Searching for drug leads targeted to the hydrophobic cleft of dengue virus capsid protein.

We synthesised and screened 18 aromatic derivatives of guanylhydrazones and oximes aromatic for their capacity to bind to dengue virus capsid protein (DENVC). The intended therapeutic target was the hydrophobic cleft of DENVC, which is a region responsible for its anchoring in lipid droplets in the infected cells. The inhibition of this process completely suppresses virus infectivity. Using NMR, we describe five compounds able to bind to the α1-α2 interface in the hydrophobic cleft. Saturation transfer difference experiments showed that the aromatic protons of the ligands are important for the interaction with DENVC. Fluorescence binding isotherms indicated that the selected compounds bind at micromolar affinities, possibly leading to binding-induced conformational changes. NMR-derived docking calculations of ligands showed that they position similarly in the hydrophobic cleft. Cytotoxicity experiments and calculations of in silico drug properties suggest that these compounds may be promising candidates in the search for antivirals targeting DENVC.

Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase.

Analogs of pralidoxime, which is a commercial antidote for intoxication from neurotoxic organophosphorus compounds, were designed, synthesized, characterized, and tested as potential inhibitors or reactivators of acetylcholinesterase (AChE) using the Ellman's test, nuclear magnetic resonance, and molecular modeling. These analogs include 1-methylpyridine-2-carboxaldehyde hydrazone, 1-methylpyridine-2-carboxaldehyde guanylhydrazone, and six other guanylhydrazones obtained from different benzaldehydes. The results indicate that all compounds are weak AChE reactivators but relatively good AChE inhibitors. The most effective AChE inhibitor discovered was the guanylhydrazone derived from 2,4-dinitrobenzaldehyde and was compared with tacrine, displaying similar activity to this reference material. These results indicate that guanylhydrazones as well as future similar derivatives may function as drugs for the treatment of Alzheimer's disease.

NMR determination of Electrophorus electricus acetylcholinesterase inhibition and reactivation by neutral oximes.

Neurotoxic organophosphorus compounds (OPs), which are used as pesticides and chemical warfare agents lead to more than 700,000 intoxications worldwide every year. The main target of OPs is the inhibition of acetylcholinesterase (AChE), an enzyme necessary for the control of the neurotransmitter acetylcholine (ACh). The control of ACh function is performed by its hydrolysis with AChE, a process that can be completely interrupted by inhibition of the enzyme by phosphylation with OPs. Compounds used for reactivation of the phosphylated AChE are cationic oximes, which usually possess low membrane and hematoencephalic barrier permeation. Neutral oximes possess a better capacity for hematoencephalic barrier permeation. NMR spectroscopy is a very confident method for monitoring the inhibition and reactivation of enzymes, different from the Ellman test, which is the common method for evaluation of inhibition and reactivation of AChE. In this work (1)H NMR was used to test the effect of neutral oximes on inhibition of AChE and reactivation of AChE inhibited with ethyl-paraoxon. The results confirmed that NMR is a very efficient method for monitoring the action of AChE, showing that neutral oximes, which display a significant AChE inhibition activity, are potential drugs for Alzheimer disease. The NMR method showed that a neutral oxime, previously indicated by the Ellman test as better in vitro reactivator of AChE inhibited with paraoxon than pralidoxime (2-PAM), was much less efficient than 2-PAM, confirming that NMR is a better method than the Ellman test.

Review about Structure and Evaluation of Reactivators of Acetylcholinesterase Inhibited with Neurotoxic Organophosphorus Compounds.

BACKGROUND: Neurotoxic chemical warfare agents can be classified as some of the most dangerous chemicals for humanity. The most effective of those agents are the Organophosphates (OPs) capable of restricting the enzyme Acetylcholinesterase (AChE), which in turn, controls the nerve impulse transmission. When AChE is inhibited by OPs, its reactivation can be usually performed through cationic oximes. However, until today, it has not been developed one universal defense agent, with complete effective reactivation activity for AChE inhibited by any of the many types of existing neurotoxic OPs. For this reason, before treating people intoxicated by an OP, it is necessary to determine the neurotoxic compound that was used for contamination, in order to select the most effective oxime. Unfortunately, this task usually requires a relatively long time, raising the possibility of death. Cationic oximes also display a limited capacity of permeating the Blood-Brain Barrier (BBB). This fact compromises their capacity to reactivating AChE inside the nervous system. METHODS: We performed a comprehensive search on the data about OPs available on the scientific literature today in order to cover all the main drawbacks still faced in the research for the development of effective antidotes against those compounds. RESULTS: Therefore, this review about neurotoxic OPs and the reactivation of AChE, provides insights for the new agents' development. The most expected defense agent is a molecule without toxicity and effective to reactivate AChE inhibited by all neurotoxic OPs. CONCLUSION: To develop these new agents, the application of diverse scientific areas of research, especially theoretical procedures as computational science (computer simulation, docking and dynamics), organic synthesis, spectroscopic methodologies, biology, biochemical and biophysical information, medicinal chemistry, pharmacology and toxicology, is necessary.

