Sweet-Tasting Ionic Conjugates of Local Anesthetics and Vasoconstrictors.

Local anesthetics are widely utilized in dentistry, cosmetology, and medicine. Local anesthesia is essential to providing a pain-free experience during dental and local surgeries as well as cosmetic procedures. However, the injection itself may produce discomfort and be a source of aversion. A novel approach toward the taste modulation of local anesthetics is proposed, in which the anesthetics of the "-caine" family serve as cations and are coupled with anionic sweeteners such as saccharinate and acesulfamate. Ionic conjugates of vasoconstrictor epinephrine such as epinephrine saccharinate and epinephrine acesulfamate have also been synthesized. Novel ionic conjugates were developed using anion exchange techniques. Reported compounds are sweet-tasting and are safe to use both topically and as injections.

Macrocyclic peptidomimetics with antimicrobial activity: synthesis, bioassay, and molecular modeling studies.

Novel, cyclic peptidomimetics were synthesized by facile acylation reactions using benzotriazole chemistry. Microbiological testing of the synthesized compounds revealed an exceptionally high activity against Candida albicans with a minimum inhibitory concentration (MIC) two orders of magnitude lower than the MIC of the antifungal reference drug amphotericin B. A strikingly high activity was also observed against three Gram-negative bacterial strains (Pseudomonas aeruginosa, Klebsiella pneumoniae and Proteus vulgaris), two of which are known human pathogens. Thus the discovered chemotype is a potential polypharmacological agent. The toxicity against mammalian tumor cells was found to be low, as demonstrated in five different human cell lines (HeLa, cervical; PC-3, prostate; MCF-7, breast; HepG2, liver; and HCT-116, colon). The internal consistency of the experimental data was studied using 3D-pharmacophore and 2D-QSAR.

An ionic liquid process for mercury removal from natural gas.

Efficient scrubbing of mercury vapour from natural gas streams has been demonstrated both in the laboratory and on an industrial scale, using chlorocuprate(II) ionic liquids impregnated on high surface area porous solid supports, resulting in the effective removal of mercury vapour from natural gas streams. This material has been commercialised for use within the petroleum gas production industry, and has currently been running continuously for three years on a natural gas plant in Malaysia. Here we report on the chemistry underlying this process, and demonstrate the transfer of this technology from gram to ton scale.

Ionic conjugates of lidocaine and sweeteners as better tasting local anesthetics for dentistry.

Lidocaine is the most widely utilized intraoral injected dental anesthetic, used for more than 500 million dental injections per year. Local anesthesia is essential for pain-free dentistry, yet intraoral injections are often considered painful and a source of anxiety for many patients. Any new anesthetics that will reduce the stress and anxiety of dental injection are expected to be beneficial. A novel chemical approach to taste modulation is proposed, in which the lidocaine cation is coupled with anionic sweeteners such as saccarinate and acesulfamate. The ionic conjugates synthesized using anion exchange techniques, were much less bitter, demonstrated a high local anesthetic potential in animal studies, and were as safe as the original hydrochloride. Based on the currently robust market for lidocaine it is expected that the resulting anesthetics will be in high demand in clinical practices worldwide.

Dual inhibition of the α-glucosidase and butyrylcholinesterase studied by molecular field topology analysis.

A striking dual inhibition of enzymes α-glucosidase and butyrylcholinesterase by small drug-like molecules, including 1,4-disubstituted-1,2,3-triazoles, chalcones, and benzothiazepines, was rationalized with the help of Molecular Field Topology Analysis, a 3D QSAR technique similar to CoMFA. A common pharmacophore supported the concept of a link existing between type-2 diabetes mellitus and Alzheimer's disease. These findings will be instrumental for rational design of drug candidates for both of these conditions.

Traceless chemical ligation from S-, O-, and N-acyl isopeptides.

