Synthesis and activity of amide derivatives of piperine
3
3
RESULTS AND DISCUSSION
.1 Synthesis
mortality caused by the other three (5a, 5e and 2)
varied from 40.0 to 45.0%.
Piperine (1), obtained from extraction of dried seeds of
Piper nigrum, was converted into the acid (3) with 85%
yield by means of hydrolysis using LiOH/EtOH. An
initial attempt to convert the acid (3) into the amide
Extracts of P nigrum have been shown to be active,
by ingestion, against several stored grain insects,
1±4,8
including A obtectus
In the present study only ®ve
compounds (1, 5d, 5l, 5m and 5o) were active against
this insect, and the mortality varied from 25.0 to
30.0%. This low activity could, in part, be due to the
(
5) was carried out using thionyl chloride followed by
20
the appropriate amine, but the yields of the products
were very low, and partial decomposition of the
starting material was observed. The use of Ph P/
�
1
lower dose applied (2.6mgmg insect).
B brassicae was sensitive to 13 amides, with
mortalities ranging from 52.5 to 92.5%. The most
active amides in this case were 5a, 5g, 5i, 5o and 2 that
caused mortality ranging from 75.0 to 92.5%. The
natural amide piperine (1) was not active against this
insect.
3
21
CCl4 to convert the amide (1) into the acid chloride
4), followed by addition of an amine, resulted in the
amides with low yield (<20%). Another drawback
(
with this methodology was the formation of large
amount of Ph P=O that caused some dif®culties in
3
the isolation of the required amides.
A methodology involving the use of oxalyl chloride
The most active compound against C cumulans was
5d (42.5% mortality), and three other compounds
(5b, 5m and 2) were also toxic, causing 22.5 to 27.5%
mortality. In this case also, the low toxicity could be
22
was successfully applied for the preparation of the
chloride (4). This chloride was then converted into 16
amides as shown in Fig. 2. For the preparation of
amides 5a±k, 2 equivalents of the amines were used. In
all other cases, as the amines were very expensive and
available in small amounts, only 1 equivalent was used,
along with 2 equivalents of triethylamine to neutralize
the HCl formed.
�
1
due to the lower dose (1.1mgmg insect) used.
For the Vespidae P exigua, the compounds 5e, 5j, 5l
and 5o presented low toxicity, with mortalities ranging
from 25.6% to 33.2%. The most toxic compound was
5d (45.0% mortality). It was also observed that amides
5b and 5d had some selectivity for P exigua, a predator
for the Lepidoptera A monuste orseis. These com-
pounds were respectively 12.7 and 2.1 times more
toxic to A monuste orseis than P exigua.
All amides prepared were characterized from their
1
spectroscopic and physical data (IR, [ H]NMR, MS
and C,H,N analysis).
To the best of our knowledge and according to the
Although several reports have shown that the most
active piperamides are those N-isobutyl substi-
literature investigated, only the amides 5a, 5b, 5d±f,
5
7
h and 5k have been prepared previously. Even in
12,16,23
tuted,
in the present study this was not
these cases no spectroscopic data were given, so we
present full data for all compounds.
observed. Compound 5f (N-isobutylpiperamide) was
active only against B brassicae, a species sensitive to
most amides tested.
From the results obtained (Table 1), no clear
correlation between structure and activity was ob-
served, but in the case of A monuste orseis the most
active amides were those N,N-disubstituted.
3
.2 Biological activity
The effects of the natural amides piperine (1) and
piperiline (2) and also several amides (5) prepared
from piperine (1) were evaluated against A monuste
orseis, A obtectus, B brassicae, C cumulans and P exigua.
The ®rst four are insect species of economic impor-
tance and the last one is a natural enemy of A monuste
ACKNOWLEDGEMENTS
The authors are grateful to the Brazilian Agencies:
Conselho Nacional de Desenvolvimento Cient Âõ ®co e
Tecnol o gico (CNPq), for research fellowships (LCAB
and DPV) and a DS studentship to VFP; and
Funda cË aÄ o de Amparo aÁ Pesquisa do Estado de Minas
Gerais (FAPEMIG) and CNPq/PADCT for ®nancial
support.
orseis and other insects. Although amides 5a, 5b, 5d±f,
5
7
h and 5k have been prepared previously, their effects
were evaluated only against the house¯y (Musca
domestica L). In this work, the aim was to evaluate
the contact toxicity of each compound, and ®nd out if
the structural modi®cation carried out on piperine
would result in a synthetic product more active than
the natural product. In order to avoid possible oral
intoxication, the insects were not supplied with food.
Preliminary experiments were set up to evaluate the
adequate exposure time.
REFERENCES
1
2
3
Scott WP and McKibben GH, Toxicity of black pepper extract to
boll weevils. J Econ Entomol. 71:343±344 (1978).
Su HCF, Insecticidal properties of black pepper to rice weevils
and cowpea weevils. J Econ Entomol 70:18±21 (1977).
The results of the contact bioassays are shown on
Table 1. The dose applied and the period of
incubation varied according to the species.
Su HCF and Horvat R, Isolation, identi®cation, and insecticidal
properties of Piper nigrum amides. J Agric Food Chem 29:115±
Of the 16 synthetic amides tested, only six were
active against A monuste orseis. The most toxic were 5b
(97.5%) and 5d (95.0%), which were comparable to
the reference piperine (1) (95% mortality). The
1
18 (1981).
4
Flores WL, Sampaio LSV, Marques OM and Costa JA, Efeito
dos extratos de pimenta do reino e cinamomo e do malation no
controle do caruncho Zabrotes subfasciatus (Boheman, 1833)
Pest Manag Sci 56:168±174 (2000)
171