Isobutylamides activities

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. 

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-...

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. 

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). 

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. ...

The insecticidally active natural isobutylamides, such as dehydropipercide (60), and their synthons have been synthesized by Pd-catalyzed coupling reactions. For example, the aryl iodide (58) can couple in the dark with the alkynic amide (59) in the presence of a Pd-Cul catalyst in triethylamine to give dehydropipercide (60). 

Some of the plants belonging to the families Compositae and Rutaceae contain the insecticidally active isobutylamides of unsaturated, straight-chain acids with... 

Piperovatine (21) is a crystalline isobutylamide first isolated from the leaves [24], roots and stems [25] of the shrub Ottonia vahlii (syn Piper ovatum) native to the West Indies and from Piper callosum [26], and exibits mild insecticidal and local anaesthetic activity [27]. The piperide trienamide (22) and the dienamide (9) have been isolated from Otanthus maritima [28]. 

The insecticidal activity of aliphatic amides such as pellitorine, 5, is limited, at least in part, by their instability [81]. The presence of an aromatic ring at the distal end of a dienoic acid isobutylamide of suitable chain length, as in dihydropipercide, confers increased stability and enhanced insect toxicity. Structure-activity studies by Miyakado et al. [81,82,127] based on the aromatic amide dihydropipercide as lead compound and with C. chinensis males as the test insects, led to the following general conclusions ... 

Because commercial drug preparations involving the roots of Echinacea purpurea (Asteraceae) were frequently adulterated with the roots of Par-thenium integrifolium, a reexamination of this source of insecticidal and immunostimulatory active material has been carried out. Five new alk-amides have been isolated, and their structures were determined as undec-2 ,4Z-dien-8,10-diynoic acid isobutylamide (114), dodeca-2 ,4Z-dien-8,10-diynoic acid isobutylamide (115), dodeca-2 ,4 ,10 -trien-8-ynoic acid isobutylamide (116), dodeca-2 ,4 ,8Z-trienoic acid isobutylamide (117), and dodeca-2 , 4Z-dien-8,10-diynoic acid 2-methylbutylamide (118) by MS, IR, and NMR spectroscopic techniques (96). (See Fig. 11.)... 

Five known isobutylamides, namely fagaramide, piperlongumine, 4,5-dihydropiperlongumine, pellitorine, and (2 ,4 )-A-isobutylocta-2,4-dienamide, were isolated as the molluscidal and insecticidal active principles from Fagara macrophylla (Rutaceae) (112). 

Isobutylamides are a subclass of alkamides based on the amine group 2-methylpropyl. They first aroused the interest of researchers for their insecticidal activities, being toxic to numerous classes of insects including the ubiquitous housefly and mosquito. Upon further investigation, it was obvious the most active insecticidal compounds were the ones that produced the most potent sialagogue (stimulating saliva flow) effects in humans (Brinker 1991/92). Isobutylamides so far investigated are derived from four plant families—Asteracea, Rutaceae, Piperaceae and Aristolochiaceae (see Table 8.3). 

Brinker, F. 1991/92, The insecticidal and therapeutic activity of natural isobutylamides , British Journal of Phytotherapy 2 160-168. 

Alkamides also displayed marked inhibitory activity in vitro in the 5-lipoxygenase (porcine leukocytes) and cyclooxygenase (microsomes from ram seminal vesicles) assays. Dodeca-2 ,4 ,8Z,10 /Z-tetraenoic acid isobutylamides inhibited cyclooxygenase-1 at a concentration of 50 p g/ml by 54.7% and 5-lipoxygenase at a concentration of 50 liM by 62.2% [56]. 

Kubo I, Matsumoto T, Klocke J A, Kamikawa T 1984 Molluscicidal and insecticidal activities of isobutylamides isolated from Fagara macrophylla. Experientia 40 340-341... 

Multiple activities have been observed for extracts of Zanthoxylum xanthoxyhides, a widely used medicinal plant. The principal active compounds are the isobutylamides pellitorine (IV) and fagaramide (V), which display termite and lepidopteran feeding deterrent activities. The insecticide activity of isobutylamides isolated from various plant families, has been previously investigated (11) and their level of activity has warranted patent applications. We have demonstrated also that these compoxmds may act as feeding deterrents in addition to their toxicity properties. 

Cannabinomimetic activity. The echinacea alkamides dodeca-2 , 4 , 8Z,10Z-tetraenoic acid isobutylamide and dodeca-2 , 4 -dienoic acid isobutylamide bind more strongly to the human CB2 cannabinoid receptor (Zj 60 uM) than the endogenous cannabinoid anandamide (A i > 200 run). The CB2 binding resulted in inhibition of LPS-induced inflammation in human whole blood." An earlier study with rodent cannabinoid receptors (CBl and CB2) also showed that alkamides from E. angusti-folia roots displayed selective CB2 binding. ... 

Unsaturated Amides. In 1971, a group of pungent compounds (isobutylamides) obtained from members of the families Compositae and Rutaceae were described by Jacobsen (Jacobsen, 1971) to have limited use as insecticides. The compounds were characterized as unstable with a marked tendency to polymerize. Examination of extracts of the fruit of the black pepper Piper nigrum, using the aduzki bean weevil as a bioassay, resulted in the isolation of three isobutylamides (13-15) which displayed insecticidal activity (when combined equimolarly) to the pyrethrins (Miyakado et al., 1983, 1989). Based upon the observations of Miyakado and earlier reported test results for synthetic analogs of the compounds described by Jacobsen, Elliot and co-workers defined a basic amide structure to... 

Since the work of Elliott and Miyakado, several synthetic analogs of the insecticidal isobutylamides have been synthesized (Addor, 1995). Increased information about struc-ture/activity relationships among these compounds has been compiled with some synthetic analogs displaying higher insecticidal activity than the pyrethrins. However, none of the analogs have provided the necessary combination of potency, breadth of action and stability to warrant commercialization. 

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