Synthesis, Functional Assays, Electrophysiological Activity, and Field Tests of Pheromone Antagonists of the Tomato Leafminer, Tuta absoluta.

The tomato leafminer, Tuta absoluta, is one of the major pests of tomato and other Solanaceae in many regions worldwide. In the search for new strategies to control this pest, we present herewith the stereoselective synthesis, electrophysiological activity, functional analysis, and field tests of new chemicals as possible antagonists of the sex pheromone of the leafminer. The chemicals are methyl ketone (MK) and trifluoromethyl ketone (TFMK) structural analogues of both components of the pheromone. Most of the chemicals exerted per se some electrophysiological activity and inhibited the electroantennographic response to the pheromone when vapors of the inhibitor were passed over the antennae. Except TFMK 3, which elicited a modest effect, the compounds did not exhibit antiesterase activity on the pheromone-degrading enzymes of the antennae, but in the field the chemicals, particularly MK 5, notably decreased the number of catches when mixed with the pheromone in 1:1 and 10:1 ratios, regardless the infestation level of the plot. These results suggest that MK 5 is a good behavioral antagonist of the pheromone to be considered as a putative agent to control the pest in new future integrated pest management (IPM) strategies.

Electrophilic derivatives antagonise pheromone attraction in Cydia pomonella.

BACKGROUND: Pheromone antagonists are good disruptants of the pheromone communication in insects and, as such, have been used in mating disruption experiments. In this study, new non-fluorinated electrophilic keto derivatives structurally related to the pheromone of Cydia pomonella (codlemone) have been synthesised and tested as putative pheromone antagonists. RESULTS: Codlemone (1) was prepared in excellent stereoselectivity in a new, iterative approach involving two Horner-Wadsworth-Emmons reactions. Methyl ketone (2), keto ester (3) and diketone (4) were obtained from codlemone in straightforward approaches in good overall yields and excellent stereochemical purity (≥98% E,E). In electrophysiology, only compound 2 displayed inhibition of the antennal response to the pheromone after presaturation of the antennal receptors. Compounds 2 to 4 did not inhibit the pheromone-degrading enzyme responsible for codlemone metabolism, but mixtures of ketone 2 and diketone 4 with codlemone elicited erratic flights on males in a wind tunnel. In the field, blends of either compound (2 or 4) with the pheromone caught significantly fewer males than codlemone alone. CONCLUSION: Codlemone and the potential antagonists 2 to 4 have been synthesised in good yields and excellent stereoselectivity. These chemicals behave as pheromone antagonists of the codling moth both in the laboratory and in the field.

Enzymatic enantiomeric resolution of phenylethylamines structurally related to amphetamine.

Both enantiomers of several phenylethylamines, structurally related to amphetamine, have been prepared in good yields and excellent enantiomeric purity by enzymatic kinetic resolution using CAL-B and ethyl methoxyacetate as the acyl donor. In the case of the 4-hydroxyderivative of amphetamine (compound 4i), the S enantiomer racemized possibly in a dynamic kinetic resolution (DKR) under the enzymatic conditions used.

Synthesis of allylic trifluoromethyl ketones and their activity as inhibitors of the sex pheromone of the leopard moth, Zeuzera pyrina L. (Lepidoptera: Cossidae).

BACKGROUND: Trifluoromethyl ketones (TFMKs), structurally related to the pheromones, are good inhibitors of pheromone communication in insects. To determine their activity on Zeuzera pyrina L. (Lepidoptera: Cossidae), a polyphagous pest, the authors have prepared two diunsaturated TFMK analogues of the major (3) and the minor (4) pheromone components, and two monounsaturated ones (5, 6). Their biological activity in electroantennogram (EAG), wind tunnel and field tests is presented. RESULTS: The synthetic strategy to obtain the allylic TFMKs 3 and 5 is based on the reactions of diene 10 and 1-octadecene with trifluoroacetaldehyde ethyl hemiacetal, followed by Dess-Martin oxidation of the resulting homoallylic trifluoromethyl alcohols. In EAG, topical application of analogues 3 and 4 on male antennae significantly reduced the pheromone response. In the wind tunnel, compound 4 reduced the number of contacts with the pheromone source. In the field, traps baited with mixtures of pheromone and inhibitors captured significantly fewer males than the pheromone alone. CONCLUSION: An efficient synthesis of allylic TFMKs is reported, with good overall yield, regiospecificity and diastereoselectivity. These compounds are good inhibitors of the pheromone in electrophysiology, wind tunnel and field tests. The results show the importance of two unsaturations at positions 2 and 13 of the trifluoroacyl group in the structure of the analogues, the latter being critical for inhibitory activity.