Peptides are ubiquitous in nature where they play crucial roles as catalysts (enzymes), cell membrane ion transporters, and structural elements (proteins) within biological systems. In addition, both linear and cyclic peptides have found use as pharmaceuticals and components of various conjugate molecular systems. Small wonder then that chemists throughout the ages have sought to mimic nature by synthesis of the amide polymers known as peptides and proteins. The fundamental reaction in the formation of a peptide bond is condensation of an amine of one amino acid with the activated carbonyl group of another. This "fragment condensation" has been achieved in many ways both in solution and by solid-phase peptide synthesis (SPSS) on resin. The most successful method for in-solution coupling is known as native chemical ligation (NCL), and the technique dates back to the pioneering work of Wieland (1953) and subsequently Kent (1994) among many others. This Account builds on the established principles of NCL as applied specifically to S-, O-, and N-isopeptides, molecules that are generally more soluble and less prone to aggregation than native peptides. This Account also covers NCL of isopeptides containing terminal and nonterminal S-acylated cysteine units, reactions that enable the synthesis of native peptides from S-acyl peptides without the use of auxiliaries. With C-terminal S-acyl isopeptides, NCL was carried out under microwave irradiation in phosphate buffer (pH 7.3) at 50 °C. Intramolecular acyl migration was observed through 5-19-membered transition states with relative rates, as assessed by product analysis, in the order, 5 > 10 > 11 > 14, 16, or 17 > 12 > 13, 15, or 19 > 18 ≫ 9 > 8. The rate/pH profile for the 15-membered TS showed a maximum for ligated product versus transacylation at pH 7.0-7.3 presumably associated with the pKa of the N-nucleophile in the hydrogen-bonded TS. Cysteine occurs at low abundance (1.7%) in natural peptides and is rarely available in a terminal position thus limiting the utility of the method. This Account reports, however, NCL at nonterminal acyl cysteine through 5-, 8-, 11-, and 14-membered TSs with relative rates of ligation in the order, 5 ≫ 14 > 11 ≫ 8, thus paralleling the results with acylated terminal cysteine residues. In an obvious sequel to the work with acylated cysteine, we discuss intramolecular O- to N-acyl shift in O-acyl serine and O-acyl tyrosine isopeptides where the story becomes more complex in terms of viable conditions and optimum size of the cyclic TS. N- to N-acyl migration in acyl tryptophan isopeptides is described, and finally, chemical ligation is applied to the synthesis of cyclic peptides. Conformational analysis and quantum chemical calculations are used to rationalize ligation through a range of cyclic transition states. This Account highlights the fact that NCL of acyl isopeptides is an extremely useful strategy for the synthesis of a wide variety of native peptides in good yields and under mild conditions. Mechanistic aspects of the ligations are not fully resolved, but theoretical studies indicate that hydrogen bonding within the various cyclic transition states plays a major role.

Synthesis, bioassay, and molecular field topology analysis of diverse vasodilatory heterocycles.

A diverse training set composed of 76 in-house synthesized and 61 collected from the literature was subjected to molecular field topology analysis. This resulted in a high-quality quantitative structure-activity relationships model (R² = 0.932, Q² = 0.809) which was used for the topological functional core identification and prediction of vasodilatory activity of 19 novel pyridinecarbonitriles, which turned out to be active in experimental bioassay.

Promising Aedes aegypti repellent chemotypes identified through integrated QSAR, virtual screening, synthesis, and bioassay.

Molecular field topology analysis, scaffold hopping, and molecular docking were used as complementary computational tools for the design of repellents for Aedes aegypti, the insect vector for yellow fever, chikungunya, and dengue fever. A large number of analogues were evaluated by virtual screening with Glide molecular docking software. This produced several dozen hits that were either synthesized or procured from commercial sources. Analysis of these compounds by a repellent bioassay resulted in a few highly active chemicals (in terms of minimum effective dosage) as viable candidates for further hit-to-lead and lead optimization effort.

Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics.

The chemical similarity of antibacterial cyclic peptides and peptidomimetics was studied in order to identify new promising cyclic scaffolds. A large descriptor space coupled with cluster analysis was employed to digitize known antibacterial structures and to gauge the potential of new peptidomimetic macrocycles, which were conveniently synthesized by acylbenzotriazole methodology. Some of the synthesized compounds were tested against an array of microorganisms and showed antibacterial activity against Bordetella bronchistepica, Micrococcus luteus, and Salmonella typhimurium.

Cu(I)-catalyzed regioselective synthesis of pyrazolo[5,1-c]-1,2,4-triazoles.

