THREE DIMENSIONAL STRUCTURE-ACTIVITY RELATIONSHIPS (3D-OSAR) FOR INSECT REPELLENCY OF DIASTEREOISOMERIC COMPOUNDS: A HIERARCHICAL MOLECULAR OVERLAY APPROACH

Authors: BASAK, SUBHASH - UNIV. OF MN.; NATARAJAN, R. - UNIV. OF MN.; NOWAK, WIESLAW - COPERNICUS UNIV.; MISZTA, P. - COPERNICUS UNIV.; Klun, Jerome

Submitted to: Structure-Activity Relationship and Quantitative Structure-Activity Relationship in Environmental Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/8/2006
Publication Date: 6/7/2007
Citation: Basak, S.C., Natarajan, R., Nowak, W., Miszta, P., Klun, J.A. 2007. Three dimensional structure-activity relationships (3d-osar) for insect repellency of diastereoisomeric compounds: a hierarchical molecular overlay approach. Structure-Activity Relationship and Quantitative Structure-Activity Relationship in Environmental Research, 18:237-250. 2007

Interpretive Summary: Insect repellents are the first line of defense for protection of humans from diseases vectored by mosquitoes and other arthropods. New and more effective repellents are needed. The three dimensional shape of three known highly effective repellents were studied. The study provided important information about what the three repellents have in common. The three dimensional data will be used by organic chemists to design new repellents that are patterned after the known most effective chemicals.

Technical Abstract: 1-methylisopropyl 2-(2-hydroxyethyl) piperidine-1-carboxylate (Picaridin), and 1-(cyclohex-3-ene-1-ylcarbonyl)-2-methylpiperidine (AI3-37220; 220) are alternatives to DEET (N, N-diethy-3-methylbenzamide), the most popular mosquito repellents. Picaridin, and AI3-37220 exhibit polychiral diastereoisomerism and each has four diastereoisomers due to the presence of two asymmetric centers in their molecules. The diastereoisomers of these compounds have differing degrees of mosquito-repellent activity according to quantitative behavioral assays conducted at the United States Department of Agriculture. An insight into the stereochemical requirements for repellency is of great importance in the development of better repellents. Molecular overlay of the optimized geometries of the diastereoisomers was considered as a novel tool for Stereochemical Structure-Activity Relationship (SSAR) modeling. An earlier study using molecular mechanics (MM2) optimized geometries showed good promise. In continuation of this effort and to overcome certain defects in using MM2 geometries, a hierarchical overlay approach was developed. In this method geometry of the low energy conformer of each diastereoisomer was optimized using: the following quantum chemical methods in a graduated manner: a) semiempirical AM1, b) Hartree Fock (STO3G, 6-31G, and 6-311G), and c) Density Functional Theory (B3LYP/6-31G, B3LYP/6-311G). The optimized geometries of different diastereoisomers were overlaid in various user defined combinations to calculate the root mean square distances (RMSD) of the overlaid structures. The RMSD with respect to the most active diastereoisomer were found to be well correlated with biological potency. Common motifs in shapes and molecular surfaces that are probably critical for effective repellent activity were identified. The method also gave valuable information on the refinement attained, and the quantum chemical level (basis set) at which optimization must be carried out to get reliable predictions.