Isobutylamides

In addition to chemotype patterning revealed by statistical analysis of the data, latitudinal relationships emerged as well. Concentrations of cichoric acid and echinacoside and one of the amides, undeca-2Z,4Z-diene-8,10-diynoic acid 2-methylbutyl amide [246], with a larger amine-bearing group increased with latitude. The inverse relationship was observed for caftaric acid and hexadeca-2 , 9Z-diene-12,14-diynoic acid isobutylamide. The latitudinal differences may be of importance in helping to identify populations for selection of seed for propagation. 

Insecticidal and MoUuscicidal Activities of Isobutylamides Isolated from Fagara macrophylbi and Their Synthetic Analogs... 

Five isobutylamides were isolated as insect growth inhibitors and toxicants from Fagara macrophylla and identified from their spectroscopic and chemical data. Synthesis and bioassay of the five natural products plus four analogs showed pellitorine to be the most active against a variety of insects, but not against a species of snail. 

Biologically active isobutylamides have been isolated from plants of the Compositae and the Rutaceae. Some of the isohutyla-mides were found to have paralytic and toxic activities against insects, especially when applied topically to several species of Coleopterans and Dipterans.The present work describes the isolation, spectral identification, synthesis, and insect and snail bioassays of five isobutylamides from the Rutaceae plant, Fagara macrophylla. In addition, the synthesis and bioassay of four analogs of the isbbutylamide natural products are described. 

Four isobutylamide analogs of the natural products were synthesized in order to compare their insecticidal efficacy with that of the natural products. The synthetic scheme for the preparation of cis-fagaramide ( ) is shown in Figure 1. The syntheses of the cis (9) and trans (8) isomers of N -isobutyl-cinnamamide were accomplished by procedures similar to those utilized in the preparation of the cis (7) and trans (1 ) isomers of fagaramide, with the exception that benzaldehyde was used as starting material in the former case, piperonal in the latter. Isobutylbenzamide (10) was synthesized from benzoyl chloride and isobutylamine. 

Table I shows the growth inhibitory activity of the four synthetic isobutylamides on the four lepidopterous larvae. The activity of the synthetic cis isomer (7) of fagaramide (J ) was 2- to 4-fold greater, depending on the insect species tested, than was fagaramide itself. Bioassay of synthetic amides identi-...

Thus, the most potent of the natural isobutylamides was pellitorine (4), while the most potent of the synthetic isobutylamides was the cis isomer il) of fagaramide (J ). 

Through a comparison of the activities of the nine natural and synthetic compounds in Table I, certain functionalities appeared to be important in the efficacy of the isobutylamides to inhibit the growth of the lepidopterous larvae. These functionalities included the chain length, presence of the methylenedioxy moiety, the number of the side chain double bonds, and the stereochemistry of the side chain. Combinations of these functionalities would likely enhance the activity. For instance, Miyakado et al.H found that addition of the methylenedioxy moiety to pellitorine (4) increased its toxicity when topically applied to adults of the beetle, Callosobruchus chinensis. 

Previous work with extracts of various plant species containing isobutylamide compounds indicated the larvicidal effects of the extracts against several species of mosquito.Other work has shown the molluscicidal activity of some unsaturated aliphatic isobutylamides against Physa occidentalis. 

Therefore, we conducted additional bioassays of four of the F. macrophylla isobutylamides with the house mosquito, Culex pipiens and the freshwater snail, Biomphalaria glabratus (Tables II, III). Both species are of medical importance. 

The lethal activity of the isobutylamides on C. pipiens is shown in Table II. The amides were dissolved in 0.1% acetone in distilled water to give concentrations of 1-20 ppm. Third-instar C. pipiens were transferred (5 larvae/10 ml test solution) into 1 oz. plastic cups using a 1 x 1-inch circle of ordinary window screen. Each treatment was replicated 4 times and the minimum concentration of each compound which caused 100% mortality (LDioo) within 48 h at 25 C and 16L/8D photoperiod was determined. In a result similar to that found with the artificial diet bioassay with lepidopterous larvae, pellitorine proved to be the most toxic of the assayed amides (LDjqq = 5 ppm). 

