Synthesis and Design

The discovery of the first nonsteroidal, insecticidal BAH (RH-5489)1 revealed a broad spectrum of activity against lepidopteran, coleopteran and dipteran insects. Extensive work with this new class of chemistry, which involved synthesis guided by structure-activity relationship (SAR) analysis of over 4000 BAH analogs, led to the discovery of the three insecticides selected for commercialization at R&H: tebufenozide, methoxyfenozide and halofenozide. The synthetic routes of these three insecticides and chromafenozide, discovered by Nippon Kayaku and Sankyo, are described by Dhadialla and Ross.5 The structures of 20E, the first BAH insecticidal prototype (RH-5489) and the first four commercial BAH insecticides are shown in Figure 6.1.

The activity bioassays used to characterize the performance of the BAH insecticides ranged from whole-insect toxicity to insect-cell-based and

Addition Worksheets
Figure 6.1 Chemical structures of the insect molting hormone (20E), the first BAH prototype (RH-5489) and the first four commercial BAH insecticides (tebufenozide, halofenozide, methoxyfenozide and chromafenozide).

competitive ecdysone receptor (EcR) ligand-binding radiometric assays.3,5 The SAR results indicated the importance of the core hydrazine structure with two phenyl-substituted rings outside the two negative centers and a bulky, conformation-influencing lipophilic group located asymmetrically between the two negative centers.

SAR studies conducted by Dinan and Hormann4 also indicated that six-membered aryl groups on either side of the two negative centers favored activity against lepidopteran and coleopteran insects. Activity on lepidopteran larvae could be further enhanced by modifying the substitutions on the A-ring at the 4 position with 1-2-carbon-containing lipophilic groups, or with 2,3- or 2,(3,4)-ring patterns. Substitutions on the B-ring were found to be less specific, though 2-, 2,5-, 3,5- or 3,4,5-positions were favorable.4 The main difference between the three BAH insecticides discovered at R&H and chromafenozide is that in chromafenozide, the A-ring is fused at the 3-4-positions with a six-membered oxygen and a carbon-containing heterocycle (see Figure 6.1).

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