Three-Dimensional Structure-Activity Relationships of Synthetic Pyrethroids: 1. Similarity in Bioactive Conformations and Their Structure-Activity Pattern

Abstract

The three-dimensional``bioactive'' conformations of various types of pyrethroid insecticides were deduced from among optimized conformations which were generated on the basis of the exhaustive conformational exploration of the reference compound, MTI-800. A``folded'' rather than an``extended'' conformation was proposed to be thè`b ioactive structure'' of pyrethroid molecules included in this study. The folded``bioactive'' structures were further analyzed in terms of molecular (dis)similarity indices to elucidate the effect of the``local'' structural variations on the activity. The results indicate that the overall bioactive conformation as well as the local 3D similarity of the molecule are important in governing the potency variations in the insecticidal activity.

Three-Dimensional Structure-Activity Relationships of Synthetic Pyrethroids: 2. Three-Dimensional and Classical QSAR Studies

“…Series I±IV compounds used for the analyses are listed in Tables 1±4, respectively. The bioactive conformation of 3-phenoxybenzyl esters of Series II, III, and IV was established previously [5]. For the other substituted benzyl esters, the phenoxy group was replaced with the corresponding substituent each followed by the partial optimization for the substituent conformation using the AM1 molecular orbital calculation [7,8].…”

“…For the other substituted benzyl esters, the phenoxy group was replaced with the corresponding substituent each followed by the partial optimization for the substituent conformation using the AM1 molecular orbital calculation [7,8]. For Series I compounds, the partial optimization of the``decyanidated'' structure of (1R, 3S, 1 H S)-deltamethrin, the bioactive conformation of which was established previously [5], was carried out before the substituent optimization. The 3D coordinates of compounds were calculated according to these bioactive conformations.…”

“…For these compounds, the coordinates were de®ned by the partial optimization after replacing substituents of related reference compounds [5]. Scheme 1.…”

“…The reference compound in Series V was that in Series II. The coordinates of (1R, 3S)-cis-kadethrates(V:X OPh) were established previously [5].…”

“…For the 3D-QSAR study, the most logical as well as probable procedure for the 3D superimposition among various series of pyrethroids is of necessity. Thus, in the preceding paper [5] of this project, we carried out detailed conformational analyses to identify the``bioactive'' conformation of various series of pyrethroids. The bioactive conformation, de®ned as the most``plausible'' conformation under conditions bound with their``common receptor'', was selected from among energetically stable conformations and further optimized by the 3D¯exible superimposition procedure accompanied with modi®cations of the originally selected conformation.…”