title: Design, synthesis and pharmaco-toxicological assessment of 5-mercapto-1,2,4-triazole derivatives with antibacterial and antiproliferative activity.
abstract: The extensive biochemical research of multiple types of cancer has revealed important enzymatic signaling pathways responsible for tumor occurrence and progression, thus compelling the need for the discovery of new means with which to block these signaling cascades. The phosphoinositide 3-kinase/ protein kinase B (PI3K/AKT) pathway, which plays an important role in maintaining relevant cellular functions, exhibits various alterations in common human cancers, thus representing a suitable target in cancer treatment. Molecules bearing the 1,2,4-triazole moiety are known to possess multiple biological activities, including anticancer activity. The current study used molecular docking in the design of 5-mercapto-1,2,4-triazole derivatives with antiproliferative activity targeting the PI3K/AKT pathway. Three structures emerged as the result of this method, which indicated for these a highly favorable accommodation within the active binding site of PI3K protein, thus acting as potential PI3K inhibitors, and hence interfering with the above-mentioned pathway. The molecules were synthesized and their chemical structure was confirmed. The antiproliferative activity of these compounds was tested on 4 cancer cell lines (A375, B164A5, MDA-MB-231 and A549) and on normal human keratinocytes (HaCaT) by in vitro alamarBlue assay. The 3 compounds revealed antitumor activity against the breast cancer cell line (MDA-MB-231) and reduced toxicity on the normal cell line. The antibacterial activity of the compounds was also tested in vitro on Gram-positive and Gram-negative bacterial strains, revealing moderate activity.
authors.affiliation: Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania.
authors.forename: Marius
authors.initials: M
authors.lastname: Mioc
authors.affiliation: Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania.
authors.forename: Codruta
authors.initials: C
authors.lastname: Soica
authors.affiliation: S.C. SINOFIN S.R.L., Timisoara 300544, Romania.
authors.forename: Vasile
authors.initials: V
authors.lastname: Bercean
authors.affiliation: Department of Computational Chemistry, Institute of Chemistry Timisoara of the Romanian Academy, Timisoara 300223, Romania.
authors.forename: Sorin
authors.initials: S
authors.lastname: Avram
authors.affiliation: Institute of Macromolecular Chemistry 'Petru Poni', Iasi 700487, Romania.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Balan-Porcarasu
authors.affiliation: Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania.
authors.forename: Dorina
authors.initials: D
authors.lastname: Coricovac
authors.affiliation: Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania.
authors.forename: Roxana
authors.initials: R
authors.lastname: Ghiulai
authors.affiliation: Faculty of Medicine, Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania.
authors.forename: Delia
authors.initials: D
authors.lastname: Muntean
authors.affiliation: Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania.
authors.forename: Florina
authors.initials: F
authors.lastname: Andrica
authors.affiliation: Faculty of Pharmacy, 'Victor Babes' University of Medicine and Pharmacy, Timisoara 300041, Romania.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dehelean
authors.affiliation: Laboratory of Clinical Virology, Medical School, University of Crete, Heraklion 71409, Greece.
authors.forename: Demetrios A
authors.initials: DA
authors.lastname: Spandidos
authors.affiliation: Department of Forensic Sciences and Toxicology, Medical School, University of Crete, Heraklion 71003, Greece.
authors.forename: Aristides M
authors.initials: AM
authors.lastname: Tsatsakis
authors.affiliation: Department of Computational Chemistry, Institute of Chemistry Timisoara of the Romanian Academy, Timisoara 300223, Romania.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Kurunczi