Discovery of Biphenyl–Sulfonamides as Novel β-N-Acetyl-d-Hexosaminidase Inhibitors via Structure-Based Virtual Screening

Abstract

Novel insecticidal targets are always in demand due to the development of resistance. OfHex1, a β-N-acetyl-d-hexosaminidase identified in Ostrinia furnacalis (Asian corn borer), is involved in insect chitin catabolism and has proven an ideal target for insecticide development. In this study, structure-based virtual screening, structure simplification, and biological evaluation are used to show that compounds with a biphenyl–sulfonamide skeleton have great potential as OfHex1 inhibitors. Specifically, compounds 10k, 10u, and 10v have K i values of 4.30, 3.72, and 4.56 μM, respectively, and thus, they are more potent than some reported nonglycosyl–based inhibitors such as phlegmacin B1 (K i = 26 μM), berberine (K i = 12 μM), 2 (K i = 11.2 μM), and 3 (K i = 28.9 μM). Furthermore, inhibitory kinetic assessments reveal that the target compounds are competitive inhibitors with respect substrate, and based on toxicity predictions, most of them have potent drug properties. The obtained results indicate that the biphenyl–sulfonamide skeleton characterized by simple chemical structure, synthetic tractability, potent activity, and low toxicity has potential for further development in pest management targeting OfHex1.

The Role of Chitooligosaccharidolytic β-N-Acetylglucosamindase in the Molting and Wing Development of the Silkworm Bombyx mori

“…Some HEXs inhibitors have been uncovered via structure-based virtual screening [ 7 , 38 , 52 , 53 , 54 ] but they are all based on the crystal structure information of OfHex1. This is because the OfHex1 of O. furnacalis is the only insect-derived HEX with crystal structure information.…”

“…Many OfHex1-targeted inhibitors have been reported. These have the potential for development in pest management and include TMG-chitotriomycin [ 31 ], allosamidin [ 32 ], PUGNAc [ 33 ], NMAGT [ 34 ], glycosylated naphthalimide [ 35 ], the natural products phlegmacin B1 [ 36 ] and berberine [ 37 ], and biphenyl–sulfonamides [ 38 ].…”

Primary Mode of Action of the Novel Sulfonamide Fungicide against Botrytis cinerea and Field Control Effect on Tomato Gray Mold

“…Among the plethora of various unique chemical structures, sulfonamides, the most common scaffolds in sulfur-containing molecules, have received considerable attention from all walks of life due to their eminent biological activities and serve an important function in the pharmaceutical industry [8,9]. In addition to medical applications, sulfonamides have also been registered as commercial pesticides (e.g., fungicides of flusulfamide, tolnifanide, cyazofamid, and amisulbrom, herbicides of pyroxsulam and penoxsulam, and the insecticide of fluorosulamid) and developed as pesticide candidates [10][11][12][13]. These results clearly demonstrate that developing sulfonamide pesticides with new structures and mechanisms is still highly desirable and promising.…”

Design, Synthesis, and Herbicidal Activity of Naphthalimide–Aroyl Hybrids as Potent Transketolase Inhibitors

“…1,3,4 Target-based drug design (TBDD) has attracted great attention because of its numerous advantages, including high selectivity, high efficiency, and safety for nontarget organisms. 5 There are currently about 26 herbicide sites of action, including acetohydroxyacid synthase, 6 acetyl-coenzyme A carboxylase, 7 protoporphyrinogen IX oxidase, 8 and 4-hydroxyphenylpyruvatedioxygenase (HPPD)-inhibiting herbicides, 9 and so on. 10 However, due to the frequent and long-term overuse of limited types of herbicides in the fields, the weed resistance to these pesticides has become increasingly severe.…”

“…20 Structure-based virtual screening is an effective way used in TBDD, which screen large collections of compounds via molecular docking to confirm molecular structures that are most likely to bind into a specific target protein. 5,21,22 In our previous report, a series of potential hit compounds interacting with TK were virtually filtered out from the SPECS database using homology modeling and virtual screening. 23 Among them, compound 1n (Figure 1) with higher binding affinities (ΔG cal = 8.91 kcal/mol) was selected as the lead compound for further structure optimization in this study.…”