Lipase-catalyzed acylation of levoglucosan in continuous flow: antibacterial and biosurfactant studies.

Studies involving the transformation of lignocellulosic biomass into high value-added chemical products have been intensively conducted in recent years. Its matrix is mainly composed of cellulose, hemicellulose and lignin, being, therefore, an abundant and renewable source for obtaining several platform molecules, with levoglucosan (LG) standing out. This anhydrous carbohydrate can be acylated to obtain carbohydrate fatty acid esters (CFAEs). Here, these compounds were obtained via enzymatic acylation of LG, commercially obtained (Start BioScience®), with different acyl donors in continuous flow. Through the experimental design using a model reaction, it was possible to optimize the reaction conditions, temperature and residence time, obtaining a maximum conversion at 61 °C and 77 min. In addition, there was a productivity gain of up to 100 times in all comparisons made with the batch system. Finally, CFAEs were applied in tests of interfacial tension and biological activity. For a mixture of 4- and 2-O-lauryl-1,6-anhydroglucopyranose (MONLAU), the minimum interfacial tension (IFTmin) obtained was 96 mN m-1 and the critical micelle concentration (CMC) was 50 mM. Similar values were obtained for a mixture of 4- and 2-O-palmitoyl-1,6-anhydroglucopyranose (MONPAL), not yet reported in the literature, of 88 mN m-1 in 50 mM. For a mixture of 4- and 2-O-estearyl-1,6-anhydroglucopyranose (MONEST) and 4- and 2-O-oleoyl-1,6-anhydroglucopyranose (MONOLE), CMC was higher than 60 mM and IFTmin of 141 mN m-1 and 102 mN m-1, respectively. Promising data were obtained for minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of MONLAU against Staphylococcus aureus strains at 0.25 mM.

Cannabidiol Discovery and Synthesis-a Target-Oriented Analysis in Drug Production Processes.

The current state of evidence and recommendations for cannabidiol (CBD) and its health effects change the legal landscape and aim to destigmatize its phytotherapeutic research. Recently, some countries have included CBD as an antiepileptic product for compassionate use in children with refractory epilepsy. The growing demand for CBD has led to the need for high-purity cannabinoids on the emerging market. The discovery and development of approaches toward CBD synthesis have arisen from the successful extraction of Cannabis plants for cannabinoid fermentation in brewer's yeast. To understand different contributions to the design and enhancement of the synthesis of CBD and its key intermediates, a detailed analysis of the history behind cannabinoid compounds and their optimization is provided herein.

Theoretical studies and NMR assay of coumarins and neoflavanones derivatives as potential inhibitors of acetylcholinesterase.

Currently Alzheimer's disease (AD) is a devastating neurological disorder that mainly affects the elderly. The treatment of AD has as main objective to increase the levels of ACh in the synaptic cleft by inhibiting the cholinesterase enzymes, which are responsible for the degradation of ACh. Twenty one synthesized coumarins and neoflavanones (4-arylcoumarins) and theoretical studies were used to select the most promising ligands for in vitro experimental studies by Nuclear Magnetic Resonance. The eight compounds selected for the experimental study only 12b (effectiveness 68.54 ±â€¯3.22%) was promising AChE inhibitor. This compound (12b) presents substituents at positions 4, 5, 6, 7 and 8 in a coumarin nucleus, being the most significant characteristic in comparison to the other studied compounds. These results can be used for the design and synthesis of other possible derivatives with inhibitory potential of AChE.

Continuous-flow synthesis of dimethyl fumarate: a powerful small molecule for the treatment of psoriasis and multiple sclerosis.

Dimethyl fumarate (DMF) is a methyl ester of fumaric acid and has recently gained attention due to its use as a pro-drug in different pharmaceutical preparations, besides the low price of the final molecule and no active patents being available for the synthesis of DMF, the prices of multiple sclerosis treatment are still high. In our continuous effort for the development of process intensification strategies towards the synthesis of active pharmaceutical ingredients, here we present our work on a cascade methodology for dimethyl fumarate synthesis in short reaction times and quantitative yields.

Continuous-flow protocol for the synthesis of enantiomerically pure intermediates of anti epilepsy and anti tuberculosis active pharmaceutical ingredients.

Continuous-flow production of chiral intermediates plays an important role in the development of building blocks for Active Pharmaceutical Ingredients (APIs), being α-amino acids and their derivatives widely applied as building blocks. In this work we developed two different strategies for the synthesis of intermediates used on the synthesis of levetiracetam/brivaracetam and ethambutol. The results obtained show that methionine methyl ester can be continuously converted to the desired ethambutol intermediate by RANEY® Nickel dessulfurization/reduction strategy whereas levetiracetam/brivaracetam intermediates could be synthesized by both RANEY® Nickel (without H2) and Pd/C-H2 approach or by photochemical desulfurization.

New Palladacycle-Derived Acylhydrazones as Pre-catalysts in Mirozoki-Heck Coupling and Oxyarylations.

New acylhydrazone-based palladacycles are prepared and evaluated as pre-catalysts in Mirozoki-Heck and oxyarylation reactions.

Studies on the dynamic resolution of Crizotinib intermediate.

Crizotinib is an anti-cancer agent approved for treatment of non-small cell lung carcinoma. Retrosynthetic analysis revels 1-(2,6-dichloro-3-fluorophenyl)ethanol as an important intermediate, which can be made available by different biocatalytic approaches. Herein we report our results on the kinetic and dynamic resolution towards the desired chiral intermediate for Crizotinib synthesis. The results obtained show that very good conversions and high selectivity could be obtained for the kinetic resolution (45% conv. and E>200) while dynamic kinetic resolution under continuous-flow conditions afforded the desired product in 57% conversion and 98% e.e.

Evaluation of coumarin and neoflavone derivatives as HCV NS5B polymerase inhibitors.

Coumarins and coumestans represent an important family of compounds with diverse pharmacological properties. We recently identified coumestans as novel inhibitors of hepatitis C virus NS5B polymerase and predicted their binding in thumb pocket-1 (TP-1) of NS5B. As the coumarins are structurally related to coumestans by virtue of their common A- and B-rings, we postulated them to also exhibit similar binding interaction with NS5B and inhibit its polymerase function. We therefore investigated 24 coumarin and neoflavone derivatives as candidate NS5B inhibitors and identified 14 compounds inhibiting NS5B polymerase activity with IC50 values between 17 and 63 µm. Of these, the newly synthesized 6,8-diallyl-5,7-dihydroxycoumarin (8a) was produced in three steps in high chemical yield from floroglucinol and found to be the most potent of this series, exhibiting activity similar to the reference coumestan LQB-34. The binding site of 8a was mapped to TP-1 of NS5B by counter screening against P495L NS5B mutant, employed as a screen for TP-1 site binders. NS5B-TP-1-8a interaction map provided insight into 8a binding and offered clues for future SAR optimization.

Molecular modeling of a phenyl-amidine class of NMDA receptor antagonists and the rational design of new triazolyl-amidine derivatives.

Recently, many efforts have been made to develop N-methyl-D-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives (1a-1q), reported as N-methyl-D-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting (R = 0.914) was able to explain 83.6% of the biological data variance (R(2) = 0.836), presented a satisfactory internal predictive ability (Q(2) = 0.609) and contained the descriptors (E(HOMO), Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl-D-aspartic acid receptor antagonists.