RESUMEN
Molecular similarity analysis of stereoelectronic properties between natural insect juvenile hormone (JH), -a synthetic insect juvenile hormone mimic (JH-mimic, undecen-2-yl carbamate), and N, N-diethyl-m-toluamide (DEET) and its analogs reveals similarities that may aid the design of more efficacious insect repellents and give a better insight into the mechanism of repellent action. The study involves quantum chemical calculations using the AM1 semi-empirical computational method enabling a conformational search for the lowest and most abundant energy conformers of JH, JH-mimic, and 15 DEET compounds, followed by complete geometry optimization of the conformers. Similarity analyses of stereoelectronic properties such as structural parameters, atomic charges, dipole moments, molecular electrostatic potentials, and highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies were performed on JH, JH-mimic and the DEET compounds. The similarity of stereoelectronic attributes of the amide/ester moiety, the negative electrostatic potential regions beyond the van der Waals surface, and the large distribution of hydrophobic regions in the compounds appear to be the three important factors leading to a similar interaction with the JH receptor. The similarity of electrostatic profiles beyond the van der Waals surface is likely to play a crucial role in molecular recognition interaction with the JH receptor from a distance. This also suggests electrostatic bioisosterism of the amide group of the DEET compounds and JH-mimic and, thus, a model for molecular recognition at the JH receptor. The insect repellent property of the DEET analogs may thus be attributed to a conflict of complementarity for the JH receptor binding sites.
Asunto(s)
DEET/química , Diseño de Fármacos , Repelentes de Insectos/química , Hormonas Juveniles/química , Algoritmos , Animales , Biología Computacional , Modelos Químicos , Imitación Molecular , Estructura Molecular , Conformación Proteica , EstereoisomerismoRESUMEN
Considerable data now support the hypothesis that chloroquine (CQ)-hematin binding in the parasite food vacuole leads to inhibition of hematin polymerization and parasite death by hematin poisoning. To better understand the structural specificity of CQ-hematin binding, 13 CQ analogues were chosen and their hematin binding affinity, inhibition of hematin polymerization, and inhibition of parasite growth were measured. As determined by isothermal titration calorimetry (ITC), the stoichiometry data and exothermic binding enthalpies indicated that, like CQ, these analogues bind to two or more hematin mu-oxo dimers in a cofacial pi-pi sandwich-type complex. Association constants (K(a)'s) ranged from 0.46 to 2.9 x 10(5) M(-1) compared to 4.0 x 10(5) M(-1) for CQ. Remarkably, we were not able to measure any significant interaction between hematin mu-oxo dimer and 11, the 6-chloro analogue of CQ. This result indicates that the 7-chloro substituent in CQ is a critical structural determinant in its binding affinity to hematin mu-oxo dimer. Molecular modeling experiments reinforce the view that the enthalpically favorable pi-pi interaction observed in the CQ-hematin mu-oxo dimer complex derives from a favorable alignment of the out-of-plane pi-electron density in CQ and hematin mu-oxo dimer at the points of intermolecular contact. For 4-aminoquinolines related to CQ, our data suggest that electron-withdrawing functional groups at the 7-position of the quinoline ring are required for activity against both hematin polymerization and parasite growth and that chlorine substitution at position 7 is optimal. Our results also confirm that the CQ diaminoalkyl side chain, especially the aliphatic tertiary nitrogen atom, is an important structural determinant in CQ drug resistance. For CQ analogues 1-13, the lack of correlation between K(a) and hematin polymerization IC(50) values suggests that other properties of the CQ-hematin mu-oxo dimer complex, rather than its association constant alone, play a role in the inhibition of hematin polymerization. However, there was a modest correlation between inhibition of hematin polymerization and inhibition of parasite growth when hematin polymerization IC(50) values were normalized for hematin mu-oxo dimer binding affinities, adding further evidence that antimalarial 4-aminoquinolines act by this mechanism.
