Neurotoxicity of Pesticides: The Roadmap for the Cubic Mode of Action

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Author(s): Bogdan Bumbăcilă, Mihai V. Putz*.

Journal Name: Current Medicinal Chemistry

Abstract:

Pesticides are widely used on a planetary basis. The growing need for substances with such biological activity due to the increasing consumption of agricultural and animal husbandry products due to the development of urban areas and for economic reasons, make the chemical industry constantly investigate molecules known to improve their physicochemical characteristics, increase their biological activities and improve their toxicity. On the other side, molecule databases are increasingly accessible for in vitro and in vivo bioavailability studies on pests and toxicity to secondary exposed organisms. In this context, structure-activity studies, by their in silico - in cerebro methods, are called to preceded in vitro and in vivo studies in plants and experimental animals because they can indicate trends by statistical methods or curves of activity expressed in mathematical equations or graphical correlations, so that one can develop a direction of study or abandon another, saving financial resources, time and animals from biobases. Following this line of research this paper reviews the Structure-Activity Relationship (SAR) review as based on the correlation of key a topological connectivity index with biological activities, particularly the toxicity of 11 molecules of organophosphate compounds, randomly chosen, with a basic structure including a Phosphorus atom double bounded to an Oxygen atom or to a Sulfur one and having three other simple covalent bonds with two alkoxy (- methoxy or -ethoxy) groups and to another functional group different from the alkoxy groups. The molecules were packed on a cubic structure consisting of three adjacent cubes, respecting a principle of topological efficiency, that of occupying a minimal space in that cubic structure, a method that was called the Clef Method. The central topological index selected for correlation was the Wiener index, since it was possible this way to discuss different adjacencies between the nodes in the graphs corresponding to the organophosphate compounds molecules packed on the cubic structure; accordingly, "three dimensional" variants of these connectivity indices could be considered and further used for studying the qualitative-quantitative relationships for the specific molecule-enzyme interaction complexes, including correlation between the Wiener Weights (nodal specific contributions to the total Wiener index of the molecular graph) and the biochemical reactivity of some of the atoms. Finally, when passing from SAR to Q(uantitative)- SAR studies may ensure a predictability of the toxicity of different compounds, facilitating the in vivo experiments or improving the usage of pesticides, especially by the present advanced method of the cubic molecule and its (neurotoxic) mode of action.

Keywords: pesticides, toxicity, organophosphates, the Clef Method, cubic system, Wiener Index, Wiener difference, Cubic Molecule

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(E-pub Ahead of Print)
DOI: 10.2174/0929867326666190704142354
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