Synthesis, crystal structure and larvicidal activity of novel diamide derivatives against Culex pipiens
© Wu et al.; licensee Chemistry Central Ltd. 2012
Received: 11 July 2012
Accepted: 28 August 2012
Published: 11 September 2012
Culex is an important mosquito as vectors for the transmission of serious diseases, such as filariasis, West Nile virus, dengue, yellow fever, chikungunya and other encephalitides. Nearly one billion people in the developing countries are at risk. In order to discover new bioactive molecules and pesticides acting on mosquito, we designed active amide structure and synthesized a series of novel diamide derivatives.
A series of novel diamide derivatives were designed and synthesized. Their structures were characterized by 1 H NMR, FTIR and HRMS. The single crystal structure of compound 6n was determined to further elucidate the structure. Biological activities of these compounds were tested. Most of them exhibited higher mosquito larvicidal activity. Especially compound 6r displayed relatively good activity to reach 70% at 2 μg/mL.
A practical synthetic route to amide derivatives by the reaction of amide with another acid is presented. This study suggests that the diamide derivatives exhibited good effective against mosquito.
Culex is an important mosquito as vectors for the transmission of serious diseases [1, 2], such as filariasis, West Nile virus, dengue, yellow fever, chikungunya and other encephalitides. Lymphatic filariasis, which may be caused by different species of filarial worm, e.g., Wuchereria bancrofti, has a scattered distribution in the tropics and subtropics . Nearly one billion people in the developing countries are at risk. Culex pipiens L. is the most commonly occurring mosquito pest in urban and suburban areas , which is mainly the intermediate host and vector of Bancroftian filariasis.
According to World Health Organisation (WHO), the one of strategies is to destroy their vectors or intermediate hosts. The best method is control of mosquito larvae using insecticides [5–7], such as organo-phosphates, natural products and heterocycles types. It is an urgent need to develop new insecticides which are more environmentally safe and also biodegradable and target specific against mosquitoes.
Amide derivatives have become one of the focuses in the development of pesticides because of their high biological activities, such as fungicidal activities [8–11], herbicidal activities [12–15], insecticidal activities [16, 17], anticancer activity [18, 19], antibacterial activity  and so on. In line with our continueous efforts to synthesize bioactive lead compounds, the title compounds were designed by introducing amide pharmacophore into the valine scaffold. Thus, guaiacol was used as start materials, 22 novel diamides were synthesized. All the compounds were unequivocally characterized by NMR, IR, HRMS. The single crystal structure of compound 6n was determined to further elucidate the structure. The biological activities of title compounds against Culex pipiens were determined, the results showed that most of the synthesized compounds exhibited antibacterial activity against Culex pipiens, compounds 6n showed good activity against Culex pipiens at 2 μg/mL.
Results and discussion
Synthesis and spectra
The structures of all new compounds were confirmed by their spectra (1 H NMR and FTIR) data. Additional file shows the structures, yields and HRMS data for title compounds in more detail [see Additional file 2]. The proton magnetic resonance spectra of the amides have been recorded in CDCl3. The COOH of amide intermediates 4 is not determined. All the title compounds of HRMS are M + H, or M + Na peak.
Larvicidal activity against mosquito
Larvicidal activity against Mosquito of title compounds at 5 μg/mL
Death rate (%)
Death rate (%)
Melting points were determined by an X-4 apparatus and uncorrected. 1 H NMR spectra were measured on a Bruker AV-400 instrument using TMS as an internal standard and DMSO-d6 as the solvent. HRMS data was obtained on a FTICR-MS instrument (Ionspec 7.0 T). Crystallographic data of the compound were collected on a rigaku saturn diffractometer. Microwave activation was carried out with CEM Discover™ focused microwave (2450 MHz, 300 W). All the reagents are of analytical grade or freshly prepared before use. The course of the reactions was monitored by TLC; analytical TLC was performed on silica gel GF 254. Intermediates 2, 3, 4 and 5 were prepared according to the reported methods [21–29] and used without further purifications, the process for preparing of them can be found in Additional file 2.
The crystal of compound 6n with dimensions of 0.20 mm × 0.18 mm × 0.14 mm was mounted on a Rigaku Saturn CCD area-detector diffractometer with a graphite-monochromated MoKα radiation (λ = 0.71073 Å) by using a phi and scan modes at 293(2) K in the range of 2.55° ≤ θ ≤ 27.85°. The crystal belongs to Triclinic system with space group P-1 and crystal parameters of a = 9.4583(19) Å, b = 10.494(2) Å, c = 11.545(2) Å, α = 70.49(3)°, β = 73.27(3)°, γ = 64.00(3)°, V = 957.2(3)A3,Dc = 1.245 g/cm3. The absorption coefficient μ = 0.0815 mm-1 and Z = 2. The structure was solved by direct methods with SHELXS-97 and refined by the full-matrix least squares method on F2 data using SHELXL-97 . The empirical absorption corrections were applied to all intensity data. H atom of N-H was initially located in a difference Fourier map and were refined with the restraint Uiso(H) = 1.2Ueq(N). Other H atoms were positioned geometrically and refined using a riding model, with d(C---H) = 0.93-0.97 Å and Uiso(H) = 1.2Ueq(C) or 1.5Ueq(Cmethyl). The final full-matrix least squares refinement gave R = 0.0476 and wR 2 = 0.0971.
Larvicidal activity against mosquito
where the Al (%) is the mortality in treatment group, and the A2 (%) is the mortality in control group.
In summary, a novel series of diamide derivatives were designed and synthesized. The synthesized compounds were characterized by spectral data (1 H NMR) and HRMS (ESI). All of the compounds were subjected to larvicidal activity against mosquito. The results indicated that the synthesized compounds possessed good larvicidal activity against mosquito. Further studies are currently underway to optimize to enhance the larvicidal activity of the diamide derivatives.
We are grateful to the financial support for this work from the National Natural Science Foundation of China (21172124), the National Basic Research Science Foundation of China (2010CB126105) for financial support of this research and the National Key Technologies R&D Program (2011BAE06B05).
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