Asunto(s)
Antimaláricos/química , Cloroquina/análogos & derivados , Cloroquina/química , Hemina/química , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/farmacología , Biopolímeros , Cloroquina/farmacología , Colorimetría , Depresión Química , Concentración 50 Inhibidora , Modelos Moleculares , Plasmodium falciparum/crecimiento & desarrollo , Relación Estructura-ActividadRESUMEN
For most potent antimalarial activity, the cinchona alkaloids appear to require certain electronic features, particularly a sufficiently acidic hydroxyl proton and an electric field direction pointing from the aliphatic nitrogen atom towards the quinoline ring. These observations are the result of an analysis of molecular electronic properties of eight cinchona alkaloids and an in vivo metabolite calculated using ab initio 3-21G quantum chemical methods in relation to their in vitro IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. The purpose is to provide a profile of the electronic characteristics necessary for potent antimalarial activity for use in the design of new antimalarial agents and to gain insight into the mechanistic path for antimalarial activity. Distinguishing features of the weakly active epiquinine and epiquinidine include a higher dipole moment, a different direction of the electric field, a greater intrinsic nucleophilicity, lower acidity of the hydroxyl proton, a lesser electron affinity of the lowest unoccupied molecular orbitals, and a higher proton affinity than the active cinchona alkaloids. A moderately potent quinine metabolite possesses some, but not all, of the same electronic features as the most potent cinchona alkaloids. Both the positioning of the hydroxyl and aliphatic amine groups and their electronic features appear to play a crucial role for antimalarial potency of the cinchona alkaloids, most likely by controlling the ability of these groups to form effective intermolecular hydrogen bonds.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Alcaloides de Cinchona/química , Alcaloides de Cinchona/farmacología , Animales , Plasmodium falciparum/efectos de los fármacos , Protones , Quinidina/análogos & derivados , Quinidina/química , Electricidad Estática , Relación Estructura-ActividadRESUMEN
Quantum chemical calculations on the molecular electronic structure of artemisinin (qinghaosu) and eight of its derivatives have resulted in stereoelectronic discriminators that differentiate between analogues with higher and lower neurotoxicities. Detailed ab initio quantum chemical calculations leading to complete optimization of geometry of each of the molecules were followed by calculation of their stereoelectronic properties using the 3-21G split valence basis sets and comparison of the stereoelectronic properties to in vitro neurotoxicity. The least neurotoxic compounds are more polar with an electric field pointing away from the endoperoxide bond and have a higher positive potential on the van der Waals surface of the all carbon-containing ring C, a more stable peroxide bond to cleavage, a less negative electrostatic potential by the endoperoxide, and a single negative potential region extending beyond the van der Waals surface of the molecule. In general, higher intrinsic lipophilicity is associated with greater neurotoxicity.
Asunto(s)
Antimaláricos/química , Antimaláricos/toxicidad , Artemisininas , Neurotoxinas/química , Neurotoxinas/toxicidad , Sesquiterpenos/química , Sesquiterpenos/toxicidad , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Fenómenos Químicos , Química Física , Ratones , Conformación Molecular , Peróxidos/química , Protones , Ratas , Solubilidad , Estereoisomerismo , Succinatos/química , Células Tumorales CultivadasRESUMEN
Specific molecular electronic properties of 30 N,N-diethyl-m-toluamide (DEET) analogs demonstrate functional dependence with their reported duration of protection against mosquito bites, thus providing predictors of insect repellent efficacy. No single electronic property is sufficient to predict repellent efficacy as measured by protection time, rather a set of specific electronic properties is required. Thus, the values of the van der Waals surface electrostatic potential by the amide nitrogen and oxygen atoms, the atomic charge at the amide nitrogen atom, and the dipole moment must all be in optimal ranges for potent repellency. The electronic properties were calculated using the AM semi-empirical quantum chemical method using commercial software. These easily calculable predictors of repellent efficacy should be useful in predicting the relative efficacy of newly designed compounds, thus guiding the selection of new repellents for testing.
