A set of racemic spirocyclic quinuclidinyl-Δ(2)-isoxazoline derivatives was synthesized using a 1,3-dipolar cycloaddition-based approach. Target compounds were assayed for binding affinity toward rat neuronal homomeric (α7) and heteromeric (α4β2) nicotinic acetylcholine receptors. Δ(2) -Isoxazolines 3 a (3-Br), 6 a (3-OMe), 5 a (3-Ph), 8 a (3-OnPr), and 4 a (3-Me) were the ligands with the highest affinity for the α7 subtype (K(i) values equal to 13.5, 14.2, 25.0, 71.6, and 96.2 nM, respectively), and showed excellent α7 versus α4β2 subtype selectivity. These compounds, tested in electrophysiological experiments against human α7 and α4β2 receptors stably expressed in cell lines, behaved as partial α7 agonists with varying levels of potency. The two enantiomers of (±)-3-methoxy-1-oxa-2,7-diaza-7,10-ethanospiro[4.5]dec-2-ene sesquifumarate 6 a were prepared using (+)-dibenzoyl-L- or (-)-dibenzoyl-D-tartaric acid as resolving agents. Enantiomer (R)-(-)-6 a was found to be the eutomer, with K(i) values of 4.6 and 48.7 nM against rat and human α7 receptors, respectively.

a b s t r a c tRacemic exo-epiboxidine 3, endo-epiboxidine 6, and the two unsaturated epiboxidine-related derivatives 7 and 8 were efficiently prepared taking advantage of a palladium-catalyzed Stille coupling as the key step in the reaction sequence. The target compounds were assayed for their binding affinity at neuronal a4b2 and a7 nicotinic acetylcholine receptors. Epiboxidine 3 behaved as a high affinity a4b2 ligand (K i = 0.4 nM) and, interestingly, evidenced a relevant affinity also for the a7 subtype (K i = 6 nM). Derivative 7, the closest analogue of 3 in this group, bound with lower affinity at both receptor subtypes (K i = 50 nM for a4b2 and K i = 1.6 lM for a7) evidenced a gain in the a4b2 versus a7 selectivity when compared with the model compound.Ó 2008 Elsevier Ltd. All rights reserved.Neuronal nicotinic acetylcholine receptors (nAChRs) make up a family of pentameric ligand-gated ion channels, which are formed by combinations of alpha and beta subunits 1,2 or exist as homopentamers, in the cases of a7, a8, and a9 receptors, which are inhibited by a-bungarotoxin. 3 To date, nine a (a2-a10) and three b (b2-b4) isoforms have been characterized, though only a relatively small subset of combinations generates functionally and physiologically relevant channels. 4 Nicotinic receptors are widely distributed in the brain, where they primarily modulate the release of other neurotransmitters and, to a lesser extent, mediate synaptic transmission. 5 Neuronal nAChRs, selectively activated by (S)-nicotine 1 (Fig. 1), are involved in various processes such as cognition, learning and memory, cerebral blood flow and metabolism, as well as an array of pathological conditions such as Alzheimer's and Parkinson's diseases, mild cognitive impairment (MCI), schizophrenia, epilepsy, Tourette's syndrome, anxiety, depression, attention-deficit hyperactivity disorder (ADHD), and nicotine addiction.1,2,6,7The heteromeric a4b2 receptors, the most abundant subtype in the mammalian CNS, and the homomeric a7 channels are privileged biological targets in the search for selective nAChR ligands with therapeutic potential. 2,8 As far as the number of nicotinic agonists isolated from natural sources is taken into consideration, 9 (À)-epibatidine 2 (Fig. 1), a highly toxic alkaloid identified in the skin of the Ecuadorian frog Epipedobates tricolor, 10 has inspired a huge amount of research aimed at designing subtype selective nicotinic agonists. 1,2,9,11,12 Although the pharmacological effects of (À)-2 are mediated by a variety of nAChRs, 13 which preclude any therapeutic potential for epibatidine, the analgesic potency, roughly 100 times higher than that of morphine and 30 times higher than that of nicotine, has been attributed to its high affinity for the a4b2 subtype. Worth mentioning, (À)-2 and (+)-2 are characterized by similar affinities for nAChRs and almost identical ED 50 values in the mouse tail-flick antinociception assay. 13d,14,15 Among the synthetic epibatidine-related compounds, (±)-epiboxidine 3 (Fig. 1), in which ...

Polyhydroxylated hybrid molecules have been synthesized using a protocol based on the regioselective acylation of the target compounds with activated dicarboxylic acids catalyzed by Novozym-435. The procedure implies that the mixed ester derivatives prepared and isolated from the first esterification step act as acylating agents in the second esterification step.

Abstract:The tandem use of laccases and lipases has been exploited for the simple preparative synthesis of enantiomerically enriched dimeric phenols. Laccase-catalyzed oxidation of isoeugenol (1) and vinylguaiacol (7) in biphasic systems gave as main products the racemic compounds 6 and 8, possessing structures similar to the b-5 dimers found in lignin. The synthesis of enantiomerically enriched 6 and 8 could be achieved by alcoholysis reactions catalyzed by commercial preparations of lipases in organic solvents. Although the E values were quite low (due to the "remote" stereocenters to be discriminated), the enantio-complementary behavior of the tested lipases allowed the simple isolation of the target compounds with ee up to 90%. It is noteworthy that these results have been achieved in vitro exploiting commercially available enzymes, without using the so-called "dirigent" proteins evolved by nature to direct the enantioselective coupling of phenols in vivo.

Combining chemicals. Malaria is one of the most widespread parasitic infections in the world, however, the unavailability of a vaccine and the spread and intensification of drug resistance over the past 15–20 years have led to a dramatic decline in the efficacy of the most affordable antimalarial drugs. Herein, the development of “double‐drugs” to tackle inhibition of P. falciparum growth is discussed.