Quantum Chemical Lipophilicities of Antimalarial Drugs in Relation to Terminal Half-Life.

According to the WHO, artemisinin-based combination therapies (ACTs) have been integral to the recent reduction in deaths due to Plasmodium falciparum malaria. ACT-resistant strains are an emerging problem and have evolved altered developmental stages, reducing exposure of the most susceptible stages to artemisinin drugs in popular ACTs. Lipophilicity, log K ow, is a guide in understanding and predicting pharmacokinetic properties such as terminal half-life which alters drug exposure. Consistent log K ow values are not necessarily available for artemisinin derivatives designed to extend terminal half-life, increase bioavailability, and reduce neurotoxicity. For other drugs used in ACTs, an assortment of experimental and computational log K ow values are available in the literature and in some cases, do not account for subtle but important differences between closely related structures such as between diastereomers. Quantum chemical methods such as density functional theory (DFT) used with an implicit solvent model allow for consistent comparison of physical properties including log K ow and distinguish between closely related structures. To this end, DFT, B3LYP/6-31G(d), with an implicit solvent model (SMD) was used to compute ΔG ow o and ΔG vow o for 1-octanol-water and olive oil-water partitions, respectively, for 21 antimalarial drugs: 12 artemisinin-based, 4 4-aminoquinolines and structurally similar pyronaridine, and 4 amino alcohols. The computed ΔG ow o was close to ΔG ow o calculated from experimental log K ow values from the literature where available, with a mean signed error of 2.3 kJ/mol and mean unsigned error of 3.7 kJ/mol. The results allow assignment of log K ow for α-and ß-diastereomers of arteether, and prediction of log K ow for ß-DHA and five experimental drugs. Linear least square analysis of log K ow and log K vow versus terminal elimination half-life showed strong linear relationships, once the data points for the 4-aminoquinoline drugs, mefloquine and pyronaridine were found to follow their own linear relationship, which is consistent with their different plasma protein binding. The linear relationship between the computed log K vow and terminal elimination half-life was particularly strong, R 2 = 0.99 and F = 467, and can be interpreted in terms of a simple pharmacokinetic model. Terminal elimination half-life for ß-DHA and four experimental artemisinin drugs were estimated based on this linear relationship between log K vow and terminal t 1/2. The computed log K ow and log K vow values for epimers α- and ß-DHA and α and ß-arteether provide physical data that may be helpful in understanding their different pharmacokinetics and activity based on their different molecular geometries. Relative solubility of quinine and quinidine are found to be sensitive to thermal corrections to enthalpy and to vibrational entropy and do not follow the general trend of longer terminal t 1/2 with greater predicted log K ow. Geometric relaxation of α- and ß-DHA in solvent and inclusion of thermal correction for enthalpy and entropy results in correct prediction that α-DHA is favored in aqueous environments compared to ß-DHA. Predictions made regarding experimental drugs have implications regarding their potential use in response to artemisinin drug-resistant strains.

Unspecified verticality of Franck-Condon transitions, absorption and emission spectra of cyanine dyes, and a classically inspired approximation.

The computed vertical energy, E v,a/f, from the equilibrium geometry of the initial electronic state is frequently considered as representative of the experimental excitation/emission energy, E abs/fl = hc/λ max. Application of the quantum mechanical version of the Franck-Condon principle does not involve precise specification of nuclear positions before, after, or during an electronic transition. Moreover, the duration of an electronic transition is not experimentally accessible in spectra with resolved vibrational structure. It is shown that computed vibronic spectra based on TDDFT methods and application of quantum mechanical FC analysis predict E abs = hc/λ max with a 10-fold improvement in accuracy compared to E v,a for nine cyanine dyes. It is argued that part of the reason for accuracy when this FC analysis is compared to experiment as opposed to E v,a/f is the unspecified verticality of transitions in the context of the quantum version of the FC principle. Classical FC transitions that preserve nuclear kinetic energy before and after an electronic transition were previously found to occur at a weighted average of final and initial electronic state molecular geometries known as the r-centroid. Inspired by this approach a qualitative method using computed vertical and adiabatic energies and the harmonic approximation is developed and applied yielding a 5-fold improvement in accuracy compared to E v,a. This improvement results from the dominance of low frequency vibronic transitions in the cyanine dye major band. The model gives insight into the nature of the redshift when qPCR dye EvaGreen is complexed to λDNA and is applicable to the low frequency band of similar non cyanine dyes such as curcumin. It is found that the computed vibronic cyanine dye spectra from time-dependent FC analysis at 0 K and 298 K show decreased intensity at higher temperature suggestive of increased intensity with restricted motion shown when cyanine dyes are used in biomedical imaging. A 2-layer ONIOM model of the DNA minor groove indicates restricted motion of the TC-1 dye excited state in this setting indicative of enhanced fluorescence.