Asunto(s)
Culicidae , DEET/análogos & derivados , Repelentes de Insectos/química , Animales , DEET/química , Conformación Molecular , Electricidad EstáticaRESUMEN
Specific calculated molecular electronic properties of structurally diverse synthetic aromatic carbinolamines containing phenanthrene, quinoline, and N-substituted biphenyl rings are associated with antimalarial potency allowing use of these electronic features in the prediction of antimalarial efficacy, thus aiding the design of new antimalarial agents. These electronic features include the magnitude and location of 3-dimensional molecular electrostatic potentials, lowest unoccupied molecular orbitals, and highest occupied molecular orbitals. Stereoelectronic properties were calculated using quantum chemical AM1 methods on the optimized geometry of the lowest energy or most populated conformer in both gaseous and aqueous environments. In the phenanthrene carbinolamines, the aliphatic nitrogen atom and the hydroxyl proton are intrinsically more nucleophilic and less electrophilic, respectively, than in the non-phenanthrene compounds. Hydrogen bonding ability and the electrophilic nature of the aromatic ring appear to be two important features responsible for interaction with receptor molecules.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Mefloquina/química , Mefloquina/farmacología , Modelos Moleculares , Conformación Molecular , Fenantrenos/química , Fenantrenos/farmacología , Piridinas/química , Piridinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Electricidad Estática , Relación Estructura-ActividadRESUMEN
The crystal and molecular structures and absolute configuration of (-)-halofantrine hydrochloride were determined by X-ray diffraction. The absolute configuration of the single chiral center of (-)-halofantrine was established to be in the S configuration. Thus, (+)-halofantrine, the more cardiotoxic isomer, has the R configuration. The carbon atom adjacent to the aromatic ring has the same configuration in both (+)- halofantrine and quinidine, suggesting a stereospecific component to the cardiotoxicity produced by both agents. The intramolecular N ... O distance is 4.177 +/- 0.006 A (1 A = 0.1 nm), which is close to the N ... O distance found in the crystal structure of (+/-)-halofantrine hydrochloride, even though the N-H group points in opposite directions in racemic halofantrine and (-)-halofantrine. Both the hydroxyl group and the amine group form hydrogen bonds with the chloride anions. The crystallographic parameters for (-)-halofantrine hydrochloride were as follows: chemical formula, C26H31Cl2F6NO+. Cl-; Mr, 492.4; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a was 6.290 +/- 0.001 A, b was 13.533 +/- 0.003 A, and c was 30.936 +/- 0.006 A; volume of the unit cell, 2,633.2 +/- 0.7 A(3); number of molecules per unit cell, 4; calculated density, 1.354 g cm(-3); source of radiation, Cu K(alpha) (lambda = 1.54178 A); mu (absorption coefficient), 3.50 mm(-1); F(000) (sum of atomic scattering factors at zero scattering angle), 1,120; room temperature was used; final R (residual index), 4.75% for 2,988 reflections, with absolute value of Fo > 3sigma(F), where Fo is the observed structure factor and F is the structure factor.
Asunto(s)
Antimaláricos/química , Antimaláricos/toxicidad , Cardiopatías/inducido químicamente , Fenantrenos/química , Fenantrenos/toxicidad , Cristalografía por Rayos X , Enlace de Hidrógeno , Conformación Molecular , Quinidina/química , Quinidina/toxicidad , Quinina/química , Quinina/toxicidad , EstereoisomerismoRESUMEN
A detailed computational study on a series of 4-quinolinecarbinolamine antimalarials was performed using the semiempirical Austin model 1 (AM1) quantum chemical method to correlate the electronic features with antimalarial activity and to illuminate more completely the fundamental molecular level forces that affect the function and utility of the compounds. Ab initio (3-21G level) calculations were performed on mefloquine, the lead compound in this series, to check the reliability of the AM1 method. Electron density in specific regions of the molecules appears to play the pivotal role toward activity. A large laterally extended negative potential in the frontal portion of the nitrogen atom of the quinoline ring and the absence of negative potential over the molecular plane are crucial for the potent antimalarials. These electrostatic features are likely to be the modulator of hydrophobicity or lipophilicity of the compounds and, hence, determine their activities. The magnitude of the positive potential located by the hydroxyl hydrogen atom also correlates with potent antimalarial activity. Two negative potential regions occur near the hydroxyl oxygen and piperidyl nitrogen atoms. The two negative potential regions and the positive potential located by the hydroxyl hydrogen atom are consistent with intermolecular hydrogen bonding with the cellular effectors. The present modeling study should aid in efficient designing of this class of antimalarial agents.
