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Structure-activity relationships of sulfonamides derived from carvacrol and their potential for the treatment of Alzheimer's disease.

ABSTRACT: Five synthetic sulfonamides derived from carvacrol, a natural product and a small molecule with druglike properties, were evaluated with respect to their effects on the cognitive deficits of animals with streptozotocin (STZ)-induced Alzheimer's disease (AD). Memory, ambulation, anxiety and oxidative stress were evaluated. In vitro assays were performed to assess the inhibition of acetylcholinesterase (AChE), and the data were combined with molecular docking for the establishment of structure-activity relationships. The memories of animals treated with the compounds derived from morpholine (1), hydrazine (3) and 2-phenol (5) were improved. Compound 3 was the most promising, yielding excellent results in the inhibitory avoidance test. Moreover, the compounds did not exhibit any deleterious effects on the animals' ambulation in the open field test. Molecular docking confirmed the results obtained in the AChE inhibition assay. In short, compounds 1, 3 and 5 can reduce STZ-induced deficits and show potential for the treatment of Alzheimer's. In addition, these agents produce significant anxiolytic and antioxidant effects.

SUBMITTER: de Souza MM

PROVIDER: S-EPMC7429979 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Structure-activity relationships of sulfonamides derived from carvacrol and their potential for the treatment of Alzheimer's disease.

de Souza Márcia Maria MM Andreolla Marina Corrêa MC Ribeiro Thaís Cecília TC Gonçalves Ana Elisa AE Medeiros Alex Rogério AR de Souza Anacleto Silva AS Ferreira Leonardo Luiz Gomes LLG Andricopulo Adriano Defini AD Yunes Rosendo Augusto RA de Oliveira Aldo Sena AS

RSC medicinal chemistry 20200214 2

Five synthetic sulfonamides derived from carvacrol, a natural product and a small molecule with druglike properties, were evaluated with respect to their effects on the cognitive deficits of animals with streptozotocin (STZ)-induced Alzheimer's disease (AD). Memory, ambulation, anxiety and oxidative stress were evaluated. <i>In vitro</i> assays were performed to assess the inhibition of acetylcholinesterase (AChE), and the data were combined with molecular docking for the establishment of struct ...[more]

PMID: 33479638

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Project description:The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca2+)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified β-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring C-terminal amides and diversely substituted N'-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca2+ entry, thereby establishing critical structure-activity relationships. While the substitution of the tert-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N'-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA).

Dataset Information

Structure-activity relationships of sulfonamides derived from carvacrol and their potential for the treatment of Alzheimer's disease.

Publications

Structure-activity relationships of sulfonamides derived from carvacrol and their potential for the treatment of Alzheimer's disease.

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