Tautomer Standardization in Chemical Databases: Deriving Business Rules from Quantum Chemistry.

Databases of small, potentially bioactive molecules are ubiquitous across the industry and academia. Designed such that each unique compound should appear only once, the multiplicity of ways in which many compounds can be represented means that these databases require methods for standardizing the representation of chemistry. This is commonly achieved through the use of "Chemistry Business Rules", sets of predefined rules that describe the "house style" of the database in question. At Syngenta, the historical approach to the design of chemistry business rules has been to focus on consistency of representation, with chemical relevance given secondary consideration. In this work, we overturn that convention. Through the use of quantum chemistry calculations, we define a set of chemistry business rules for tautomer standardization that reproduces gas-phase energetic preferences. We go on to show that, compared to our historic approach, this method yields tautomers that are in better agreement with those observed experimentally in condensed phases and that are better suited for use in predictive models.

Design, synthesis and biological evaluation of 6-aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines as antiplasmodial antifolates.

The design, synthesis and biological evaluation of a series of 6-aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines is described. These compounds exhibited in vitro antiplasmodial activity in the low nanomolar range against both drug sensitive and drug resistant strains of P. falciparum, with 1-(3-(2,4-dichlorophenoxy)propyl)-6-phenyl-1,6-dihydro-1,3,5-triazine-2,4-diamine hydrochloride identified as the most potent compound from this series against the drug resistant FCR-3 strain (IC50 2.66 nM). The compounds were not toxic to mammalian cells at therapeutic concentrations and were shown to be inhibitors of parasitic DHFR in a biochemical enzyme assay.

Imidazo[1,2-a]pyridin-3-amines as potential HIV-1 non-nucleoside reverse transcriptase inhibitors.

During random screening of a small in-house library of compounds, certain substituted imidazo[1,2-a]pyridines were found to be weak allosteric inhibitors of HIV-1 reverse transcriptase (RT). A library of these compounds was prepared using the Groebke reaction and a subset of compounds prepared from 2-chlorobenzaldehyde, cyclohexyl isocyanide and a 6-substituted 2-aminopyridine showed good inhibitory activity in enzymatic (RT) and HIV anti-infectivity MAGI whole cell assays. The compound showing the best anti-HIV-1 IIIB whole cell activity (MAGI IC(50)=0.18 µM, IC(90)=1.06 µM), along with a good selectivity index (>800), was 2-(2-chlorophenyl)-3-(cyclohexylamino)imidazo[1,2-a]pyridine-5-carbonitrile 38.

Expeditious synthesis and biological evaluation of novel 2,N6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines as potential antimalarials.

A small set of novel 2,N6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines was prepared possessing a flexible tether between the exocyclic nitrogen bonded to C-6 of the 1,2-dihydro-1,3,5-triazine-4,6-diamine heterocycle and the distal aryl ring. Three zones were varied in this series of compounds, namely the nature of the substituent(s) on C-2; the nature of the substituent(s) on the distal aryl ring; as well as the nature and length of the flexible tether between the rings. The compound showing the best antimalarial activity (cycloguanil-resistant FCR-3 Plasmodium falciparum IC50=0.99 µM) was N6-(3-(4-chlorophenoxy)propyl)-2-(furan-2-yl)-1,2-dihydro-1,3,5-triazine-4,6-diamine hydrochloride.

Conformational analysis: crystallographic, NMR, and molecular mechanics studies of flexible sulfonic esters.

Two novel X-ray structures of the sulfonic ester derivatives 2-(6-iodo-1,3-benzodioxol-5-yl)ethyl 4-nitrobenzenesulfonate, 3, and 2-(6-iodo-1,3-benzodioxol-5-yl)ethyl 4-methylbenzenesulfonate, 4, have been obtained in a study aimed at analyzing the structures and conformations of sulfonic ester derivatives that are routinely used in alkaloid syntheses. The crystal structure of 4 is highly unusual, containing four independent molecules that belong to two distinct conformational types: (1) a hairpin conformation (stabilized mainly by intramolecular pi-stacking) and (2) a stepped conformation (stabilized mainly by intermolecular pi-stacking). Compound 3, on the other hand, crystallizes exclusively as the hairpin conformer. New MM+ force field parameters for sulfonic esters have been developed using the X-ray data, empirical rules, and DFT calculations to estimate the bond dipole parameters. Grid searches of conformational space for 3 and 4 using MM methods show that there are several gas-phase conformations within 5 kcal/mol of the global minimum and that the lowest energy conformations (by approximately 4.6 kcal/mol) are of the hairpin type. Analysis of the MM conformational energies suggests that the dominant intramolecular interaction stabilizing the hairpin conformations of 3 and 4 is van der Waals attraction. Moreover, the lattice energies for packing the hairpin conformations of 3 and 4 are approximately 4 kcal/mol more favorable than for the stepped conformations. Various intermolecular interactions contribute to the complexity of the observed crystal structures of 3 and 4, including electrostatic attraction between O and I atoms in neighboring molecules. Langevin dynamics (LD) simulations at several temperatures (6.0 ns, friction coefficient = 2.5 ps(-1)) indicate that the conformational exchange rates are approximately 10(10)-10(11) s(-1) over the temperature range 213-400 K, accounting for the temperature-independent (1)H NMR spectra of 3 and 4.

New developments in the Peterson olefination reaction.

Noteworthy developments of the Peterson olefination reaction are reviewed. Evidence for both concerted and stepwise mechanisms for the Peterson olefination reaction is presented. The strong affinity of the oxygen anion for the silyl moiety is emphasised when the Peterson olefination reaction takes preference over both the Julia and Wittig reactions in the presence of S- and P-stabilised silyl carbanions. Cerium-mediated Peterson methylenation reactions are discussed.