Synthesis, chemical properties and search for molecular descriptors of the fungicidal activity of new hybrids of 1,2,4-triazole(1,3,4-oxadiazole) bearing a pyrimidine fragment

This paper reports the synthesis and identification of molecular descriptors of the fungicidal action of novel hybrid compounds combining 1,2,4-triazole and 1,3,4-oxadiazole with a pyrimidine fragment. Initially, 12 compounds with predicted fungicidal potential were selected from a virtual library of 1,000 azole-containing heterocycles – pyrimidine, 1,2,4-triazole, and 1,3,4-oxadiazole – using bioinformatic tools, including ADME filtering and molecular docking. The target compounds were synthesized via the [3+2] heterocyclization reaction, involving 2-(pyrimidin-2-ylthio)acetohydrazides with phenylisothiocyanate and carbon disulfide in an alkaline medium, resulting in a thiomethylene-linked heterocyclic system. The synthesized thiones were subsequently alkylated at the sulfur atom to yield a series of S-derivatives. The structures of the synthesized compounds were confirmed by elemental analysis, chromatography-mass spectrometry, and 1H NMR spectroscopy. Docking simulations were performed using the X-ray crystallographic structure of lanosterol 14--demethylase from Candida albicans, retrieved from the Protein Data Bank. Lipinski’s Rule of Five and Egan’s rule were applied, showing that four compounds fully conformed to these guidelines. Among them, two compounds exhibited the lowest binding energies (–7.710 and –6.424 kcal/mol), indicating strong potential as antifungal agents. These compounds interacted with five key amino acids (ARG, HID, THR, LYS, and SER) during docking, indicating potential efficacy against fungal infections. The findings suggest promising applications for these compounds, given their strong fungicidal properties.