Cycloadditions of terminal alkynes to 1,2,4-triazolium N-imides in the presence of base and Cu(I) afford pyrazolo[5,1-c]-1,2,4-triazoles regioselectively. The scope of alkynes, the influence of the electronic nature of the leaving group, and variations in the 1-alkyl substituent were examined. Quantum chemical calculations were employed to explain the distinct reactivity of the propiolates.

Computer-assisted rational design, synthesis, and bioassay of non-steroidal anti-inflammatory agents.

A focused dataset of previously synthesized and tested [1,2,4]-triazolo[1,5-a]pyridines and pyridine-3-carboxylates was studied by Molecular Field Topology Analysis (MFTA) to identify steric and electronic determinants of anti-inflammatory activity useful for the design and synthesis of new anti-inflammatory agents. Rational design based on the MFTA model identified eleven novel pyridine-3-carboxylates (2a-e and 3a-f) as promising. After synthesis and screening, three of (2a, 2c, 3a) revealed potent anti-inflammatory activity exceeding that of indomethacin, the reference inhibitor for artificially induced edema in rats.

Long-range intramolecular S → N acyl migration: a study of the formation of native peptide analogues via 13-, 15-, and 16-membered cyclic transition states.

The intramolecular long-range S → N acyl migration via 13-, 15-, and 16-membered cyclic transition states to form native tetra- and pentapeptide analogues was studied on S-acylcysteine peptides containing ß- or γ-amino acids. The pH-dependency study of the acyl migration via a 15-membered cyclic transition state indicated that the reaction is favored at a pH range from 7.0 to 7.6. Experimental observations are supported by structural and computational investigations.

Ab initio parameterization of YFF1, a universal force field for drug-design applications.

The YFF1 is a new universal molecular mechanic force field designed for drug discovery purposes. The electrostatic part of YFF1 has already been parameterized to reproduce ab initio calculated dipole and quadrupole moments. Now we report a parameterization of the van der Waals interactions (vdW) for the same atom types that were previously defined. The 6-12 Lennard-Jones potential terms were parameterized against homodimerization energies calculated at the MP2/6-31 G level of theory. The Boys-Bernardi counterpoise correction was employed to account for the basis-set superposition error. As a source of structural information we used about 2,400 neutral compounds from the ZINC2007 database. About 6,600 homodimeric configurations were generated from this dataset. A special "closure" procedure was designed to accelerate the parameters fitting. As a result, dimerization energies of small organic compounds are reproduced with an average unsigned error of 1.1 kcal mol(-1). Although the primary goal of this work was to parameterize nonbonded interactions, bonded parameters were also derived, by fitting to PM6 semiempirically optimized geometries of approximately 20,000 compounds.

Prediction of gas solubilities in ionic liquids.

Ionic liquids (of which it is estimated that there are at least one million simple fluids) generate a rich chemical space, which is now just at the beginning of its systematic exploration. Many properties of ionic liquids are truly unique and, which is more important, can be finely tuned. Differential solubility of industrial chemicals in ionic liquids is particularly interesting, because it can be a basis for novel, efficient, environmentally friendly technologies. Given the vast number of potential ionic liquids, and the impossibility of a comprehensive empirical exploration, it is essential to extract the maximum information from extant data. We report here some computational models of gas solubility. These multiple regression- and neural network-based models cover a chemical space spanned by 48 ionic liquids and 23 industrially important gases. Molecular polarisabilities and special Lewis acidity and basicity descriptors calculated for the ionic liquid cations and anions, as well as for the gaseous solutes, are used as input parameters. The quality of fit "observed versus predicted Henry's law constants" is particularly good for the neural network model. Validation was established with an external dataset, again with a high quality fit. In contrast to many other neural network models published, our model is no "black box", since contributions of the parameters and their nonlinearity characteristics are calculated and analysed.

Alternating chemical ligation reactivity of S-acyl peptides explained with theory and computations.

Previously discovered alternating reactivity of S-acyl di-, tri-, and tetrapeptide in internal chemical ligation reactions is rationalised using conformational search, virtual screening methods and quantum chemical calculations. Conformational preorganisation is shown to be the major controller of reactivity, with hydrogen bonding providing additional stabilisation for the tetrapeptide structure.

