| Budget Amount *help |
¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2005: ¥900,000 (Direct Cost: ¥900,000)
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| Research Abstract |
1. The preparation of a possible prodrug, 1-chloronicotinyl-2-nitroimino-1,3-diamonocyclohexane-5-one or its 2-nitromethylene derivative, by oxidation of its 5-hydroxy precursors or hydrolysis of its acetals failed. The sparing solubility in solvents of the starting substances and the presumable fragile properties of the products under the reaction conditions, even if formed, may be responsible for the failure.
2. N-(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl derivatives of imidacloprid and 1-chlorothiazolylmethyl-2-nitroimino-imidazolidine were prepared. These compounds showed typical prodrug properties in the half-lives in a physiological salt solution and the time-course profiles for insecticidal tests and putch-clump nerve electrophysiological measurements. This is the practically the first prodrug of the top-selling insecticide worldwide.
3. In the effort to exploit a suitable masking site of imidacloprid the substitution at the fifth position at the pyridine ring has become a seminal s
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trategy. In addition to a possible proinsecticide by the substitution new compounds with different insecticidal profiles from those of the parent molecules are expected. We prepared a series of twenty-one substituted imidacloprid and pursued the quantitative structure activity relationships for the insecticidal tests and nerve blocking potencies. The experiment showed that the lipophilic small-sized substituent at this possition is a good activator.
4. Compound of 3-(3-fluoropropyl)-imidacloprid was prepared. This compound showed highly insecticidal activity. We are suspecting that the activity appears as the metabolic decomposition of the fluoropropyl group. Besides, we are discussing the possible hydrogen-bond acceptor of the fluorine atom.
5. We have examined the pharmacophore of the neonicotinoid in order to exploit a effective prodrug candidate. In this project we have focused on the 2-nitroimino or 2-nitromethyle imidazolidine moiety of imidacloprid or analogous neonicotinoid molecules. By studying a structure activity relationship of seventeen variants of this moiety through insecticidal test and the nerve blocking potency measurement we derived a significant equation, which tells that the biological potency is proportional both to the magnitudes of the Mulliken charge on the nitro oxygen atom and the partition coefficient Pow. Less
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