Asunto(s)
Antimaláricos/química , Piperidinas/química , Quinolinas/química , Animales , Antimaláricos/farmacología , Electrones , Enlace de Hidrógeno , Ratones , Modelos Moleculares , Conformación Molecular , Piperidinas/farmacología , Plasmodium berghei/efectos de los fármacos , Quinolinas/farmacología , Relación Estructura-Actividad , TermodinámicaRESUMEN
Provided by total synthesis, endoperoxides 18, 20, and 22 underwent intramolecular oxymercuration-demercuration leading respectively to formation of an isomeric tetracycle, (1aS, 3S, 5aS, 6R, 8aS, 9R, 12S)-10-deoxo-13-carbaartemisinin (19), (+)-10-deoxo-13-carbaartemisinin (21), and (+)-13-carbaartemisinin (4). Structure assignment to 19 and 21 was based on single-crystal X-ray crystallographic analysis. Tricyclic endoperoxide 20 was converted to methyl and benzyl ethers 23 and 24 and reduced to saturated analog 25 which was also converted to ethers 26 and 27. In vitro antimalarial screening of both tri- and tetracyclic analogs was conducted using the W-2 and D-6 clones of Plasmodium falciparum. Neither target 4 nor 21 displayed substantial antimalarial potency in vitro against P. falciparum, but the diastereomeric peroxide 19 possessed good antimalarial potency in vitro. Tricyclic analogs were uniformly impotent. Iron(II) bromide-promoted rearrangement of 21 gave, in 79% yield, the unique tetracyclic alcohol 35, while 19 provided ring-opened cyclohexanone 41 (39%) along with the tricyclic epoxide 42 (20%). Neither 41 nor 42 possessed in vitro antimalarial activity, suggesting that epoxide-like intermediates are not responsible for the mode of action of this subclass of antimalarials. Rearrangement of 10-deoxoartemisinin (43) with FeBr2 gave a major product (79%) not encountered in the rearrangement of artemisinin that resulted from unraveling of the tetracyclic system cyclohexanone 46. Minor amounts of 1,10-dideoxoartemisinin (49) (8%) were also produced in this reaction.
Asunto(s)
Antimaláricos/farmacología , Artemisininas , Sesquiterpenos/química , Sesquiterpenos/farmacología , Animales , Antimaláricos/síntesis química , Antimaláricos/química , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Plasmodium falciparum/efectos de los fármacos , Sesquiterpenos/síntesis química , Espectrofotometría Infrarroja , Relación Estructura-ActividadRESUMEN
A high-performance liquid chromatographic method was developed to quantitate the plasma concentrations of the individual enantiomers of a candidate 8-aminoquinoline antimalarial agent WR 238,605 (I). The method employed one-step liquid extraction of a 0.5-ml plasma sample followed by direct injection of the extract through a chiral column and detection by fluorescence. Quantification was achieved using an internal standard. The limit of quantification was 10 ng/ml for each enantiomer. The method is sufficiently sensitive to quantitate the plasma concentrations of both enantiomers for 30 days following a single oral dose of 400 mg of the antimalarial agent administered as the racemic succinate salt to healthy human male volunteers. In nearly all samples taken 12 h to 30 days post-dose from three subjects, the difference in the plasma concentrations of the two enantiomers is less than 10%.
Asunto(s)
Aminoquinolinas/sangre , Antimaláricos/sangre , Adolescente , Adulto , Disponibilidad Biológica , Humanos , Masculino , EstereoisomerismoRESUMEN
In the presence of amine-containing sulfhydryl compounds, binding of heat-transformed cytosolic rat liver glucocorticoid receptor complex (GRC) to double-stranded calf thymus DNA-coated cellulose and to rat liver chromatin was enhanced up to 10-fold. These observations were made under conditions when a maximum of 8% of the total GRC bound to DNA in the absence of test compound. Compounds which did not contain both a sulfhydryl and amine group were inactive. Phosphorothioate derivatives of the active sulfhydryl compounds were also inactive. However, pretreatment of the phosphorothioate compounds with alkaline phosphatase restored activity. Upon centrifugation at 8800g, amine-containing disulfide compounds at millimolar concentrations caused considerable sedimentation of the GRC in the absence of DNA-coated cellulose or chromatin and no apparent increase in GRC binding to DNA or chromatin. Amine-containing disulfide compounds at micromolar concentrations did not cause heavy sedimentation of the GRC and enhanced binding of the GRC to DNA-coated cellulose up to 9.5-fold. Thus, diaminosulfhydryl compounds and the disulfide 1,18-diamino-6,13-diaza-9,10-dithiaoctadecane (WR 149,024) possess both the ability to restore and preserve the steroid binding capacity of the glucocorticoid receptor and to enhance binding of the GRC to DNA and chromatin.
