*Article* **Crystallography of Contemporary Contact Insecticides**

**Bryan Erriah, Xiaolong Zhu, Chunhua T. Hu, Bart E. Kahr \*, Alexander Shtukenberg and Michael D. Ward \***

> Department of Chemistry and Molecular Design Institute, New York University, New York, NY 10003, USA; be733@nyu.edu (B.E.); xz1668@nyu.edu (X.Z.); chunhua.hu@nyu.edu (C.T.H.); as5243@nyu.edu (A.S.) **\*** Correspondence: bart.kahr@nyu.edu (B.E.K.); mdw3@nyu.edu (M.D.W.); Tel.: +1-212-992-9579 (B.E.K.)

**Simple Summary:** The efficacy of crystalline contact insecticides is dependent foremost on the uptake of insecticide molecules by insect tarsi contacting crystal surfaces. Insecticide molecules, however, may organize in more than one way in the crystalline state, resulting in more than one crystalline form (also known as *polymorph*). We recently discovered that the lethality of contact insecticides increases with decreasing thermodynamic stability of the crystalline forms; the most stable crystalline form is invariably the least lethal/slowest acting. Polymorphism in contact insecticides, and its importance to efficacy, was largely unknown to the vector control community. It is argued that the crystallographic characterization of contact insecticide solids should be systematic to identify more active solid forms. Herein, we report seven new crystal structures, mostly pyrethroid insecticides recommended by the WHO for indoor residual spraying, as well as a new form of a neonicotinoid insecticide. These results further highlight polymorphism in contact insecticides and the importance of solid-state chemistry in the search for more active crystal forms.

**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 <sup>λ</sup>-cyhalothrin as well as the neonicotinoid insecticide thiacloprid.

**Keywords:** deltamethrin; imidacloprid; bifenthrin; β-cyfluthrin; etofenprox; α-cypermethrin; λcyhalothrin; thiacloprid; malaria; mosquitoes