Prediction of molecular properties including symmetry from quantum-based molecular structural formulas, VIF.

Structurally covariant valency interaction formulas, VIF, gain chemical significance by comparison with resonance structures and natural bond orbital, NBO, bonding schemes and at the same time allow for additional prediction such as symmetry of ring systems and destabilization of electron pairs with respect to reference energy of -1/2 Eh. Comparisons are based on three chemical interpretations of Sinanoglu's theory of structural covariance: (1) sets of structurally covariant quantum structural formulas, VIF, are interpreted as the same quantum operator represented in linearly related basis frames; (2) structurally covariant VIF pictures are interpreted as sets of molecular species with similar energy; and (3) the same VIF picture can be interpreted as different quantum operators, one-electron density or Hamiltonian; for example. According to these three interpretations, bond pair, lone pair, and free radical electrons understood in terms of a localized orbital representation are recognized as having energies above, below, or equal to a predetermined reference, frequently-1/2 Eh. The probable position of electron pairs and radical electrons is predicted. The selectivity of concerted ring closures in allyl anion and cation is described. Symmetries of conjugated ring systems are predicted according to their numbers of pi-electrons and spin-multiplicity. The pi-distortivity of benzene is predicted.The 3c/2e- H-bridging bonds in diborane are derived in a natural way according to the notion that the bridging bonds will have delocalizing interactions between them consistent with results of the NBO method. Key chemical bonding motifs are described using VIF. These include 2c/1e-, 2c/2e-, 2c/3e-, 3c/2e-, 3c/3e-,3c/4e-, 4n antiaromatic, and 4n+2 aromatic bonding systems. Some common organic functional groups are represented as VIF pictures and because these pictures can be interpreted simultaneously as one-electron density and Hamiltonian operators, the valence shell electron pair repulsion method is applied toward understanding the energies of valence NBOs with respect to the reference energy of -1/2Eh.

Molecular structural formulas as one-electron density and hamiltonian operators: the VIF method extended.

The valency interaction formula (VIF) method is given a broader and more general interpretation in which these simple molecular structural formulas implicitly include all overlaps between valence atomic orbitals even for interactions not drawn in the VIF picture. This applies for VIF pictures as one-electron Hamiltonian operators as well as VIF pictures as one-electron density operators that constitute a new implementation of the VIF method simpler in its application and more accurate in its results than previous approaches. A procedure for estimating elements of the effective charge density-bond order matrix, Pmunu, from electron configurations in atoms is presented, and it is shown how these lead to loop and line constants in the VIF picture. From these structural formulas, one finds the number of singly, doubly, and unoccupied molecular orbitals, as well as the number of molecular orbitals with energy lower, equal, and higher than -1/2Eh, the negative of the hydrogen atom's ionization energy. The VIF results for water are in qualitative agreement with MP2/6311++G3df3pd, MO energy levels where the simple VIF for water presented in the earlier literature does not agree with computed energy levels. The method presented here gives the simplest accurate VIF pictures for hydrocarbons. It is shown how VIF can be used to predict thermal barriers to chemical reactions. Insertion of singlet carbene into H2 is given as an example. VIF pictures as one-electron density operators describe the ground-state multiplicities of B2, N2, and O2 molecules and as one-electron Hamiltonian operators give the correct electronegativity trend across period two. Previous implementations of VIF do not indicate singly occupied molecular orbitals directly from the pictorial VIF rules for these examples. The direct comparison between structural formulas that represent electron density and those that represent energy is supported by comparison of a simple electronegativity scale, chiD=N/n2, with well-known electronegativity scales of Pauling, Mulliken, and Allen. This scale comes from the method used to calculate Pmumu for sp3 hybridized period-two elements and is comparable to electronegativity because it has the same form as <1/r> for hydrogenic orbitals. It therefore provides a physical basis for the representation of one electron density and Hamiltonian operators by the same VIF picture.