Asunto(s)
Aminas/farmacología , Celulosa/análogos & derivados , Cromatina/metabolismo , ADN/metabolismo , Disulfuros/farmacología , Receptores de Glucocorticoides/metabolismo , Compuestos de Sulfhidrilo/farmacología , Animales , Celulosa/metabolismo , Proteínas de Unión al ADN/metabolismo , Hígado/metabolismo , Masculino , Estructura Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
Several 9-substituted derivatives of the antimalarial drug artemisinin have been prepared by functionalizing the double bond of artemisitene and related compounds. Stereochemical assignments for these compounds were made using a combination of NMR experiments, an X-ray diffraction study of one compound, and chemical correlations of several other compounds with this one compound of unambiguous structure and with its epimer. The compounds synthesized show a wide variation in in vitro antimalarial activity.
Asunto(s)
Antimaláricos/síntesis química , Artemisininas , Sesquiterpenos/síntesis química , Animales , Antimaláricos/química , Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Sesquiterpenos/química , Sesquiterpenos/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The (+)-isomers of mefloquine and its threo analog are 1.69 to 1.95 times more active than the (-)-isomers against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum in vitro. This large a differential between the activity of (+)- and (-)-isomers was not observed for other synthetic amino alcohol antimalarial agents containing a piperidine ring. The enantiomers of amino alcohol antimalarial agents in which the amine is part of an acyclic group, such as in halofantrine, displayed little, if any, differential antimalarial activity. Thus, the effect of absolute stereochemistry of the amino alcohol antimalarial agents on antimalarial activity appears to depend upon both the flexibility of the amine portion of the molecule and the structure of the aromatic portion of the molecule.
Asunto(s)
Antimaláricos/farmacología , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/química , Cloroquina/farmacología , Resistencia a Medicamentos , Mefloquina/química , Mefloquina/farmacología , Fenantrenos/química , Fenantrenos/farmacocinética , Fenantrenos/farmacología , Piridinas/química , Piridinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
9-Epiquinine hydrochloride dihydrate [(9S)-6'-methoxycinchonan-9-ol hydrochloride dihydrate], C20H25N2O2+.Cl-.2H2O, M(r) = 396.9, orthorhombic, P212121, a = 8.059 (2), b = 11.537 (3), c = 22.311 (6) A, V = 2074.1 (9) A3, Z = 4, Dx = 1.271 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 18.58 cm-1, F(000) = 848, room temperature, final R = 6.56% for 1344 reflections with magnitude of Fo > 3 sigma (F). 9-Epiquinine crystallized as a hydrated tertiary amine hydrochloride salt. The intramolecular N(1)+ ...O distance is 2.816 A. All H atoms attached to O or N atoms form intermolecular hydrogen bonds. The Cl ion is involved in four hydrogen bonds including one with the hydroxyl group of 9-epiquinine. The N(1)+-H moiety hydrogen bonds to a water molecule. The O(12)-C(9)...N(1)+-H(1) torsion angle was equal to -0.2 (3.8) degrees in comparison to 97.0 degrees for quinidine sulfate [Karle & Karle (1981). Proc. Natl Acad. Sci. USA, 78, 5938-5941]. Two theories have been proposed in the literature to explain the low antimalarial activity of 9-epiquinine. The crystal structure of 9-epiquinine hydrochloride is not consistent with the hypothesis that 9-epiquinine prefers to form intramolecular rather than intermolecular hydrogen bonds, but is consistent with the hypothesis that N(1) and the hydroxyl group of 9-epiquinine are in an orientation which is unfavorable towards exerting antimalarial activity.
