of synthesis and cardiovascular activity of some furoxan derivatives as potential NO-donors.

A series of hybrid molecules incorporating the furoxan and nicorandil moieties were designed as potential NO donors with cardiovascular and cerebrovascular activities. Thirty-six target molecules were successfully synthesized by conventional methods and characterized by infrared spectroscopy, 1H-NMR spectroscopy and high resolution mass spectra. The compounds were tested for their effects on KCl-induced contraction of rabbit thoracic aorta whose endothelium was denuded. Eight compounds were found to reduce KCl-induced contraction by more than 30% at 10 microM. All except one of these compounds are characterized by the presence of electron withdrawing groups in the phenyl ring attached via an amide or ester linkage to the furoxan moiety. The nature of the terminal carbonyl linkage (ester or amide) and the length or type of the alkyl chain bridging the two carbonyl functions have little effect on the activity. One of the active compounds, N-(4-methoxy-benzoyl)-N'-[3-methylfuroxanyl-4-carbonyl)piperazine (17i) was tested for hypotensive effects on anaesthesized rats at 1.5 mg/kg, and found to demonstrate a gradual and sustained hypotensive effect. The results suggest that the furoxan-nicorandil derivatives are a useful lead in the design of NO-donor compounds for hypertension.

Animals↗
PubMed1999

Chiral resolution of atropine, homatropine and eight synthetic tropinyl and piperidinyl esters by capillary zone electrophoresis with cyclodextrin additives.

Chiral resolution of atropine, homatropine and eight synthetic tropinyl and piperidinyl esters were studied by capillary zone electrophoresis with cyclodextrin additives. Atropine and eight synthetic derivatives were successfully resolved by heptakis-(2,3,6-tri-O-methyl)-beta-cyclodextrin (TM-beta-CD) at concentrations ranging from 10 to 40 mM. Homatropine was baseline resolved by 10 mM beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin (HP-beta-CD), respectively. The developed method was employed for the determination of atropine enantiomers in human serum.

Atropine↗
PubMed1999

M3/M1-Selective antimuscarinic tropinyl and piperidinyl esters.

The binding affinities of some tropinyl and piperidinyl esters for the submandibulary glands (M3/M1) and heart ventricle (M2) were determined from displacement experiments using 3H-labelled N-methylscopolamine as radioligand. The antimuscarinic activities of these esters were also evaluated on guinea pig bronchi. The esters inhibited the M3-mediated carbachol-induced contraction of the bronchial smooth muscle and a reasonable correlation was obtained between the binding affinities of the esters for the submandibulary glands (pKM3,M1) and their inhibitory activities (pIC50) on guinea pig bronchi. A promising compound, N-methylpiperidinyl cyclohexylphenylpropionate (NCPP) which combined good antimuscarinic activity (pA2=9.34) with a 20-fold selectivity at the M3/M1 receptors, was identified. Quantitative structure-activity relationships (QSAR) showed that the size of the ester was the main structural feature determining both binding affinity for the M3/M1 receptors and inhibitory activity on guinea pig bronchi. Esters with substituted acyl side chains (fewer hyperconjugable H atoms at the alpha-carbon) are generally associated with better activity and affinity.

Animals↗
PubMed1999

The antimalarial agent halofantrine perturbs phosphatidylcholine and phosphatidylethanolamine bilayers: a differential scanning calorimetric study.

The interaction of halofantrine with phosphatidylcholine and phosphatidylethanolamine bilayers has been investigated by differential scanning calorimetry. Halofantrine caused a broadening of the gel to liquid crystalline phase transition endotherm of the phosphatidylcholines. A decrease in the transition temperature Tm and enthalpy (delta H) of transition was also observed. This varied with the chain length of the phospholipid and was more pronounced with short chain members. Halofantrine-induced changes to the thermotropic characteristics of dipalmitoylphosphatidylcholine (DPPC)/cholesterol bilayers suggested that the penetration of halofantrine into the bilayer was diminished in the presence of cholesterol. A more complex calorimetric profile was observed in the interaction of halofantrine with phosphatidylethanolamines and the results suggested that halofantrine did not disrupt the cooperativity of the phosphatidylethanolamine bilayers to the same extent as that observed with the phosphatidylcholines. Halofantrine caused significant perturbation of phospholipids and this property might have an important bearing on its pharmacodynamic effects.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1998

Synthesis and pharmacological characterization of O-alkynyloximes of tropinone and N-methylpiperidinone as muscarinic agonists.