New selective haloform-type reaction yielding 3-hydroxy-2,2-difluoroacids: theoretical study of the mechanism.

Experimental results of an unprecedented haloform-type reaction in which 4-alkyl-4-hydroxy-3,3-difluoromethyl trifluoromethyl ketones undergo base-promoted selective cleavage of the CO-CF(3) bond, yielding 3-hydroxy-2,2-difluoroacids and fluoroform, are rationalized using DFT (B3LYP) calculations. The gas-phase addition of hydroxide ion to 1,1,1,3,3-pentafluoro-4-hydroxypentan-2-one (R) is found to be a barrierless process, yielding a tetrahedral intermediate (INT), involving a DeltaG(r)(298 K) of -61.4 kcal/mol. The CO-CF(3) bond cleavage in INT leads to a hydrogen-bonded [CH(3)CHOHCF(2)CO(2)H...CF(3)](-) complex by passage through a transition structure (TS1) with a DeltaG()(298 K) of 20.8 kcal/mol and a DeltaG(r)(298 K) of 9.8 kcal/mol. This complex undergoes a proton transfer between its components, yielding a hydrogen-bonded [CH(3)CHOHCF(2)CO(2)...CHF(3)](-) complex. This process has associated with it a DeltaG()(298 K) of only 3.1 kcal/mol and a DeltaG(r)(298 K) of -43.3 kcal/mol. The CO-CF(2) bond cleavage in INT leads to a hydrogen-bonded [CH(3)CHOHCF(2)...CF(3)CO(2)H](-) complex by passage through a transition structure (TS3) with a DeltaG()(298 K) of 29.2 kcal/mol and a DeltaG(r)(298 K) of 25.1 kcal/mol. The lower energy barrier found for CO-CF(3) bond cleavage in INT is ascribed to the larger number of fluorine atoms stabilizing the negative charge accumulated on the CF(3) moiety of TS1, as compared to the number of fluorine atoms stabilizing the negative charge on the CH(3)CHOHCF(2) moiety of TS3. The solvent-induced effects on the two pathways, introduced within the SCRF formalism through PCM calculations, do not reverse the predicted preference of the CO-CF(3) over the CO-CF(2) bond cleavage of R in the gas phase.

Antagonism of pheromone response of Ostrinia nubilalis males and implications on behavior in the laboratory and in the field.

The antagonistic effect on the pheromone response and catabolism of male European corn borers, Ostrinia nubilalis, by several trifluoromethyl ketones is reported. (Z)-11-Tetradecenyl trifluoromethyl ketone (Z11-14:TFMK), the most closely related analogue of the main component of the pheromone, elicits a remarkable disruptive effect on close approach and source contact of males flying to a source baited with mixtures of the pheromone and the antagonist in 5:1 and 10:1 ratios. In this experiment, the male displayed an erratic flight track with frequent counter turns and intersections with the plume. In the field, the TFMK significantly lowered the number of males caught when mixed with the pheromone in a 10:1 ratio in comparison with the natural attractant. The compound was also a good inhibitor of the antennal esterase of the insect with a IC(50) value of 0.28 muM. The homologous (Z)-10-tridecenyl trifluoromethyl ketone, with one carbon less in the chain, also elicited an antagonistic effect in the wind tunnel, but in the field, the results were not conclusive. The effect induced was lower than the one displayed by Z11-14:TFMK including the activity as the esterase inhibitor (IC(50) value of 7.55 muM). The saturated tetradecyl trifluoromethyl ketone, tetradecyltrifluoropyruvamide, and (Z)-11-2-thiatetradecenyl trifluoromethyl ketone resulted completely inactive. The results obtained in conjunction to the previously shown low toxicity to mice by related trifluoromethyl ketones provide new important data for the putative utilization of these chemicals as new pest control agents.

