Crystallography of Contemporary Contact Insecticides

Abstract

The active forms of contact insecticides used for combatting mosquito-borne infectious diseases are typically crystalline solids. Numerous molecular crystals are polymorphic, crystallizing in several solid forms characterized by different physicochemical properties, including bioavailability. Our laboratory recently found that the activity of crystalline contact insecticides is inversely dependent on the thermodynamic stability of their polymorphs, suggesting that efficacy can be enhanced by the manipulation of the solid-state structure. This paper argues that crystallography should be central to the development of contact insecticides, particularly because their efficacy continues to be compromised by insecticide resistance, especially among Anopheles mosquito populations that spread malaria. Although insecticidal compounds with new modes of action have been introduced to overcome resistance, new insecticides are expensive to develop and implement. The repurposing of existing chemical agents in metastable, more active crystalline forms provides an inexpensive and efficient method for 'evergreening' compounds whose risks are already well-established. We report herein seven new single-crystal structures of insecticides used for controlling infectious disease vectors. The structures reported herein include pyrethroid insecticides recommended by the WHO for indoor residual spraying (IRS)-bifenthrin, β-cyfluthrin, etofenprox, α-cypermethrin, and λ-cyhalothrin as well as the neonicotinoid insecticide thiacloprid.

Keywords: bifenthrin; deltamethrin; etofenprox; imidacloprid; malaria; mosquitoes; thiacloprid; α-cypermethrin; β-cyfluthrin; λ-cyhalothrin.

Figure 1

(A) Single-crystal structure of DM Form I. (B) Single-crystal structure of DM Form II. (C) The conformations of DM in Forms I and II overlaid, illustrating distinct molecular conformations in the polymorphs. The crystal structure of Form II was reported for the first time by our laboratory [1]. The crystal structure of DM Form I, redetermined by our laboratory is identical to that previously reported [19].

Figure 2

Molecular structures of the insecticides discussed herein. Notes on stereochemistry: Configurations of stereogenic centers are read directly in structures above from left to right throughout, a shortcut past naming conventions that are cumbersome here. β-cyfluthrin (β-CF): SRS-enantiomer shown in racemic mixture A (rac-A), and the SSR-enantiomer in racemic mixture B (rac-B). Bifenthrin (BF): RR-enantiomer of a racemic mixture is shown. λ-cyhalothrin (λ-CH): RRS-enantiomer of a racemic mixture is shown. α-cypermethrin (α-CP): RRS-enantiomer of racemic mixture shown. Deltamethrin (DM, RRS stereoisomer) is enantiomerically pure.

Figure 3

Crystal structures of (A) bifenthrin (BF), (B) etofenprox (ET), (C) rac-A β-cyfluthrin (β-CF), and (D) rac-B β-cyfluthrin (β-CF).

Figure 4

Crystal structure of α-cypermethrin Form I.

Figure 5

(A,B) Single-crystal structures of λ-cyhalothrin Forms I (A) and II (B). In (A), the unit cell contains 8 symmetry-related molecules. In (B), the unit cell contains 4 symmetry-related molecules.

Figure 6

Thin film of thiacloprid crystals grown by cooling its melt, as viewed between crossed polarizers. Form I presents as banded spherulites and a chaotic texture, Form II as smooth spherulites.

Figure 7

Single-crystal structures of thiacloprid Forms I (A) and II (B). The unit cell of Form I contains 8 symmetry-related molecules, whereas the unit cell of Form II contains 4 symmetry-related molecules.