A number of O-alkynyloximes of tropinone and N-methyl-4-piperidinone have been synthesized and evaluated for muscarinic activity. The affinities of these oximes were tested in homogenates of cerebral cortex, heart, and submandibulary glands from rats using [3H]pirenzepine and [3H]-N-methylscopolamine as radioligands. The oximes bind to the cortical muscarinic receptors with pKi values varying from 3 to 7. Higher binding affinities were observed for the O-alkynyl tropinone oximes than the corresponding piperidinone analogues. Binding to the muscarinic sites in the heart and submandibulary glands was also observed but with lower affinities. Good M1 subtype selectivity (10-fold or greater) was observed with some oximes (26a, 28a, 32a) at the cortical sites. These oximes also attenuated scopolamine-induced impairment of the water mask task in mice. Functional assays for M3 activity on the rat aorta showed that all oximes possessed M3 agonist action but M2 agonist activity was not observed at the endothelium-denuded rabbit aorta. Analysis of the quantitative structure-activity relationship (QSAR) indicated that the Connolly surface area is an important determinant of activity, accounting for 70% of the variation in cortical binding affinity among the oximes.

Animals↗
PubMed1998

Synthesis, antimuscarinic activity and quantitative structure-activity relationship (QSAR) of tropinyl and piperidinyl esters.

A series of tropinyl and piperidinyl esters was synthesized and evaluated for inhibitory activities on the endothelial muscarinic receptors of rat (M3) and rabbit (M2) aorta. Some of the esters (cyclohexylphenylglycolates and cyclohexylphenylpropionates) were found to be better antimuscarinic compounds than standard M2 and M3 inhibitors such as AFDX116 and 4-diphenylacetoxy-N-methylpiperidine (DAMP), with pKEC50 values in the range of 8-9. A few esters were found to be more selective M3 than M2 inhibitors, but these tended to have low activities. The hydrophobic, electronic and steric characteristics of these esters were correlated with antimuscarinic activity by using appropriate parameters representing hydrophobicity (HPLC capacity factor, log kw), size (molecular volume) and electronic character (Taft's polar substituent constant sigma * and 13C chemical shift difference delta delta). Finally, 92% of the M2-inhibitory activities of the esters could be accounted for by the size and electronic character sigma * of the side chain. In contrast, the M3-inhibitory activities of these esters were mainly attributed to the electronic nature (sigma *, delta delta) of the side chain, with good activity being associated with electron-withdrawing groups. Visualization of the comparative molecular field analysis (CoMFA) steric and electrostatic fields provided further confirmation of the structure-activity relationship (SAR) derived from traditional quantitative structure activity relationship (QSAR) approaches.

Animals↗
PubMed1997

Thermodynamics of partitioning of the antimalarial drug mefloquine in phospholipid bilayers and bulk solvents.

The antimalarial drug mefloquine binds avidly to phospholipids in biomembranes. The thermodynamics of the partitioning process in dimyristoylphosphatidylcholine (DMPC) bilayers was investigated to give some insight into the drug-phospholipid interaction. Thermodynamic parameters for the partition equilibria were evaluated from the equilibrium partition coefficients measured as a function of temperature. Negative values of delta H and delta S were obtained for the transfer of mefloquine from the aqueous to the gel phase of the phospholipid. The partitioning is enthalpy controlled which suggests that mefloquine interacts strongly with the phospholipid phase. In contrast, the partitioning of mefloquine into the liquid crystalline phase of DMPC is entropy controlled which is typical of a hydrophobic interaction between mefloquine and the aqueous phase. The partitioning of mefloquine into the bulk solvents octanol and hexane were found to be enthalpy and entropy controlled, respectively. The enthalpy dominated partitioning of mefloquine into gel phase DMPC and octanol is attributed to the occurrence of hydrogen bonding and van der Waals interactions between solute and solvent. The flat shape of mefloquine may further aid its interaction with the orderly domains of the lipidic/organic phase. This is apparent from a comparison of the partitioning characteristics of another structurally related but conformationally different molecule, quinine into DMPC and octanol.

1-Octanol↗
PubMed1994

Molecular geometry and physiochemical characteristics of selected anilinoquinolines, indolo[3,2-c]quinolines and tetrahydroindolo[3,2-d]benzazepines.

The molecular geometry, acid dissociation constants and partition coefficients of the anilinoquinoline (I), indolo[3,2-c]quinoline (II) and tetrahydroindolo[3,2-d] [1]benzazepine (III) ring systems have been determined using representative compounds: 7-chloro-4-(p-anisidino)quinoline (Ia), 3-chloro-8-methoxy-11H-indolo[3,2-c]-quinoline (IIa) and 3-chloro-9-methoxy-5,6,7,12-tetrahydroindolo[3,2-d] [1]benzazepine (IIIa). Ring systems II and III are cyclic analogues of I. The minimum energy conformation was determined by molecular mechanics. Compound IIa is the most planar and conformationally restricted, followed by IIIa and Ia. The acid dissociation constants (pKa) were determined by the solubility method. The ring nitrogen of Ia is most basic, followed by that of IIa and IIIa. The partition coefficient (log P) was determined between octanol and appropriate aqueous buffers by the shaken flask method. Hydrophobicity decreases in the order of Ia > IIa > IIIa. Factors contributing to the different molecular geometry, pKa and hydrophobicity of these related compounds are discussed. The present study may contribute to the design of better drugs with ring system I, II or III.

Benzazepines↗
PubMed1993

Pharmacological activity and structure-activity relationship of (+/-)-erythro-mefloquine and related compounds on the isolated mouse phrenic nerve diaphragm preparation.

