A successful virtual screening application: prediction of anticonvulsant activity in MES test of widely used pharmaceutical and food preservatives methylparaben and propylparaben

Abstract

A discriminant function based on topological descriptors was derived from a training set composed by anticonvulsants of clinical use or in clinical phase of development and compounds with other therapeutic uses. This model was internally and externally validated and applied in the virtual screening of chemical compounds from the Merck Index 13th. Methylparaben (Nipagin), a preservative widely used in food, cosmetics and pharmaceutics, was signaled as active by the discriminant function and tested in mice in the Maximal Electroshock (MES) test (i.p. administration), according to the NIH Program for Anticonvulsant Drug Development. Based on the results of Methylparaben, Propylparaben (Nipasol), another preservative usually used in association with the former, was also tested. Both methyl and propylparaben were found active in mice at doses of 30, 100, and 300 mg/kg. The discovery of the anticonvulsant activities in the MES test of methylparaben and propylparaben might be useful for the development of new anticonvulsant medications, specially considering the well-known toxicological profile of these drugs.

Anticonvulsant effect of sodium cyclamate and propylparaben on pentylenetetrazol‐induced seizures in zebrafish

“…SC (an artificial sweetener) showed moderate anticonvulsant activities in mice (Talevi et al, , Di Ianni et al, ) in both scPTZ and MES tests, whereas PP (a food preservative) displayed an anticovulsant effect using the MES test in mice (Talevi et al, ). We decided then to evaluate them in an alternative seizure model such as adult zebrafish, quantifying the effects of these two compounds which present the additional benefit that they are used by human beings daily without apparent side effects at the acceptable daily intake.…”

“…SC has shown protective effects in MES test (30 mg/kg, mice) and sc PTZ test (abolishment of myoclonic and tonic–clonic seizures at 30 and 100 mg/kg and increased latencies to seizures at 30 mg/kg, mice) (Di Ianni et al, and refs therein). PP has shown protective effects in MES test (Talevi et al, ) and its neuroprotective effects following status epilepticus have been the object of an international patent application (PCT/IB2014/064484).…”

“…We have previously reported the anticonvulsant effects of non‐nutritive sweetener sodium cyclamate (SC) and antimicrobial agent propylparaben (PP), which were identified through computer‐guided virtual screening (Talevi, Bellera, Castro, & Bruno‐Blanch, ; Talevi, Enrique, & Bruno‐Blanch, ; Di Ianni et al, ). Here, we have exposed adult zebrafish to the chemoconvulsant drug PTZ, examining their responses using a detailed behavioral analysis, and we have explored the anticonvulsant effects of SC and sodium PP in this model to verify if their protective effects could be observed in nonrodent vertebrate species.…”

Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage

“…Drugs Selected for Evaluation. The 5 anticonvulsant compounds classified as nonsubstrates by our model ensemble and selected for experimental evaluation were methylparaben (Compound 12, Figure 2), 79 2-(2-oxo-2Hchromen-3-yl)benzoic acid (Compound 1, Figure 2), 1-methyl-1,2,3′,4′-tetrahydro-1′H-spiro[indole-3,2′-quinazoline]-2,4′dione (Compound 16, Figure 2), N-(3,3-dimethylbutan-2-yl)-2-methylfuran-3-carboxamide (Compound 17, Figure 2), 71,72 and N,N′-dibenzylsulfamide (Compound 13, Figure 2). 80 Experimental Model Validation.…”

Computer-Aided Identification of Anticonvulsant Effect of Natural Nonnutritive Sweeteners Stevioside and Rebaudioside A

“…The first model applied to screen the stevia constituents was a four-feature linear classificatory model based on conformation-independent topological molecular descriptors and information indices. 11 The molecular descriptors included in this model were computed with Dragon Software for molecular descriptors calculation v. 4. 0 (Milano Chemometrics, 2003).…”