The research of synthesis and bioactivity of the novel indanedione anticoagulant rodenticides.

Three new anticoagulant rodenticides R1, R2, and R3 were designed. The containing fluorine acute toxicity groups was added to 1,3-indandione derivative. Analysis method of synthesized anticoagulant rodenticides were IR, 1H NMR. Acute bioactivity of the new rodenticides was evaluated, including the coefficient of absorb food and median lethal dose (LD50). Average coefficient of absorbed food for R1 was 0.54 and LD50 of R1 was 2.15 mg/kg. Average coefficient of absorbed food for R2 was 0.59 and the acute oral LD50 of R2 was 2.65 mg/kg. Average feeding coefficient of R3 was 0.68 and the acute oral LD50 of R3 was 3.12 mg/kg. Experiments showed that rat's death peak was at about 72 h and rodenticides had good characteristics of acute medicine. The LD50 of three new fluoride anticoagulant rodenticides showed that they had good palatability for big white rats, and they had a strong poison effect on rodent. The result of all experiments proved that the synthesis of 1,3-indan diketone used as parent compound of new anticoagulant rodenticides could replace the current 4-hydroxyl coumarin as parent compound of the second-generation anticoagulant rodenticides. 1,3-Indan diketone would be widely used as parent compound of anticoagulant rodenticides.

Synthesis and methemoglobinemia-inducing properties of benzocaine isosteres designed as humane rodenticides.

A number of isosteres (oxadiazoles, thiadiazoles, tetrazoles and diazines) of benzocaine were prepared and evaluated for their capacity to induce methemoglobinemia-with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed within each series, with 1,2,4-oxadiazole 3 (metHb%=61.0±3.6) and 1,3,4-oxadiazole 10 (metHb%=52.4±0.9) demonstrating the greatest activity. Of the 5 candidates (compounds 3, 10, 11, 13 and 23) evaluated in vivo, failure to induce a lethal end-point at doses of 120mg/kg was observed in all cases. Inadequate metabolic stability, particularly towards hepatic enzymes such as the CYPs, was postulated as one reason for their failure.

Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenone designed as humane rodenticides.

A number of structural analogues of the known toxicant para-aminopropiophenone (PAPP) have been prepared and evaluated for their capacity to induce methemoglobinemia--with a view to their possible application as humane pest control agents. It was found that an optimal lipophilicity for the formation of methemoglobin (metHb) in vitro existed for alkyl analogues of PAPP (aminophenones 1-20; compound 6 metHb% = 74.1 ± 2). Besides lipophilicity, this structural sub-class suggested there were certain structural requirements for activity, with both branched (10-16) and cyclic (17-20) alkyl analogues exhibiting inferior in vitro metHb induction. Of the four candidates (compounds 4, 6, 13 and 23) evaluated in vivo, 4 exhibited the greatest toxicity. In parallel, aminophenone bioisosteres, including oximes 30-32, sulfoxide 33, sulfone 34 and sulfonamides 35-36, were found to be inferior metHb inducers to lead ketone 4. Closer examination of Hammett substituent constants suggests that a particular combination of the field and resonance parameters may be significant with respect to the redox mechanisms behind PAPPs metHb toxicity.

[Warfarin - its synthesis and properties in a twenty-year retrospective*]. / Warfarín - jeho syntéza a vlastnosti v dvadsatrocnej retrospektíve*

The review paper deals with some aspects of warfarin history and its use, at the beginning as a rodenticide and later as an anticoagulant. It describes its principal physical-chemical properties and it analyzes schematically the possibilities of its preparation by both selective and non-selective synthesis from coumarin derivatives. A survey of syntheses and its results are tabulated, including the literary references, and the paper is concluded with an evaluation of the prospects of this agent in comparison with alternative anticoagulants and its advantages, disadvantages and prospects.

Design and synthesis of prodrugs of the rat selective toxicant norbormide.

Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either its unpleasant 'taste' or rapid onset of effects. A series of NRB prodrugs were prepared in an effort to 'mask' this acute response. Their synthesis and biological evaluation (in vitro vasoconstrictory activity, in vitro hydrolytic and enzymatic stability and lethality/palatability in vivo) is described. Compound 19 displayed the most promising profile with respect to a delay in the onset of symptoms and was subsequently demonstrated to be significantly more palatable to rats.

Synthesis and insecticidal activity of new 4-hydroxy-2H-1-benzopyran-2-one derivatives.

Several stable and storable anticoagulant rodenticides involving both merits of acute and chronic rodenticides have been synthesized (Holbrook et al. in Arch Intern Med 165:1095-1106, 2005; Baglin et al. in Br J Haematol 132:277-285, 2006). The structures of synthesized compounds were confirmed by IR, (1)H NMR. The compounds were also evaluated for their anticoagulant and acute biologic activity (Lipton et al., JAMA 252:3004-3005, 3).

Synthesis, lipophilicity study and in vitro evaluation of some rodenticides as acetylcholinesterase reversible inhibitors.

The anti-AChE activity of phosphoramidates has been noticed for many years. Because of the wide application of phosphoramidates in recent years, there has been a continuing research for synthesis, purification and identification of effective and safe derivatives. In this study some rodenticides with the general formula Me(2)NP(O)(p-OC(6)H(4)-X)(2), where X = H, CH(3), Cl, have been synthesized in water (without organic solvent) and characterized by (31)P, (31)P {(1)H}, (13)C and (1)H NMR spectroscopy. Since lipophilicity has been recognized for its importance in QSAR studies, efforts have been made to determine the logP values. The ability of these rodenticides to inhibit human acetylcholinesterase (hAChE) has been predicted with PASS (Prediction of Activity Spectra for Substances) software (version 1.917) and then has been evaluated by a modified Ellman's assay and spectrophotometric measurements.

Synthesis and activity studies of analogues of the rat selective toxicant norbormide.

Norbormide [5-(alpha-hydroxy-alpha-2-pyridylbenzyl)-7-(alpha-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB, 1), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. A series of NRB-related analogues were prepared to investigate the structural features responsible for, and the in vitro biological markers indicative of, in vivo lethality of the parent molecule in rats. Their synthesis and biological evaluation (vasoconstriction, vasodilation, mitochondrial dysfunction, cardiotoxicity and lethality) is described.

Synthesis, characterization and thermal studies of 2-oxo-1,3,5-trinitro-1,3,5-triazacyclohexane (Keto-RDX or K-6).

2-Oxo-1,3,5-trinitro-1,3,5-triazacyclohexane (Keto-RDX or K-6), the most powerful energetic material among nitrourea explosives, has been prepared and scaled up at laboratory level. The identity and purity of the product are tested by elemental analysis, IR, NMR, mass and HPLC techniques. Thermal response and sensitivity experiments on K-6 are also described. The data on sensitivity shows that K-6 can be utilised practically only in phlegmatized form.