Asunto(s)
Antimaláricos/química , Quinina/química , Antimaláricos/uso terapéutico , Fenómenos Químicos , Química Física , Cristalización , Enlace de Hidrógeno , Estructura Molecular , Quinina/uso terapéutico , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
Quinine and quinidine were over 100 times more active than 9-epiquinine and 9-epiquinidine against chloroquine-sensitive Plasmodium falciparum and over 10 times more active against chloroquine-resistant P. falciparum. Since the only structural difference between quinine, quinidine, 9-epiquinine, and 9-epiquinidine is their three-dimensional configuration, the three-dimensional structures of these four alkaloids were examined in order to explain the large difference in relative activities between the 9-epi alkaloids and quinine and quinidine. The crystal structure of 9-epiquinidine hydrochloride monohydrate was determined by X-ray diffraction and was compared with the crystal structures of quinine, quinidine sulfate dihydrate, and 9-epiquinine hydrochloride dihydrate. The crystallographic parameters for 9-epiquinidine hydrochloride monohydrate were as follows: chemical formula, C20H25N2O2+.Cl-.H2O; M(r), 378.9; symmetry of unit cell, orthorhombic; space group, P2(1)2(1)2(1); parameters of unit cell, a was 7.042 +/- 0.001 A (1 A = 0.1 nm), b was 9.082 +/- 0.001 A, c was 31.007 +/- 0.005 A; the volume of unit cell was 1,983.1 +/- 0.6 A3; number of molecules per unit cell was 4; the calculated density was 1.27 g cm-3; the source of radiation was Cu K alpha (lambda = 1.54178 A); mu (absorption coefficient) was 18.82 cm-1; F(000) (sum of atomic scattering factors at zero scattering angle) was 808; room temperature was used; final R (residual index) was 5.72% for 1,501 reflections with magnitude of F(o) greater than 3 sigma (F). The intramolecular distance from N-1 to O-12 in 9-epiquinidine and 9-epiquinine, although shorter than the corresponding distance in quinine and quinidine, was similar to those of other active amino alcohol antimalarial agents. In all four alkaloids, both the hydroxyl and amine groups formed intermolecular hydrogen bonds, showing the potential for forming hydrogen bonds with cellular constituents. However, the positioning of the N+-1--H-N1 and O-12--H-O12 groups relative to each other was quite different in the 9-epi alkaloids versus quinidine. This difference in positioning may determine the relative strengths, of the formation of hydrogen bonds with cellular constituents important to antimalarial activity and, therefore, may determine the relative strength of antimalarial activity.
Asunto(s)
Antimaláricos/farmacología , Alcaloides de Cinchona/farmacología , Plasmodium falciparum/efectos de los fármacos , Animales , Cristalografía , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
C20H28NS+.Cl-, 2-(diethylamino)ethyl 1,1-diphenylethyl sulfide hydrochloride (thiodeacylaprophen hydrochloride), M(r) = 349.9, orthorhombic, P2(1)2(1)2(1), a = 8.933 (2), b = 11.710 (3), c = 18.934 (4) A, V = 1980.6 (7) A3, Z = 4, Dx = 1.173 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 26.70 cm-1, F(000) = 752, room temperature, final R = 4.1% for 1417 reflections with /Fo/ greater than 3 sigma (F). Thiodeacylaprophen crystallized as a tertiary amine hydrochloride salt. The S--C--C--N+ segment adopts a trans configuration as does one of the Cphenyl--C--S--C segments. A comparison of the structure of thiodeacylaprophen with the crystal structures of potent antimuscarinic agents suggests that the relatively weak antimuscarinic activity of thiodeacylaprophen compared to atropine and aprophen may be substantially due to the short intramolecular S...N+ distance of 4.106 (6) A. Other contributing structural factors may include the direction of the N+--H bond and restricted accessibility of the sulfur atom for interatomic interactions.
