Jean M. Karle

Stereochemical evaluation of the relative activities of the cinchona alkaloids against Plasmodium falciparum.

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.

Crystal Structure of (−)-Mefloquine Hydrochloride Reveals Consistency of Configuration with Biological Activity

ABSTRACT The absolute configuration of (−)-mefloquine has been established as 11R,12S by X-ray crystallography of the hydrochloride salt, thus allowing comparison of the configuration of mefloquines optical isomers to those of quinine and quinidine. (−)-Mefloquine has the same stereochemistry as quinine, and (+)-mefloquine has the same stereochemistry as quinidine. Since (+)-mefloquine is more potent than (−)-mefloquine in vitro against the D6 and W2 strains of Plasmodium falciparum and quinidine is more potent than quinine, a common stereochemical component for antimalarial activity is implicated. The crystal of (−)-mefloquine hydrochloride contained four different conformations which mainly differ in a small rotation of the piperidine ring. These conformations are essentially the same as the crystalline conformations of racemic mefloquine methylsulfonate monohydrate, mefloquine hydrochloride, and mefloquine free base. The crystallographic parameters for (−)-mefloquine hydrochloride hydrate were as follows: C17H17F 6N2O+Cl− · 0.25 H2O; Mr, 419.3; symmetry of unit cell, orthorhombic; space group, P212121; parameters of unit cell, a = 12.6890 ± 0.0006 Å (1 Å = 0.1 nm), b = 18.9720 ± 0.0009 Å, c = 32.189 ± 0.017 Å; volume of unit cell, 7,749 ± 4 Å3; number of molecules per unit cell, 16; calculated density, 1.44 g cm−3; source of radiation, Cu Kα (λ = 1.54178 Å); μ (absorption coefficient), 2.373 mm−1; room temperature was used; final R1 (residual index), 0.0874 for 3,692 reflections with intensities greater than 2σ. All of the hydroxyl and amine hydrogen atoms participate in intermolecular hydrogen bonds with chloride ions. The orientation of the amine and hydroxyl groups in (+)-mefloquine may define the optimal geometry for hydrogen bonding with cellular constituents.

Stereoelectronic features of the cinchona alkaloids determine their differential antimalarial activity.

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.

Functional correlation of molecular electronic properties with potency of synthetic carbinolamine antimalarial agents.

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.

Molecular similarity analysis between insect juvenile hormone and N, N-diethyl-m-toluamide (DEET) analogs may aid design of novel insect repellents.

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. Copyright

Crystal structure and molecular structure of mefloquine methylsulfonate monohydrate: implications for a malaria receptor.

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.

The synthesis of 8,8-disubstituted tricyclic analogs of artemisinin

Abstract Two tricyclic analogs of artemisinin were designed based on a Comparative Molecular Field Analysis (CoMFA) model, and synthesized for antimalarial testing as part of a program to construct and validate modeling tools for drug design of novel antimalarial agents based on the natural product lead, (+)-artemisinin.

An Unusual Reversal of Stereoselectivity in a Boron Mediated Aldol Reaction: Enantioselective Synthesis of the C1–C6 Segment of the Epothilones

Abstract Enantioselective syntheses of differentially protected C1–C6 fragments, (3S)-3-hydroxy-4,4-dimethyl-5-oxoheptanoic acid 4, (5S)-7-[1,1-bis(methylethyl)-2-methyl-1-silapropoxy]-5-hydroxy-4,4-dimethylheptan-3-one 5 and (4S)-2-(2,2-dimethyl-1,3-dioxan-4-yl)-2-methylpentan-3-one 23, common to both epothilones A and B, are reported.

Replacement of the nonperoxidic trioxane oxygen atom of artemisinin by carbon: Total synthesis of (+)-13-carbaartemisinin and related structures

Abstract Provided by total synthesis, endoperoxides 17 , 19 and 21 underwent intramolecular oxymercuration-demercuration leading respectively to formation of an isomeric tetracycle, (1aS,3S,5aS,6R,8aS,9R,12S)-10-deoxo-13-carbaartemisinin 18 , (+)-10-deoxo-13-carbaartemisinin 20 , and (+)-13-carbaartemisinin 4 . Neither target 4 nor 20 displayed substantial antimalarial potency in vitro against Plasmodium falciparum , but the isomeric peroxide 18 possessed reasonable antimalarial potency in vitro .

Toward the total synthesis of pseudolaric acid B. Preparation of a key intermediate by degradation and its use in the reassembly of the natural product

Synthetic studies of pseudolaric acid B, 2, provided a relay synthesis of pseudolaric acid B (PLAB) via aldehyde 5. The aldehyde 5 can serve: to complete the total synthesis of PLAB; as a precursor for the synthesis of PLAB analogs; or as a substrate for the generation of radiolabeled PLAB for mechanistic studies.