Synthesis, molecular modeling and cholinesterase inhibitory effects of 2-indolinone-based hydrazinecarbothioamides

Background: 2-Indolinone-based hydrazinecarbothioamides carrying a 3-phenylsulfonamide moiety (7–9) were designed by replacement of donepezil's pharmacophore group indanone with a 2-indolinone ring. Method: Compounds 7–9 were synthesized by reaction of N-(3-sulfamoylphenyl)hydrazinecarbothioamide (6) with 1 H-indolin-2,3-diones (1–3). Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory effects of compounds 7–9 were assayed. Molecular modeling studies of 5-chloro-1,7-dimethyl-substituted compound 8e were carried out to determine the possible binding interactions at the active site of AChE. Results: Compound 8e showed the strongest inhibition against AChE ( Ki = 0.52 ± 0.11 μM) as well as the highest selectivity (SI = 37.69). The selectivity for AChE over BuChE of compound 8e was approximately 17-times higher than donepezil and 26-times higher than galantamine. Conclusion: Further development of compounds 7–9 may present new promising agents for Alzheimer's treatment.

A pedagogical view about the design of isoxazolyl-penicillins of the ampc betalactamase receptor 1fcm using the docking molecular technique

The present work mainly exposes the result of the search for molecules, derived from the structural changes of the drug Cloxacillin in its phenyl radical, which is chlorinated, likewise, the selection of the pharmacophore group is evidenced, which allowed to specify the aforementioned objective. Secondly, the selected target was beta-lactamase, with 1FCM nomenclature, registered in the database, Protein Data Bank, in the same way, the amino acids involved in non-covalent interactions are found, in this order of ideas, they were raised, 22 molecules that presented an affinity energy lower than -8.0 Kcal/mol, this data stated above, will become the reference value, to postulate 6 molecules that have registered a lower affinity, generated by the Autodock Vina software. To conclude, the structural optimization of the leading drug is given as a result, together with its new interactions in the amino acids LYS64, ASN149, THR313 and SER61.

SYNTHESIS OF PROPERTIES N-METHYL-2-(PYRID-4-YL)-3,4-FULLEROPYRROLIDINE

The article is devoted to the reactions of [2+3] cycloaddition of pyridine-4-aldehyde to fullerene C60, as well as to the preparation of its water-soluble from of the resulting reaction product N-methyl-2-(pyrid-4-yl)-3,4-fulleropyrrolidine. A literature review of organic compounds containing the pyrrolidine cycle was carried out. It is noted that such compounds have a wide spectrum of biological activity and are part of many drugs of both natural and synthetic origin. In this regard, an interesting “pharmacophore” group is the pyridine cycle, which is part of about 5% of all known drugs. The reaction of pyridin-4-aldehyde with fullerene C60 was carried out in the presence of sarcosine under the conditions of the Prato reaction. The reaction mechanism of 1,2-dipolar cycloaddition, leading to fulleropyrrolidine, is described. The water-soluble complex fulleropyrrolidinas with poly-N-vinylpyrrolidone was obtained. The structures of the synthesized compounds were studied by IR, UV, 1H and 13C NMR spectroscopy, as well as by the date of two-dimensional spectra of COSY (1H-1H) and HMQC (1H-13H). The values of chemical shifts, multiplicity and integrated intensity of 1H and 13C NMR signals in one-dimensional NMR spectra were determined. Using spectra in the formats COSY (1H-1H) and HMQC (1H-13C) homo- and heteronuclear interaction were established, confirming the structure of the studied compounds. Key words: fullerene C60, sarcosine, pyridine-4-aldehyde, fulleropyrrolidines, Prato reaction, NMR spectra.

EVALUATION OF A GROUP OF PYRROLE DERIVATIVES AS TUBERCULOSTATIC AGENTS

: This research aims to contribute to the global search for more effective tuberculostatics that has been triggered by recent outbreaks of tuberculosis. A group of pyrrole-containing derivatives are designed and theoretically elucidated. The identification of the pharmacophore group using the PharmaGist webserver is attempted. Also, the corresponding drug-like properties of the tested compounds are evaluated, together with their possible toxicity risks. The pharmacokinetic behavior of the structures is predicted, based on the Lipinski’s Rule of Five. The effects of some structural parameters are tested. In addition, in vitro evaluations of the anti-tubercular activity against Mycobacterium tuberculosis H37Rv are performed, with compound GA-9 registering the highest activity.