Asunto(s)
Dietilaminas/química , Contracción Muscular/efectos de los fármacos , Parasimpatolíticos/química , Sulfuros/química , Animales , Dietilaminas/farmacología , Cobayas , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Masculino , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Parasimpatolíticos/farmacología , Relación Estructura-Actividad , Sulfuros/farmacología , Difracción de Rayos XRESUMEN
The crystal structure of (+/-)-mefloquine methylsulfonate monohydrate was determined by X-ray diffraction and was compared with the crystal structures of mefloquine hydrochloride and mefloquine free base. The conformation of mefloquine was essentially the same in all three crystalline environments and was not dependent on whether mefloquine was a salt or a free base. In mefloquine methylsulfonate monohydrate, the angle between the average plane of the quinoline ring and the average plane of the piperidine ring was 76.9 degrees. The intramolecular aliphatic N-13...O-1 distance was 2.730 +/- 0.008 A (1 A = 0.1 nm), which is close to the aliphatic N...O distance found in the antimalarial cinchona alkaloids. The hydroxyl group formed a hydrogen bond with the water molecule, and the amine group formed hydrogen bonds with two different methylsulfonate ions. The crystallographic parameters for (+/-)-mefloquine methylsulfonate monohydrate were as follows: C17H17F6N2O(+).CH3SO3(-).H2O; Mr = 492.4; symmetry of unit cell, monoclinic; space group, P2(1)/a; parameters of unit cell, a was 8.678 +/- 0.001 A, b was 28.330 +/- 0.003 A, c was 8.804 +/- 0.001 A, beta was 97.50 +/- 0.01 degrees; the volume of the unit cell was 2145.9 A3; the number of molecules per unit cell was 4; the calculated density was 1.52 g cm(-3); the source of radiation was Cu K alpha (lambda = 1.54178 A); mu (absorption coefficient) was 20.46 cm(-1); F(000) (sum of atomic scattering factors at zero scattering angle) was 1,016; room temperature was used; and the final R (residual index) was 6.58% for 1,740 reflections with magnitude of Fo greater than 3 sigma (F). Since the mechanism of antimalarial action and the mechanism of mefloquine resistance may involve hydrogen bond formation between mefloquine and a cellular effector or transport proteins, the common conformation of mefloquine found in each crystalline environment may define the orientation in which mefloquine forms these potentially critical hydrogen bonds with cellular constituents.
Asunto(s)
Malaria/metabolismo , Mefloquina/química , Receptores de Droga/metabolismo , Cristalización , Enlace de Hidrógeno , Mefloquina/metabolismo , Conformación Molecular , Estructura Molecular , Difracción de Rayos XRESUMEN
A comparison of the crystalline structure of the potent azaprophen with the crystalline structures of aprophen and four other structurally related antimuscarinic agents reveals the potential for an ionic interaction of the cationic nitrogen atom and the carbonyl oxygen atom with the muscarinic receptor and an aromatic interaction with a phenyl group. 6-Methyl-6-azabicyclo[3.2.1]octan-3 alpha-ol 2,2-diphenylpropionate hydrochloride (azaprophen hydrochloride), C23H28NO2+.Cl-, Mr = 385.9, monoclinic, P2(1)/c, a = 8.490 (1), b = 14.335 (2), c = 16.847 (2) A, beta = 93.63 (1) degree, V = 2046.2 A3, Z = 4, Dx = 1.253 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 17.86 cm-1, F(000) = 824, room temperature, final R = 4.25% for 2460 reflections with [Fo[ greater than 3 sigma. 2-Diethylaminoethyl 2,2-diphenylpropionate hydrochloride (aprophen hydrochloride), C21H28NO2+.Cl-, Mr = 361.9, orthorhombic, Pbca, a = 15.118 (3), b = 7.488 (2), c = 36.306 (10) A, V = 4110.8 A3, Z = 8, Dx = 1.316 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 17.45 cm-1, F(000) = 1552, room temperature, final R = 7.96% for 1846 reflections with [Fo[ greater than 3 sigma. Both azaprophen and aprophen were crystallized as tertiary amine salts. The overall conformation of both molecules is similar as demonstrated by space-filling models and superimposed stick drawings. Although the interatomic distance between the nitrogen atom and the carbonyl oxygen atom of azaprophen and aprophen is comparable at 5.41 and 5.07 A, respectively, the nitrogen atoms of azaprophen and aprophen are 1.16 A apart when the acyloxy portion (--O--C = O) of both molecules is superimposed. A conformational analysis of azaprophen, aprophen and the structurally similar antimuscarinic agents reveals a buried ether oxygen atom and an exposed carbonyl oxygen atom as well as the common placement of a phenyl group on the same side of the acyloxy plane as the cationic nitrogen atom.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Parasimpatolíticos/análisis , Fenilpropionatos/análisis , Receptores Muscarínicos/efectos de los fármacos , Tropanos/análisis , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
