Structural-based analysis of sulfonamide derivatives: from solid states to acetolactate synthase enzyme interactions

The discovery of non-toxic compounds with herbicidal activity remains a significant challenge in agricultural weed management practices. In this study, we conducted a comparative analysis of sulfonamide derivatives, namely sulfadiazine, sulfamerazine, and sulfamethazine, which are commonly used as antibiotic drugs. Our aim was to understand the impact of the –CH₃ substituent group on the pyrimidine ring and its potential as herbicide candidates. We examined the geometric and electronic structures using density functional theory with the M06-2X hybrid exchange–correlation functional, coupled with the 6-311++G(d, p) basis set, in the gas phase. These geometric parameters were then compared to crystallographic data for validation. The frontier molecular orbital energies were employed to predict chemical reactivity descriptors, while molecular electrostatic potentials and Fukui functions aided in identifying the reactive sites within the sulfonamides. To gain insights into the supramolecular arrangement, we conducted molecular topology analyses, including the Hirshfeld surface and quantum theory of atoms in molecules. These analyses revealed that the intermolecular interactions in the respective crystals are primarily closed-shell, characterized as van der Waals forces and hydrogen bonds. Additionally, the stability of these interactions was confirmed through natural bond orbital calculations. Furthermore, we carried out toxicophoric modeling against the acetolactate synthase enzyme to identify potential interacting groups. Molecular docking studies were carried out to examine the interactions of sulfonamides with the enzyme's binding site. The quantum theory of atoms in molecules was employed to gain insights into the nature of interactions between the toxicophoric groups and the lateral chains of amino acids present at the enzyme's binding site. Tests of Human Ether-a-go-go-Related Gene Inhibition, AMES Toxicity, Fish Toxicity, Tetrahymena Pyriformis toxicity, and honey bee toxicity showed that the sulfonamide derivatives do not cause toxicity in these species and may present good environmental tolerance. The results obtained in this study suggest the need for biological tests to validate the herbicidal potential of sulfonamides.