Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase.

Malaria is a devastating disease in sub-Saharan Africa, and current vector control measures are threatened by emerging resistance mechanisms. With the goal of developing new, selective, resistance-breaking insecticides we explored α-fluorinated methyl ketones as reversible covalent inhibitors of Anopheles gambiae acetylcholinesterase (AgAChE). Trifluoromethyl ketones 5 demonstrated remarkable volatility in microtiter plate assays, but 5c,e-h exhibited potent (1-100 nM) inhibition of wild type (WT) AgAChE and weak inhibition of resistant mutant G119S mutant AgAChE. Fluoromethyl ketones 10c-i exhibited submicromolar to micromolar inhibition of WT AgAChE, but again only weakly inhibited G119S AgAChE. Interestingly, difluoromethyl ketone inhibitors 9c and 9g had single digit nanomolar inhibition of WT AgAChE, and 9g had excellent potency against G119S AgAChE. Approach to steady-state inhibition was quite slow, but after 23 h incubation an IC50 value of 25.1 ± 1.2 nM was measured. We attribute the slow, tight-binding G119S AgAChE inhibition of 9g to a balance of steric size and electrophilicity. However, toxicities of 5g, 9g, and 10g to adult A. gambiae in tarsal contact, fumigation, and injection assays were lower than expected based on WT AgAChE inhibition potency and volatility. Potential toxicity-limiting factors are discussed.

Hydrolytically Stable and Thermo-Mechanically Tunable Poly(Urethane) Thermoset Networks that Selectively Degrade and Generate Reusable Molecules.

Cross-linked polymeric networks that possess tunable properties and degrade on-demand have broad applications in today's society. Herein, we report on silyl-containing poly(urethane) (silyl-PU) thermoset networks, which are highly cross-linked stimuli-responsive materials with hydrolytic stability at 37.7 °C and 95% relative humidity, thermal stability of 280-311.2 °C, tensile properties of 0.38-51.7 MPa strength and 73.7-256.4% elongation, including storage modulus of 2268-3499 MPa (in the glassy state). However, unlike traditional (i.e., nondegradable) PU thermosets, these silyl-PUs selectively activate with fluoride ion under mild and static conditions to completely degrade, via cascading bond cleavages, and generate recoverable and reusable molecules. Silyl-PUs, as thin films, also demonstrated complete removal (within 30 min) from a strongly adhered epoxy thermoset network without altering the structure of the latter. Silyl-PU thermosets have potential applications in composite parts, vehicle and industrial coatings, and rigid plastics for personal devices, and may reduce environmental waste compared to nondegradable, single-use materials.

Synthesis and kinetics of disassembly for silyl-containing ethoxycarbonyls using fluoride ions.

In this study, a series of silyl-containing ethoxycarbonates and ethoxycarbamates on electron poor anilines and phenols were synthesized and their kinetics of disassembly determined in real-time upon exposure to fluoride ion sources at room temperature. The results provide a greater understanding of stability and kinetics for silyl-containing protecting groups that eliminate volatile molecules upon removal, which will allow for simplification of orthogonal protection in complex organic molecules.