Electronic structure calculations carried out at the BLYP/6-311G** level of theory accurately predict the dissociation energy of the C-H bond in benzene. The analogous energies of the homolytic C-H bond cleavage in the other nine polycyclic aromatic hydrocarbons (PAHs) are found to be governed almost entirely by steric factors, the hydrogens from congested regions of the PAHs being removed preferentially. The removal of hydrogens is accompanied by highly regular changes in the molecular geometries, namely a widening of the ipso bond angle by ca. 6.0°and a concomitant shortening of the adjacent C-C bonds by ca. 0.02 Å. These observations suggest an almost complete localization of the unpaired σ electrons on single carbon atoms and the separation of the local σ and π effects in the aryl radicals under study. This localization is confirmed by the computed charges and spin populations of atoms in the phenyl, 1-naphthalenyl, and 2-naphthalenyl radicals. In contrast with their UHF counterparts, the UBLYP electronic wave functions are only mildly spin contaminated.

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The conventional approach to the electronegativity equalization principle suffers from a serious conceptual drawback that stems from discontinuities in the first derivative of the electronic energy with respect to the total charge of a molecule. A formalism that avoids the resulting ill-defined atomic hardness matrices employs a simple definition of the atomic softness matrix σ. The matrix σ, which is a generalization of the Hückel atom–atom polarizability matrix, can be easily and rigorously computed to arbitrary accuracy with any of the contemporary electronic structure methods. Properties of the atomic softness matrix are reviewed and illustrated with several numerical examples involving the first-row hydrides and a linear polyyne.

Effects of nonspecific solvation on chemical bonding, described with a simple self-consistent reaction field model, are rigorously analyzed in terms of electron flow and electronegativity equalization between two molecular fragments A and B. In most (but not all) systems AB, the energy-lowering rise in the dipole moment that accompanies solvation is the result of an enhanced charge transfer between A and B, the enhancement stemming from both the increased electronegativity difference ΔχAB and the decreased bond hardness κAB. In systems, such as H⋅Cl, H⋅CN, and CH3⋅CN, that ensue from interactions between charged closed-shell fragments (H++Cl−, H++CN−, CH+3+CN−, etc.) the energy-stabilizing effect of solvation is a trade-off between the energy lowering due to the enhanced charge-transfer component of bonding and destabilization due to diminished covalent bonding. On the other hand, interactions between electrically neutral fragments (NH3+SO3, etc.) produce systems, such as the zwitterion of sulfamic acid (+H3N⋅SO−3), in which charge-transfer and covalent components of bonding are strengthened in tandem by solvation. The aforementioned phenomena account for the experimentally observed solvation-induced changes in the A–B bonds, namely their lengthening (or even a complete dissociation) in the former systems and shortening in the latter ones.

BackgroundDeveloping resistance towards existing anti-malarial therapies emphasize the urgent need for new therapeutic options. Additionally, many malaria drugs in use today have high toxicity and low therapeutic indices. Gradient Biomodeling, LLC has developed a quantum-model search technology that uses quantum similarity and does not depend explicitly on chemical structure, as molecules are rigorously described in fundamental quantum attributes related to individual pharmacological properties. Therapeutic activity, as well as toxicity and other essential properties can be analysed and optimized simultaneously, independently of one another. Such methodology is suitable for a search of novel, non-toxic, active anti-malarial compounds.MethodsA set of innovative algorithms is used for the fast calculation and interpretation of electron-density attributes of molecular structures at the quantum level for rapid discovery of prospective pharmaceuticals. Potency and efficacy, as well as additional physicochemical, metabolic, pharmacokinetic, safety, permeability and other properties were characterized by the procedure. Once quantum models are developed and experimentally validated, the methodology provides a straightforward implementation for lead discovery, compound optimizzation and de novo molecular design.ResultsStarting with a diverse training set of 26 well-known anti-malarial agents combined with 1730 moderately active and inactive molecules, novel compounds that have strong anti-malarial activity, low cytotoxicity and structural dissimilarity from the training set were discovered and experimentally validated. Twelve compounds were identified in silico and tested in vitro; eight of them showed anti-malarial activity (IC50 ≤ 10 μM), with six being very effective (IC50 ≤ 1 μM), and four exhibiting low nanomolar potency. The most active compounds were also tested for mammalian cytotoxicity and found to be non-toxic, with a therapeutic index of more than 6,900 for the most active compound.ConclusionsGradient's metric modelling approach and electron-density molecular representations can be powerful tools in the discovery and design of novel anti-malarial compounds. Since the quantum models are agnostic of the particular biological target, the technology can account for different mechanisms of action and be used for de novo design of small molecules with activity against not only the asexual phase of the malaria parasite, but also against the liver stage of the parasite development, which may lead to true causal prophylaxis.