Hydrazone-Based Small-Molecule Chemosensors

The hydrazone functional group is widely applied in several fields. The versatility and large use of this chemotype are attributed to its easy and straightforward synthesis and unique structural characteristics which is useful for different chemical and biological purposes. Recently hydrazone scaffold has been widely adopted in the design of small-molecule fluorescent and colorimetric chemosensors for detecting metals and anions because of its corresponding non-covalent interactions. This chapter provides an overview of hydrazone-based fluorescent and colorimetric chemosensors for anions and metals of biological interest, with their representative rational designs in the last 15 years. We hope this chapter inspires the development of novel and powerful fluorescent and colorimetric chemosensors for a broad range of applications

Design, Synthesis and Biological Evaluation of Novel Triazole N-acylhydrazone Hybrids for Alzheimer's Disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves different pathogenic mechanisms. In this regard, the goal of this study was the design and synthesis of new compounds with multifunctional pharmacological activity by molecular hybridization of structural fragments of curcumin and resveratrol connected by an N-acyl-hydrazone function linked to a 1,4-disubstituted triazole system. Among these hybrid compounds, derivative 3e showed the ability to inhibit acetylcholinesterase activity, the intracellular formation of reactive oxygen species as well as the neurotoxicity elicited by Aβ42 oligomers in neuronal SH-SY5Y cells. In parallel, compound 3e showed a good profile of safety and ADME parameters. Taken together, these results suggest that 3e could be considered a lead compound for the further development of AD therapeutics

Design, synthesis, and biological evaluation of new thalidomide–donepezil hybrids as neuroprotective agents targeting cholinesterases and neuroinflammation

A new series of eight multifunctional thalidomide–donepezil hybrids were synthesized based on the multi target-directed ligand strategy and evaluated as potential neuroprotective, cholinesterase inhibitors and anti neuroinflammatory agents against neurodegenerative diseases. A molecular hybridization approach was used for structural design by combining the N-benzylpiperidine pharmacophore of donepezil and the isoindoline 1,3-dione fragment from the thalidomide structure. The most promising compound, PQM-189 (3g), showed good AChE inhibitory activity with an IC50 value of 3.15 μM, which was predicted by docking studies as interacting with the enzyme in the same orientation observed in the AChE–donepezil complex and a similar profile of interaction. Additionally, compound 3g significantly decreased iNOS and IL-1β levels by 43% and 39%, respectively, after 24 h of incubation with lipopolysaccharide. In vivo data confirmed the ability of 3g to prevent locomotor impairment and changes in feeding behavior elicited by lipopolysaccharide. Moreover, the PAMPA assay evidenced adequate blood–brain barrier and gastrointestinal tract permeabilities with an Fa value of 69.8%. Altogether, these biological data suggest that compound 3g can treat the inflammatory process and oxidative stress resulting from the overexpression of iNOS and therefore the increase in reactive nitrogen species, and regulate the release of pro-inflammatory cytokines such as IL-1β. In this regard, compound PQM-189 (3g) was revealed to be a promising neuroprotective and anti-neuroinflammatory agent with an innovative thalidomide–donepezil-based hybrid molecular architectur

Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives

Herein we describe NMR experiments and structural modifications of 4-methyl-2-phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their 1H- and 13C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z) or CO-NH bond conformers (syn and anti-periplanar). NMR data from NOEdiff, 2D-NOESY and 1H-NMR spectra at different temperatures, and also the synthesis of isopropylidene hydrazone revealed the nature of duplicated signals of a 4-methyl-2-phenylpyrimidine-N-acylhydrazone derivative as a mixture of two conformers in solution. Further we investigated the stereoelectronic influence of substituents at the ortho position on the pyrimidine ring with respect to the carbonyl group, as well as the electronic effects of pyrimidine by changing it to phenyl. The conformer equilibrium was attributed to the decoplanarization of the aromatic ring and carbonyl group (generated by an ortho-alkyl group) and/or the electron withdrawing character of the pyrimidine ring. Both effects increased the rotational barrier of the C-N amide bond, as verified by the DG≠ values calculated from dynamic NMR. As far as we know, it is the first description of aryl-NAH compounds presenting two CO-NH bond- related conformations

Development of a L-Tryptophan-Based Ligand for Regioselective Copper Catalyzed N 2 -Arylation of 1,2,3-Triazoles

International audienc

O uso de aparelhos de micro-ondas domésticos em aulas experimentais de química orgânica: nitração de salicilaldeído The use of domestic microwave oven in experimental classes of organic chemistry: salicylaldehyde nitration

<abstract language="eng">The use of microwave in chemistry has known benefits over conventional heating methods, e.g. reduced reaction times, chemical yield improvement and the possibility if reducing or eliminating the use of organic solvents. We describe herein a procedure for the nitration of salicylaldehyde in water using a domestic microwave oven, which can be used as an experiment in the undergraduate chemistry laboratory. The experiment involves safe and rapid preparation and identification of the position isomers by thin layer chromatography and 1H NMR, or by their melting points

Design, synthesis and antiproliferative evaluation of new acridine-thiosemicarbazone derivatives as topoisomerase IIα inhibitors

Thiosemicarbazone-acridine hybrids are prominent inhibitors of topoisomerases II. This study reports the design, synthesis, and antiproliferative evaluation of eighteen new acridine–thiosemicarbazone derivatives as possible inhibitors of topoisomerase IIα. In general, compounds showed moderate to low cytotoxicity in the first screening performed on three cell lines, with emphasis on the DT-3OCH3 series, in which five of the six compounds have been active. Further studies against resistant leukemic cells indicated an interesting profile for derivatives DT-3OCH3-H (IC50 = 8.83 µM) and DT-3OCH3-3OH (IC50 = 10.69 µM) in the resistant cell Lucena-1, with relative resistance (RR) index of 0.11 and 0.10, respectively. A cytotoxicity assay on Vero cells showed low toxicity for most of the antileukemic compounds, with only DT-3OCH3-3OH derivative indicating a highlighted reduction in cell viability at a concentration of 61.25 µM. Five compounds were selected for topoisomerase IIα inhibition and all presented enzyme inhibition activity. Also, Topo IIα-DNA docking and molecular dynamics studies indicated that better scores were obtained for compounds interacting with residues Arg487 and Asp463, presenting electron donor groups on the acridine nucleus, as well as the presence of the hydroxyl substituents in the benzylidene. Finally, two selected compounds had their in vitro gastrointestinal absorption profile evaluated in Caco-2 cells, indicating good membrane permeation, with an apparent permeability coefficient greater than 10 × 10-6 cm/s for both