Benzimidazoles Containing Piperazine Skeleton at C-2 Position as Promising Tubulin Modulators with Anthelmintic and Antineoplastic Activity

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creativework.keywordsabsolute free energy of perturbation (ABFEP), anthelmintic activity, antitumor activity, benzimidazole, cell migration, IFD-MD, induced fit docking, LDH cellular release, molecular dynamics simulation, piperazine, tubulin modulators
creativework.publisherMultidisciplinary Digital Publishing Institute (MDPI)en
dc.contributor.authorAnichina K.
dc.contributor.authorMavrova A.
dc.contributor.authorVuchev D.
dc.contributor.authorPopova-Daskalova G.
dc.contributor.authorBassi G.
dc.contributor.authorRossi A.
dc.contributor.authorMontesi M.
dc.contributor.authorPanseri S.
dc.contributor.authorFratev F.
dc.contributor.authorNaydenova E.
dc.date.accessioned2024-07-10T14:27:06Z
dc.date.accessioned2024-07-10T14:51:05Z
dc.date.available2024-07-10T14:27:06Z
dc.date.available2024-07-10T14:51:05Z
dc.date.issued2023-11-01
dc.description.abstractBenzimidazole anthelmintic drugs hold promise for repurposing as cancer treatments due to their interference with tubulin polymerization and depolymerization, manifesting anticancer properties. We explored the potential of benzimidazole compounds with a piperazine fragment at C-2 as tubulin-targeting agents. In particular, we assessed their anthelmintic activity against isolated Trichinella spiralis muscle larvae and their effects on glioblastoma (U-87 MG) and breast cancer (MDA-MB-231) cell lines. Compound 7c demonstrated exceptional anthelmintic efficacy, achieving a 92.7% reduction in parasite activity at 100 μg/mL after 48 hours. In vitro cytotoxicity analysis of MDA-MB 231 and U87 MG cell lines showed that derivatives 7b, 7d, and 7c displayed lower IC50 values compared to albendazole (ABZ), the control. These piperazine benzimidazoles effectively reduced cell migration in both cell lines, with compound 7c exhibiting the most significant reduction, making it a promising candidate for further study. The binding mode of the most promising compound 7c, was determined using the induced fit docking–molecular dynamics (IFD–MD) approach. Regular docking and IFD were also employed for comparison. The IFD–MD analysis revealed that 7c binds to tubulin in a unique binding cavity near that of ABZ, but the benzimidazole ring was fitted much deeper into the binding pocket. Finally, the absolute free energy of perturbation technique was applied to evaluate the 7c binding affinity, further confirming the observed binding mode.
dc.identifier.doi10.3390/ph16111518
dc.identifier.issn1424-8247
dc.identifier.scopusSCOPUS_ID:85178331524en
dc.identifier.urihttps://rlib.uctm.edu/handle/123456789/885
dc.language.isoen
dc.source.urihttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85178331524&origin=inward
dc.titleBenzimidazoles Containing Piperazine Skeleton at C-2 Position as Promising Tubulin Modulators with Anthelmintic and Antineoplastic Activity
dc.typeArticle
oaire.citation.issue11
oaire.citation.volume16
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