General Purpose Electronegativity Relaxation Charge Models Applied to CoMFA and CoMSIA Study of GSK-3 Inhibitors.

Two fast empirical charge models, Kirchhoff Charge Model (KCM) and Dynamic Electronegativity Relaxation (DENR), had been developed in our laboratory previously for widespread use in drug design research. Both models are based on the electronegativity relaxation principle (Adv. Quantum Chem. 2006, 51, 139-156) and parameterized against ab initio dipole/quadrupole moments and molecular electrostatic potentials, respectively. As 3D QSAR studies comprise one of the most important fields of applied molecular modeling, they naturally have become the first topic to test our charges and thus, indirectly, the assumptions laid down to the charge model theories in a case study. Here these charge models are used in CoMFA and CoMSIA methods and tested on five glycogen synthase kinase 3 (GSK-3) inhibitor datasets, relevant to our current studies, and one steroid dataset. For comparison, eight other different charge models, ab initio through semiempirical and empirical, were tested on the same datasets. The complex analysis including correlation and cross-validation, charges robustness and predictability, as well as visual interpretability of 3D contour maps generated was carried out. As a result, our new electronegativity relaxation-based models both have shown stable results, which in conjunction with other benefits discussed render them suitable for building reliable 3D QSAR models.

Chlorometallate(III) ionic liquids as Lewis acidic catalysts--a quantitative study of acceptor properties.

The Gutmann Acceptor Number (AN), which is a quantitative measure of Lewis acidity, has been estimated using the (31)P NMR chemical shift of a probe molecule, triethylphosphine oxide, for a range of chlorometallate(III) ionic liquids, based on Group 13 metals (aluminium(III), gallium(III) and indium(III)) and the 1-octyl-3-methylimidazolium cation, at different compositions. The results were interpreted in terms of extant speciation studies of chlorometallate(III) ionic liquids, and compared with a range of standard molecular solvents and acids. The value of these data were illustrated in terms of the selection of appropriate ionic liquids for specific applications.

New developments in hydrogen bonding acidity and basicity of small organic molecules for the prediction of physical and ADMET properties. Part 2. The universal solvation equation.

Theoretical quantifications of hydrogen bonding (HB) basicities and acidities, originally developed for aliphatic systems (J. Chem. Inf. Comput. Sci. 2004, 44, 1042-1055), are now extended to cover aromatic, heterocyclic, anionic, cationic and zwitter-ionic molecular fragments, thus encompassing a majority of druggable chemical space. The addition of terms accounting for cavity formation, polarity, hydrophobicity, and resonance allowed us to derive a new equation able to predict accurately free energies of solvation of diverse solutes, interphase transfers, and aqueous solubilities (log S(w)). We thus provide a "universal solvation equation" (USE) available for the accurate estimation of desolvation energies in protein-ligand docking, for the prediction of many physical and ADMET properties, and for studying fluid phase equilibria.

Kirchhoff atomic charges fitted to multipole moments: implementation for a virtual screening system.

The Kirchhoff charge model is a viable method of generating inexpensive and electrostatically reasonable atomic charges for molecular mechanical force fields. The charging method uses a computationally fast algorithm based on the principle of electronegativity relaxation. Parameters of the method, orbital electronegativities and hardnesses, are fitted to reproduce reference, ab initio calculated dipole and quadrupole moments of a representative training set of neutral and charged organic molecules covering most medicinal chemistry relevant bonding situations. Transferability and accuracy of the derived parameters are confirmed on an external test set. Comparisons to other charge models are made. Implementation of the new Kirchhoff charges into a virtual screening engine is elucidated.

Search for improved host architectures: application of de novo structure-based design and high-throughput screening methods to identify optimal building blocks for multidentate ethers.

This paper presents a computational approach to the deliberate design of improved host architectures. The approach, which involves the use of computer-aided design software, is illustrated by application to cation hosts containing multiple aliphatic ether oxygen binding sites. De novo molecule building software, HostDesigner, is interfaced with molecular mechanics software, GMMX, providing a tool for generating and screening millions of potential bidentate building block structures. Enhanced cation binding affinity can be achieved when highly organized building blocks are used to construct macrocyclic hosts.