The slow-motional ESR analysis appropriate for vanadyl(IV) ions is developed with an accurate treatment of the nonsecular contributions. This results in good agreement between theory and experiments on VO(acac2(pm)) in toluene with axially symmetric magnetic parameters over the whole motional range when a Brownian motion model is used. It is also found that a slightly modified motional narrowing theory based upon the stochastic Liouville equation leads to improved agreement between theory and experiment for VO(acac)2 in toluene which also obeys a Brownian motion model. It is shown that vanadyl slow-tumbling spectra are very sensitive to model (even more so than nitroxides). In particular, experiments on V0(H20)52+ in aqueous solution are approximately fit by a model of moderate jump, while those on VO(NCS)42~c ould only be crudely fit by temperature-dependent variations in model. The theory given here is appropriate for any S = 1/2 radical with a single nuclear spin I provided only the high-field approximation is valid, so that nonsecular terms may be treated by a perturbation approach. The effects of (1) angular-dependent transition probabilities and (2) fieldvs. frequency-swept spectra upon the slow-motional theory are also discussed.

ELQ-300 is a preclinical antimalarial drug candidate that is active against liver, blood, and transmission stages of Plasmodium falciparum. While ELQ-300 is highly effective when administered in a low multi-dose regimen, poor aqueous solubility and high crystallinity have hindered its clinical development. To overcome its challenging physiochemical properties, a number of bioreversible alkoxycarbonate ester prodrugs of ELQ-300 were synthesized. These bioreversible prodrugs are converted to ELQ-300 by host and parasite esterase action in the liver and bloodstream of the host. One such alkoxycarbonate prodrug, ELQ-331, is curative against Plasmodium yoelii with a single low dose of 3 mg/kg in a murine model of patent malaria infection. ELQ-331 is at least as fully protective as ELQ-300 in a murine malaria prophylaxis model when delivered 24 hours before sporozoite inoculation at an oral dose of 1 mg/kg. Here, we show that ELQ-331 is a promising prodrug of ELQ-300 with improved physiochemical and metabolic properties and excellent potential for clinical formulation.

Novel pyridine-and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.

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