Synthesis and docking studies of three new diaminochromenes as potential leads for anticancer drugs.

In this work, the new diaminochromenes: 2,5-dimono-8-methoxychromeno[4,3,2-de][1,6]naphthyridine-4-carbonitrile (4), 8-ethoxy-2-imino-3,4-dihydro-2H-chromene-3-carbonitrile-4-malononitrile (5), 2,5-diamino-8-ethoxychromene[4,3,2-de][1,6]naphthyridine-4-carbonotrile (6), were synthesized and fully characterized through 600 MHz using 1H, 13C, APT, gHSQC, gHMBC, ROESY-1D and gated decoupling 13C. Further docking studies suggested that these compounds are capable of intercalating with the Drew-Dickerson Dodecamer DNA and, therefore, be candidates to work as effective compounds to decrease the cancer radiotherapy.Communicated by Ramaswamy H. Sarma.

Complete chemical shift assignment and molecular modeling studies of two chromene derivatives as potential leads for new anticancer drugs.

The compounds 7-chloro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (5) and 5-[-7-chloro-2,4-dioxo-1H, 2H, 3H, 4H, 5H-chromeno[2,3-d]pyrimidin-5-yl)]-1,3-diazinane-2,4,6-trione (7), were synthesized from dimedone and barbituric acid and had their three-dimensional structures and precise chemical shifts assignments obtained by Nuclear Magnetic Resonance (NMR) from 1H, 13C, APT, COSY, HSQC, and HMBC spectra. Additional HOMO-LUMO DFT calculations corroborated the NMR results and pointed to the most stable stereoisomers of each compound. Besides, further docking and molecular dynamic studies suggest that the stereoisomers (9S)-7-chloro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one, and 5-[(5S)-7-chloro-2,4-dioxo-1H, 2H, 3H, 4H, 5H-chromeno[2,3-d]pyrimidin-5-yl)]-1,3-diazinane-2,4,6-trione of these compounds may act as DNA intercalators and qualify as potential leads for the development of new anticancer drugs.Communicated by Ramaswamy H. Sarma.

Erratum: Crystal structures and Hirshfeld surface analyses of (E)-N'-benzyl-idene-2-oxo-2H-chromene-3-carbo-hydrazide and the disordered hemi-DMSO solvate of (E)-2-oxo-N'-(3,4,5-trimeth-oxybenzyl-idene)-2H-chromene-3-carbohydrazide: lattice energy and inter-molecular inter-action energy calculations for the former. Corrigendum.

[This corrects the article DOI: 10.1107/S2056989019012015.].

New semicarbazones as gorge-spanning ligands of acetylcholinesterase and potential new drugs against Alzheimer's disease: Synthesis, molecular modeling, NMR, and biological evaluation.

Two new compounds (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dihydroacridin-1(2H)-ylidene)hydrazinecarbothiomide (3) and (E)-2-(5,7-dibromo-3,3-dimethyl-3,4-dhihydroacridin-1(2H)-ylidene)hydrazinecarboxamide (4) were synthesized and evaluated for their anticholinesterase activities. In vitro tests performed by NMR and Ellman's tests, pointed to a mixed kinetic mechanism for the inhibition of acetylcholinesterase (AChE). This result was corroborated through further docking and molecular dynamics studies, suggesting that the new compounds can work as gorge-spanning ligands by interacting with two different binding sites inside AChE. Also, in silico toxicity evaluation suggested that these new compounds can be less toxic than tacrine.

SHESSLOC: A selective variation of the FUCOUP sequence.

In this paper we carried out a comparison between all the possible selective versions of the basic heteronuclear correlation experiment, the FUCOUP sequence. We concluded that the best experiment is that one in which the selective pulse is given in the carbon dimension, which we called SHESSLOC (Selective HEteronuclear Simultaneous Short and LOng-range Correlations). The sensitivity of the sequence was improved with the introduction of pulsed field gradients.

Formation of p-cresol:piperazine complex in solution monitored by spin-lattice relaxation times and pulsed field gradient NMR diffusion measurements.

A study of the nature of the anthelmintic p-cresol:piperazine complex in chloroform solution has been conducted using different NMR techniques: self-diffusion coefficients using DOSY; NOE, NULL, and double-selective T1 measurements to determine inter-molecular distances; and selective and non-selective T1 measurements to determine correlation times. The experimental results in solution and CP-MAS were compared to literature X-ray diffraction data using molecular modeling. It was shown that the p-cresol:piperazine complex exists in solution in a very similar manner as it does in the solid state, with one p-cresol molecule hydrogen bonded through the hydroxyl hydrogen to each nitrogen atom of piperazine. The close correspondence between the X-ray diffraction data and the inter-proton distances obtained by NULL and double selective excitation techniques indicate that those methodologies can be used to determine inter-molecular distances in solution.