Synthesis, Optimization, and Evaluation of Glycosylated Naphthalimide Derivatives as Efficient and Selective Insect β-N-Acetylhexosaminidase OfHex1 Inhibitors

Abstract

Insect chitinolytic β-N-acetylhexosaminidase OfHex1, from the agricultural pest Ostrinia furnacalis (Gueneé), is considered as a potential target for green pesticide design. In this study, rational molecular design and optimization led to the synthesis of compounds 15r (K i = 5.3 μM) and 15y (K i = 2.7 μM) that had superior activity against OfHex1 than previously reported lead compounds. Both compounds 15r and 15y had high selectivity toward OfHex1 over human β-Nacetylhexosaminidase B (HsHexB) and human O-GlcNAcase (hOGA). In addition, to investigate the basis for the potency of glycosylated naphthalimides against OfHex1, molecular docking and molecular dynamics simulations were performed to study possible binding modes. Furthermore, the in vivo biological activity of target compounds with efficient OfHex1 inhibitory potency was assayed against Myzus persicae, Plutella xylostella, and O. furnacalis. This present work indicates that glycosylated naphthalimides can be further developed as potential pest control and management agents targeting OfHex1.

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

“…To elucidate the mechanism of Of Hex1 inhibition by compounds 10k , 10u , and 10v (three representative compounds with sulfonamide bonds at para -, meta- , or ortho- position in the terminal phenyl group), the Dixon plots of these inhibitors were analyzed. As shown in Figure , the trend lines drawn for different concentrations intersect in quadrant two, which suggests that compounds 10k , 10u , and 10v are competitive inhibitors of Of Hex1, similar to previously reported inhibitors. ,,,,, Moreover, the K i values of 10k , 10u , and 10v are 4.30, 3.72, and 4.56 μM, respectively. Although the target compounds in this work are less active than Q2 , their chemical structures are simpler, and their synthetic route is less complex.…”

“…So far, two types of Of Hex1 inhibitors have been reported (Figure ). The first type is the glycosyl-based inhibitors with K i values in the micromolar to nanomolar range, such as TMG-chitotriomycin, allosamidin, PUGNAc, NMAGT, and glycosylated naphthalimide ( 1 ). − The second type is nonglycosyl–based inhibitors with K i values in the micromolar range, such as Q1 , Q2 , and their analogs, − natural products phlegmacin B 1 and berberine, and compounds 2 and 3 (obtained from virtual screening). The application of glycosyl-based inhibitors is limited by their nonpesticide-like properties, including low clogP, metabolic instability, and membrane permeability, , as well as by their complicated structures and synthesis processes.…”

Synthesis and Enzyme Substrate Activity of p-Nitrophenyl N,N'-Diacetyl-4-thio-β-chitobioside

“…首先以 N-乙酰氨基葡萄糖为原料在乙酰氯的作用 下发生全乙酰化和氯化反应得到全乙酰化氯代糖, 然后 将全乙酰化氯代糖在丙酮存在下与硫脲反应生成硫脲 盐酸盐, 抽滤得中间体 2a, 再在温和碱偏重亚硫酸钠作 用下水解生成化合物 2', 化合物 2'中 SH 的偶合常数为 J＝9.4 Hz (d, δ 2.58), 与文献值 [30] -45.4 (c 0.5, DMSO)[文献值: [33] ＋32.4 (c 0.5, DMSO)[文献值: [31] ＋ 23.8 (c 0.5, DMSO); [ 文 献 值: [31,35] m.p. 242～245 ℃, 42.8 (c 0.5, DMSO)[文献值: [31] 辅助材料(Supporting Information) 化合物 2 的 1 H NMR, 13 C NMR 谱图, 化合物 2', 3～11 的 1 H NMR, 13 C NMR 和 HRMS 谱图. 这些材料可以免费从本刊网站 (http://sioc-journal.cn/)上下载.…”

“…62 (s, 3H, CH 3 CO);13 C NMR (75 MHz, DMSO-d 6 ) δ: 169.42, 165.66 (C＝O), 162.07, 142.18, 133.28, 130.12, 129.47, 128.69, 125.90, 116.84 (ArC), 97.78, 77.22, 76.53, 67.70, 60.24, 53.34, 22.76 (CH 3 CO). HRMS calcd for C 21 H 22 N 2 O 9 [M＋H] ＋ 447.1398, found 447.1397.…”

“…NAc);13 C NMR (75 MHz, CDCl 3 ) δ: 170.56, 170.56, 170.08, 169.64, 168.93, 166.50, 165.60 (C＝O), 160.95, 142.53, 133.79, 133.15, 129.64, 129.40, 129.27, 128.44, 128.36, 128.20, 125.28, 116.43 (ArC), 96.82 (CH, C-1), 82.14 (CH, C-1'), 75.77, 74.20, 73.58, 68.72, 67.89 (CH, C-3, C-3', C-4', C-5, C-5'), 63.67, 62.08 (CH 2 , C-6, C-6'), 56.83, 52.22 (2×CH, C-2, C-2'), 46.39 (CH, C-4), 23.03, 22.34, 20.34, 20.26, 20.24 (CH 3 CO). HRMS calcd for C 42 H 46 N 3 O 17 S [M＋H] ＋ 896.2548, found 896.2556.…”