Synthesis and biological activity of new potential agonists for the human adenosine A2A receptor.

New adenosine derivatives have been synthesized and tested as putative agonists of adenosine receptors. Compounds 2-6 derive from the introduction of several types of substituents (electron donating, electron withdrawing, and halogens) in the para-position of the phenyl ring of the parent compound 1, and compound 7 lacks the hydroxyl group of amino alcohol 1. In radioligand binding assays using recombinant human A(1), A(2A), A(2B), and A(3) receptors, all compounds showed very low or negligible affinity for A(1) and A(2B) receptors but compounds 3, 5, and 7 displayed a remarkably potent affinity for the A(2A) receptor with K(i) values of 1-5 nM. Bromo derivative 3 displayed a selectivity A(1)/A(2A) = 62 and A(3)/A(2A) = 16 whereas the presence of a hydroxyl group (compound 5) improved the selectivity of A(1)/A(2A) and A(3)/A(2A) to 120- and 28-fold, respectively. When the methoxy derivative 4 lacks the hydroxyl group on the side chain (compound 7), the binding affinity for A(2A) is increased to 1 nM, improving selectivity ratios to 356- and 100-fold against A(1) and A(3), respectively. In Chinese hamster ovary cells transfected with human A(2A) and A(2B) receptors, most compounds showed a remarkable activity for the A(2A) receptor, except chloro derivative 2, with EC(50) values ranging from 1.4 to 8.8 nM. The compounds behaved as good A(2A) agonists, and all were more selective than 5'-(N-ethylcarboxamino)adenosine (NECA), with A(2B)/A(2A) ratios of cAMP accumulation ranging from 48 for compound 2 to 666 for compound 7 while the corresponding A(2B)/A(2A) ratio for NECA was only 9. Compounds 1, 3, 5, and 7 also displayed higher selectivities than NECA up to 100-fold in isolated aortas of rat and guinea pig. In guinea pig tracheal rings precontracted by carbachol, compounds 2 and 4 were more potent than adenosine (100-fold) and NECA (10-fold), whereas compounds 1 and 7 displayed similar effects to NECA. Pretreatment of the tracheal rings with A(2), A(2A), and A(2B) receptor antagonists 3,7-dimethyl-l-propargylxanthine, 8-(3-chlorostyryl)caffeine, and alloxazine produced a marked inhibition of the tracheal relaxations induced by compounds 1, 2, and 4, but none of the compounds showed selectivity toward any of the adenosine receptors.

New fluorinated derivatives as esterase inhibitors. Synthesis, hydration and crossed specificity studies.

A variety of new fluorinated chemicals have been prepared for the first time and tested as inhibitors of esterases, one of the main enzymes involved in pheromone catabolism, in two economically important pests, the Egyptian armyworm Spodoptera littoralis (SL) and the Mediterranean corn borer Sesamia nonagrioides (SN). Using the respective major component of the pheromone as substrate, the K(m) and V(max) of the antennal esterase of both insects resulted to be 5.66 x 10(-4) M and 8.47 x 10(-6) Mmin(-1) for SL and 1.61 x 10(-7) M and 1.25 x 10(-7) Mmin(-1) for SN, pointing out that SN esterase has a higher affinity for its corresponding substrate than SL. In general, the trifluoromethyl ketones (TFMKs) exhibited higher inhibitory potency than the corresponding difluoromethyl ketones (DFMKs) or difluoroaldehydes (DFAs). The compounds appeared to hydrate differently in aqueous solution, the extent of hydration following the order: alpha,alpha-DFMKs