The purpose of this work was to examine whether the ability of dithiothreitol to preserve the steroid-binding capacity of glucocorticoid receptors in subcellular preparations is specific or a general property of sulfhydryl compounds and selected phosphorothioate and disulfide derivatives. A further goal was to see if this effect could be demonstrated in intact cells. The ability to preserve the steroid-binding capacity of the glucocorticoid receptor is not a universal property of all sulfhydryl compounds since many of the compounds tested were inactive. The steroid-binding capacity of the glucocorticoid receptor of the 100,000 g supernatant of rat liver homogenate is preserved/restored by sulfhydryl compounds containing a mercaptoethylamine or mercaptopropylamine subunit. However, small changes in the structure of the sulfhydryl compound such as the rearrangement of a methylene group significantly alter its effectiveness. All of the phosphorothioates examined are derivatives of active sulfhydryl compounds and are effective in preserving steroid-binding. The extent of metabolism of the phosphorothioates and their failure to restore steroid-binding capacity after short-time exposure to receptor preparations are consistent with the sulfhydryl form being the active form of the phosphorothioates. S-2-(3-Amino-propylamino)ethylphosphorothioic acid (WR 2721) preserved steroid-binding capacity in isolated intact rat hepatocytes down to 25 microM demonstrating that concentrations obtainable in whole animals are effective with intact cells. Disulfide derivatives of active sulfhydryl compounds are either immediately toxic or ineffective except for 1,18-diamino-6,13-diaza-9,10-dithiaoctadecane (WR 149,024) which is more effective than its corresponding sulfhydryl. The demonstration that some sulfhydryl-forming compounds preserve the steroid-binding capacity of glucocorticoid receptors in intact cells at potentially physiologically obtainable concentrations suggests a potential role for these or similar compounds to bolster the efficacy of conventional glucocorticoid therapy.
Asunto(s)
Hígado/metabolismo , Receptores de Glucocorticoides/efectos de los fármacos , Compuestos de Sulfhidrilo/farmacología , Adrenalectomía , Animales , Disulfuros/farmacología , Técnicas In Vitro , Masculino , Compuestos Organotiofosforados/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas , Receptores de Glucocorticoides/metabolismo , Relación Estructura-ActividadRESUMEN
1,3-Dichloro-alpha-[2-(dibutylamino)ethyl]-6-(trifluoromethyl)-9- phenanthrenemethanol hydrochloride, C26H31Cl2F3NO+.Cl-, Mr = 536.9, monoclinic, P21/n, alpha = 8.169 (3), b = 32.924 (13), c = 22.775 (6) A, beta = 98.99 (3) degrees, V = 6050.2 A3, Z = 8, Dx = 1.18 g cm-3, Cu K alpha, lambda = 1.54178 A, mu = 15.51 cm-1, F(000) = 2240, room temperature, final R = 18.3% for 2899 reflections with [Fo] greater than 3 sigma. The crystal structure of halofantrine hydrochloride was determined to 1.0 to 1.1 A resolution. The high R factor is due to poor crystal quality. In order to have a crystal with sufficient thickness for data collection, it was necessary to use a crystal that had grown in layers. The high R factor is also due to a disordered CF3 group, a disordered solvent channel, and high thermal factors on the long hydrocarbon chains. The two halofantrine conformers stack such that the phenanthrene rings are nearly on top of each other with the chlorine and CF3 groups on opposite sides and with the hydrocarbon side chains projected away from each other, but on the same side of the phenanthrene rings. Atoms in the phenanthrene rings of the two stacked conformers are separated by 3.4 to 3.7 A. On each of the halofantrine conformers, one of the n-butyl groups extends in a linear fashion whereas the other n-butyl group is bent back towards the phenanthrene ring.(ABSTRACT TRUNCATED AT 250 WORDS)