Heterocyclic Insecticides Acting at the GABA-Gated Chloride Channel: 5-Alkyl-2-arylpyrimidines and -1,3-thiazines

Abstract

5-tert-Butyl-2-(4-ethynylphenyI)pyrimidine and the corresponding 2,5-disubstituted-4H-1,3-thiazine block the GABA-gated chloride channel at c.20 and c.200 nM, respectively, measured as 50% inhibition of the binding of 1-(4-ethynylphenyl)-4-[3H]propyl-2,6,7-trioxabicyclo[2.2.2]octane (4-ethynyl-4-n-[3H]propylbicycloorthobenzoate; C3H]EB0B) in house fly and mouse brain membranes, and they are also toxic to topically-treated flies with LD,, values of 6-27 pg g-' alone and 2-6 pg g-' with piperonyl butoxide (PB) as synergist. In the pyrimidine series, the general pattern of effectiveness of substituents in the 5-position is tert-butyl > isopropyl z cyclohexyl z cyclopropyl > methyl, phenyl and 3-and 4-fluorophenyl, and in the 2-position is 4-ethynylphenyl % 4-bromophenyl. These planar pyrimidines and nearly-planar 4H-1,3-thiazines with 2-ethynylphenyl or 2-bromophenyl and 5-tert-butyl or 5-isopropyl substituents are more effective than the corresponding 6H-1,3-thiazine, 6-oxo-1,3-thiazines and 4,6-dioxo-1,3-thiazine examined, but they are less active than the analogous conformationally flexible trans-1,3-dioxanes and -1,3-dithianes. The heterocyclic moiety confers a region of high electron density and positions the 2-and 5-substituents in a linear or parallel relationship for optimal affinity at the receptor. Two observations indicate that the new pyrimidines and thiazines probably act as chloride channel blockers. First, the poisoning signs are identical to those of EBOB in both mice and house flies. Second, each of the pyrimidines, thiazines and dioxanes falls on the same correlation line for inhibition of C3H]EBOB binding and toxicity to house flies (with PB) as that obtained earlier for EBOB analogs, dithianes and polychlorocycloalkanes, suggesting that they all act at the same or closely coupled binding sites in the GABA-gated chloride channel.

Interactions with the Gamma-Aminobutyric Acid A-Receptor

“…A 4ethynylphenyl-substituent in the 2-position of 5-t-butyl-1, 3-dioxane (7, Figure 96.10) or 1,3-dithiane (8, Figure 96.10) was found to be more effective than a 4-bromophenylsubstituent; the trans-(linear) ethynylphenyl dithiane (8) was somewhat more toxic to houseflies than the analogous trans-dioxane (7) and cis-(angular) isomers were generally equally toxic to or less toxic than trans-isomers (Palmer and Casida, 1995;Pulman et al, 1996). With the possibility of oxidation at sulfur in vivo, which may enforce additional conformational rigidity and also increase binding propensity, the situation becomes more complex (see Section 96.4.3).…”

“…With the possibility of oxidation at sulfur in vivo, which may enforce additional conformational rigidity and also increase binding propensity, the situation becomes more complex (see Section 96.4.3). (Brooks and Mace, 1987;Ozoe et al, 1990Ozoe et al, , 1993, the trioxabicyclooctane-derived cage convulsants, and the more recent dioxans and dithianes (Pulman et al, 1996). The bracketed number following a chemical number or structure is the housefly topical LD 50 (g/g; measured in the presence of sesoxane or piperonyl butoxide).…”

“…Recently, arylpyrazoles, such as fipronil (27, Figure 96.11), and various 5-alkyl-2-arylpyrimidines (28) and 1,3thiazines (29) (Pulman et al, 1996), in which the planar heterocyclic ring replaces the spacers formed by the TBO and 1,3-dioxane and dithiane structures, have been added to the list of chloride ionophore blockers. Insecticidal activity was also found in triazoles (30, 31) (Boddy et al, 1996;Von Keyserlingk and Willis, 1992) and pyrimidinones (32) (Whittle et al, 1995) and a spirosultam (33) (Bloomquist et al, 1993), demonstrating the diversity of structures that probably act at this site.…”

“…All of the molecules discussed can be superimposed, and with the cyclodiene molecules oriented in this way, the sulfite moiety of beta-endosulfan (and the SO 2 of endosulfan sulfate) lies in the region occupied by the aromatic ring of the angular dithiane isomer. It should be noted, however, that the possibility of cis-to trans-rearrangement exists for the dithianes in vivo (Pulman et al, 1996), in which case, the cis-isomers would merely be precursors of the linear (trans-) molecules, which are more readily accommodated in the model. Among the heterocyclic compounds of recent interest that are believed to act by blocking the GABA-gated chloride ionophore, the experimental spirosultam LY 219048 (33, Figure 96.11) contains an obvious lipophilic bulky substituent in the form of the cyclohexane ring, in analogy with the compounds discussed previously.…”

Synthesis and In Vitro Antimicrobial, Anthelmintic and Insecticidal Activities Study of 4(4′‐Bromophenyl)‐6‐substituted‐aryl‐1‐acetyl pyrimidine‐2‐thiols

“…The earlier workers reported that, pyrimidine derivatives are associated with a wide spectrum of biological activities viz. antimicrobial [1][2][3][4] , anthelmintic [5][6][7] , anticancer [8][9] , antitumer 10 , anti-inflammatory [11][12] , anti-HIV agents 13 , calcium-channel-blocker 14 and insecticidal agents 15 and this significance led us to synthesize the titled compounds.…”