The lethal activity of the isobutylamides on B. glabratus is shown in Table III. Molluscicidal activity was monitored as described previously.Briefly, snails of uniform sizes (average diameter of the shell 9 mm) were placed 2 snails/ concentration into deionized water solutions containing known concentrations of the isobutylamides. Unlike the relative activities of the isobutylamides on the tested insect species, fagaramide (1 ) and N-isobutyl-2E,4E -octadienamide ( ) were more potent molluscicides than were pellitorine (4) or piperlongumine (2). 

The mode of action of the isobutylamides is unknown, although Miyakado et al. found that several isobutylamides (i.e. pipercide and related compounds) caused repetitive discharge when the nerve cord of the cockroach, Periplaneta americana was stimulated. We found that fagaramide was inactive as an acetylcholine esterase inhibitor in an m vitro assay(unpublished dat a). 

While the F. macrophylla isobutylamides, especially pellitorine, are active against several species of pest organisms of medical and agricultural importance, their activity must be enhanced before they can be used on a commercial basis. Hopefully, the results of the present work will direct future studies leading to synthetic isobutylamides of sufficient activity to warrant their practical use in insect and snail control. 

Table III. Lethal activity in ppm) of natural isobutylamides against the snail Biomphalaria glabratus. ...

McFerren MA, CordovaD, Rodriguez E, Ranh JJ, In fitroneuropharmacological evaluation of piperovatine, an isobutylamide from Piperpiscatorum (Piperaceae), JEthnopharmacol9>i-2P) —2Ql, 2002. 

There was some interest in the isobutylamides derived from various plant species including affinin (Figure 3.25) from Heliopsis longipes and pipercide (Figure 3.25) from Piper nigrum. These compounds are potent voltage-dependent blockers of the sodium channel but are too unstable to be used as products directly. 

The two sulfur-containing amides entadamides A (93) and B (94) have been isolated from the seeds and entadimides A and C (95) from the leaves of Entada phaseoloides Merr. (valid name Entada rheedii Spreng.) (Legu-minosae) (99-101). The known isobutylamide alkaloid pellitorine (N-isobutyl-2 ,4 -decadienamide) is found in the aerial parts of Piper ri-besoides Wall. (102). Pellitorine has also been isolated from the fruits of P. 

On tasting the narrow, horizontal segments of the area from the start to the solvent front in many thin—layer separations of pepper extracts, we have noticed that there is a component always coming above the piperine spot which has a tingling sensation on the tongue. This substance has not been identified, but could consist of isobutylamide-like compounds reported from other Piper species by Atal t al (38). 

Bauer and Remiger (1989) reported that the tetraenoic alkamides content was 0.04-0.39 mg/g root of E. purpurea and 0.09-1.51 mg/g root of E. angustifolia. The aerial parts had less than 0.01-0.3 mg/g of these alkamides in samples obtained from the United States and Europe. Rogers et al. (1998) found similar levels of tetraenoic alkamides in Australian-grown E. purpurea and E. angustifolia. Perry et al. (1997) observed that the tetraenoic alkamides accounted for 27% of the alkamides in the roots, 71% in the rhizome and 74% in the vegetative stem. These three parts are often harvested as a root and thus collectively the root system accounted for 84% of the total tetraenoic alkamides in the E. purpurea plant tissue. In the aerial parts of the plant, 64% of tetraenoic alkamides were found in the flower, and 31 and 5% were found in the reproductive stem and leaves, respectively. In E. purpurea, the tetraenoic alkamides accounted for 45 and 76% of the alkamides from the roots and aerial parts, respectively (Wills and Stuart, 1999). Additional research showed that the tetraenoic alkamides dodeca-2 , 4E, 8Z, lOZ-tetraenoic acid isobutylamide and... 

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