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.

Chemical Composition and Antimicrobial Activity of Essential Oil of Romanian Origanum vulgare

“…Helium was used as the carrier gas, in a flow rate of 1mL/min. This chromatographer in gas phase was coupled to a mass spectrometry (Hewlett Packard Agilent 5973) with ionization energy of 70 eV, ion source at 230 o C and interface temperature at 280 o C. In vitro antimicrobial activity The determination of antibacterial activity was performed on reference strains (table 1) both by the diffusimetric method on standardized subculture and by the method of dilutions with the MIC (minimum inhibitory concentration) determination, as previously described by other authors [5][6][7][8].…”

Synthesis and Anti‐Proliferative Activity of a Triazole‐Fused Thymidine Analogue

“…Considering that 1 showed significant toxicity in glioma and breast cancer cells, we performed in silico studies with induced fit molecular docking approach. With reference to previous reports on triazole containing molecules, we selected 16 protein targets associated with different cancers of brain, breast and colon . The docking results are presented in Table , which includes docking scores, RMSD values of re‐docked and co‐crystallized ligands, MM‐GB/SA dG bind energies, and amino acid residues involved in hydrogen bonding with the acyclic nucleoside 1 .…”

Choline Chloride Based Deep Eutectic Solvents as a Tuneable Medium for Synthesis of Coumarinyl 1,2,4‐Triazoles: Effect of Solvent Type and Temperature

“…Synthesis of triazoles, oxadiazoles, thiadiazoles, thiazolidinones is often performed from thiosemicarbazides as starting compounds, involving different reaction conditions. [15][16][17] 1,2,4-Triazoles are proven to act as antibacterials, [18] antifungals, [19] antitumor agents, [20] as well as anticonvulsant, antiinflammatory, and antimicrobial agents. [14] Triazoles are biologically active five-membered nitrogencontaining heterocyclic compounds, which can exist in two isomeric forms (Scheme 1), 1,2,3-triazole and 1,2,4-triazole, exhibiting tautomerism depending on the hydrogen atom position.…”

“…[14] Triazoles are biologically active five-membered nitrogencontaining heterocyclic compounds, which can exist in two isomeric forms (Scheme 1), 1,2,3-triazole and 1,2,4-triazole, exhibiting tautomerism depending on the hydrogen atom position. [15][16][17] 1,2,4-Triazoles are proven to act as antibacterials, [18] antifungals, [19] antitumor agents, [20] as well as anticonvulsant, antiinflammatory, and antimicrobial agents. [21] Some commercially thiosemicarbazides were obtained in choline chloride/ethane-1,2-diol (1:2), choline chloride/malic acid (1:1), choline chloride/ malonic acid (1:1), choline chloride/butane-1,4-diol (1:3) and choline chloride/glycerole (1:2) at 40°C.…”