Design, Synthesis and Biological Activity Evaluation of S-Substituted 1H-5-Mercapto-1,2,4-Triazole Derivatives as Antiproliferative Agents in Colorectal Cancer.

Colon cancer is a widespread pathology with complex biochemical etiology based on a significant number of intracellular signaling pathways that play important roles in carcinogenesis, tumor proliferation and metastasis. These pathways function due to the action of key enzymes that can be used as targets for new anticancer drug development. Herein we report the synthesis and biological antiproliferative evaluation of a series of novel S-substituted 1H-3-R-5-mercapto-1,2,4-triazoles, on a colorectal cancer cell line, HT-29. Synthesized compounds were designed by docking based virtual screening (DBVS) of a previous constructed compound library against protein targets, known for their important role in colorectal cancer signaling: MEK1, ERK2, PDK1, VEGFR2. Among all synthesized structures, TZ55.7, which was retained as a possible PDK1 (phospholipid-dependent kinase 1) inhibitor, exhibited the most significant cytotoxic activity against HT-29 tumor cell line. The same compound alongside other two, TZ53.7 and TZ3a.7, led to a significant cell cycle arrest in both sub G0/G1 and G0/G1 phase. This study provides future perspectives for the development of new agents containing the 1,2,4-mercapto triazole scaffold with antiproliferative activities in colorectal cancer.

Design, synthesis and pharmaco-toxicological assessment of 5-mercapto-1,2,4-triazole derivatives with antibacterial and antiproliferative activity.

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.

Thermal stability of synthetic thyroid hormone l-thyroxine and l-thyroxine sodium salt hydrate both pure and in pharmaceutical formulations.

In this paper, the thermal stability of pure l-thyroxine (THY) and l-thyroxine sodium salt hydrate (THYSS) vs. two pharmaceutical solid formulations commercialized on both Romanian and European market (with a content of 100µg, respectively 200µg THYSS per tablet) were investigated. In order to determine whether the presence of excipients affects the thermal stability of the active pharmaceutical ingredient (API), the preliminary study of thermal stability in air atmosphere was completed with an in-depth solid-state kinetic study. By kinetic analysis, the non-isothermal degradation of the selected active pharmaceutical ingredients vs. the solid formulation with strength of 200µg THYSS per tablet was investigated. Isoconversional methods (Kissinger-Akahira-Sunose, Flynn-Wall-Ozawa and Friedman) were employed for the estimation of activation energies values, at five different heating rates, ß=5, 7, 10, 12 and 15°Cmin(-1). Also, a fourth method was applied in the processing of data, namely NPK, allowing an objective separation in the physical and chemical processes that contribute to the thermal degradation of the selected compounds. A discussion of thermal stability from the kinetic point of view is also presented.

Solid-State Characterization and Biological Activity of Betulonic Acid Derivatives.

Betulonic acid belongs to the pentacyclic triterpenic derivative class and can be obtained through the selective oxidation of betulin. In this study we set obtaining several functionalized derivatives of this compound by its condensation with several amino compounds such as aminoguanidine, hydroxylamine, n-butylamine and thiosemicarbazide as our goal. The functionalization of the parent compound led to several molecules with antiproliferative potential, the most promising being 3-2-carbamothioylhydrazonolup-20(29)-en-28-oic acid.

Theoretical considerations regarding the thione-thiol tautomerism in 2-(5-mercapto-1,3,4-thiadiazol-2-ylthio)acetic acid.

The acidity constants Ka1 and Ka2 of 2-(5-mercapto-1,3,4-thiadiazol-2-ylthio)acetic acid have been determined both by experimental and theoretical methods. pKa computations at B3LYP/6-311+G(d,p) level of theory were carried out for the two tautomeric forms, thiol and thione, of the above-mentioned acid. Comparisons between the experimental and theoretical values led to the establishing of the most stable tautomer of 2-(5-mercapto-1,3,4-thiadiazol-2-ylthio)acetic acid in aqueous solution. Also, a DFT study regarding the reactivity, aromaticity and population analysis of the two tautomers has been performed.

Synthesis and degradation of Schiff bases containing heterocyclic pharmacophore.

This paper reports on the synthesis and characterization of two Schiff bases bearing 1,2,4-triazolic moieties, namely 4H-4-(2-hydroxy-benzylidene-amino)-5-benzyl-3-mercapto-1,2,4-triazole and 4H-4-(4-nitro-benzylidene-amino)-5-benzyl-3-mercapto-1,2,4-triazole using thin layer chromatography, melting interval, elemental analysis, spectroscopy and thermal stability studies.