The effects of the antimalarial agent, (+/-)-erythro-mefloquine and related compounds [(+/-)-threo-mefloquine, (+/-)-erythro-N-methylmefloquine and its N-oxide, quinine, WR 184806 and halofanthrine] on the isolated mouse phrenic nerve diaphragm preparation were investigated. Based on their pharmacological effects, these compounds may be divided into two groups. The group I compounds, comprising (+/)-erythro-mefloquine, (+/-)-threo-mefloquine and WR 184806, were found to exert a contractile effect on the muscle and also to inhibit the indirectly (nerve) stimulated and directly (muscle) stimulated (after alpha-bungarotoxin) twitch responses. The group II compounds, comprising the other compounds except halofanthrine, lacked a contractile effect on muscle but potentiated the directly stimulated twitch responses (after alpha-bungarotoxin). Halofanthrine did not elicit any response from the preparation. The minimum energy conformations of these compounds were determined using an interactive molecular modelling program which incorporates MMX force field for molecular mechanics calculations. Conformational analyses of the erythro and threo isomers of mefloquine hydrochloride were also undertaken using 1H-NMR. The 1H-NMR data supported the proposal made on the basis of MMX calculations that the erythro isomer exists in solution as one predominant conformer whereas the threo isomer is present in solution as a mixed population of two stable conformers. The structure-activity relationship of the compounds is discussed.

Animals↗
PubMed1990

Effects of mefloquine on the release of marker enzymes from the rat liver crude lysosomal fraction.

The effects of the antimalarial agent mefloquine on the release of marker enzymes, acid phosphatase and beta glucuronidase, from the rat liver lysosomes in a crude lysosomal preparation were investigated and compared with that of chloroquine whose membrane effects have been well-documented in the literature. At 10 microM, mefloquine decreased significantly the release of marker enzymes when compared to the control, but at the higher concentrations of 100 microM and 500 microM, it markedly accelerated the release of enzymes. This suggested that mefloquine exerted a concentration-dependent biphasic effect of membrane stabilization and labilization. In comparison, chloroquine diminished the release of enzymes over the concentration range of 10-500 microM, that is showing a membrane stabilizing effect similar to other reports. Since serum levels of 1.6-3.2 microM are reported after a weekly dose of mefloquine, the present results suggest that a predominant stabilization effect should prevail under these conditions. However, higher drug concentrations may result in labilization with undesirable consequences.

Acid Phosphatase↗
PubMed1989

Inhibition of acetylcholinesterase by diastereomers of 2-methylamino-1-phenylpropanol and their derivatives.

The anti-acetylcholinesterase activities of the ephedrine diastereomers and their N-methyl derivatives were correlated to the conformation of the molecules in solution. The stereospecificity exhibited by enantiomers of N-methyl-psi-ephedrine was attributed to the predominance of one preferred conformation. The possibility of predicting the absolute configuration of chiral inhibitors from enzyme inhibitions data is discussed.

Cholinesterase Inhibitors↗
PubMed1988

Action of mefloquine on agonist-induced contractions of the guinea-pig isolated ileum.

1. Responses of the guinea-pig isolated ileum to cumulative concentrations of acetylcholine (ACh), histamine (H), and prostaglandin E2 (PGE2) were obtained in the presence or absence of mefloquine or quinine. 2. The effects of increasing the external calcium concentration and the presence of a low concentration (1.8 nmol/l) of PGE2 on the mefloquine- and quinine-induced inhibition of the ACh cumulative dose-response curves were also investigated. 3. Mefloquine (1-10 mumol/l) and quinine (50-100 mumol/l) both caused a dose-dependent non-parallel right shift of the log concentration-response curve of every agonist. Mefloquine is a more potent inhibitor of PGE2-induced responses whereas quinine inhibited all three agonist-induced responses to the same extent. 4. Increasing the external calcium concentration enhanced the inhibitory effects of both drugs on ACh-induced responses. Pre-incubation with 1.8 nmol/l PGE2 had a similar effect. 5. The actions of mefloquine on ACh- and H-induced contractions are non-specific, like other antimalarials, but its greater inhibitory action on PGE2 may involve a more complex effect.

Acetylcholine↗
PubMed1988

Action of mefloquine on toad isolated rectus abdominis muscle.

The effects of mefloquine and quinine on acetylcholine-induced contractures of the toad rectus abdominis muscle have been investigated. Both drugs depressed acetylcholine-induced contractures in a dose-related and non-competitive manner. A partial reversal of the block was observed in the presence of 4-aminopyridine (10, 50 microM) and increased Ca2+ content (1.25x) of the Ringer solution. In both cases, the mefloquine-induced blockade was more readily reversed than that induced by quinine. Mefloquine and quinine at concentrations greater than 100 and 500 microM, respectively, also elicited a direct contractile response on the muscle. Quantitative differences in their contractile activity have been attributed to the greater lipid solubility and tissue binding affinity of mefloquine.

4-Aminopyridine↗