The design, synthesis of amide KARI inhibitors and their biological activities

Abstract

Ketol-acid reductoisomerase(KARI) is a promising target for the design of herbicides yet there are only few reports on the molecular design of KARI inhibitors. In this paper, based on the reported 0.165 nm high resolution crystal structure of the spinach KARI complex, 279 molecules with low binding energy toward KARI were obtained from an MDL/ACD 3D database search using the program DOCK 4.0. According to the structural information of 279 molecules provided, some amide compounds have been designed and synthesized. The bioassay results show that most of these amides had inhibitory activity to rice KARI at a test concentration of 200 μg/mL. Among which eight amides, compounds 1 and 6 show 57.4% and 48.1% inhibitory activity to KARI. The herbicidal activities of these amides were further investigated on di-cotyledonous rape (Brassica campestris) and mono-cotyledonous barnyardgrass (Echinochloa crusgalli). Compounds 1 and 6 were more favorable than others and showed 52.0% and 72.6% inhibitory activity on rape root at 100 μg/mL concentration, respectively. These amides could be further optimized for finding more potent candidates.Ketol-acid reductoisomerase (KARI, EC 1.1.1.86), also known as acetohydroxy acid isomeroreductase (AHIR), is one of the key enzymes for the synthesis of branched-chain amino acids (isoleucine, leucine and valine). There are reviews proposing KARI as a herbicidal target [1]. Although the molecular design of potential KARI inhibitors is in accord with green herbicidal research, there are few reports of new KARI inhibitors except Hoe 704, IpOHA, 1,2,3-thiadiazoles and CPD derivatives, which are potent inhibitors of the enzyme only in vitro, but their activities in vivo as herbicides are weak [2][3][4].In our previous work [5], 279 molecules with low combining energy toward KARI were obtained by an MDL/ACD-3D database search using the DOCK 4.0 program based on the crystal structure of the KARI complex, which provides us plentiful structural information for our research. Many amides were found among the 279 molecules. In looking for novel potent KARI inhibitors, several types of amides were synthesized and their herbicidal activities both in vitro and in vivo were investigated. The novel structures are shown in Fig. 1. Experiments Apparatus and materialsThe DOCK (version 4.0) program was employed. The computational work was based on the 0.165 nm crystal structure of the spinach KARI complex (PDB code 1YVE) and finished on the SGI Indigo R10000 of the Shanghai . The MDL/ACD 3D database of 250000 organic compounds was searched for potential KARI inhibitors.Melting points were determined using a Taike X-4 apparatus and were uncorrected. The infrared spectra were recorded on a BRUCK EQUINOX55 FTIR spectrophotometer as KBr tablets. 1 H-NMR and 13 C-NMR spectra were measured on a Bruker AV-300 instrument (300 MHz) using TMS as an internal standard. Mass spectra were recorded on a Hewlett Packard G1800A and an HP-1100 LC/MS instruments. Elemental analyses were performed on a Yanaco MT-3CHN elemental ana...

Targeting Amide Herbicides by KARI of Staphylococcus aureus- an in silico Analysis

“…[37][38][39] Efficacy of herbicides is related to an imbalance in carbon-nitrogen after comparing the physiological consequences of inhibitors of consecutive enzymes in the biosynthesis of branched-chain amino acids, acetolactate synthase (ALS), and ketolacid reductoisomerase (KARI). 40 Free natural compound accumulation brought on via way of means of herbicides in wild-kind vegetation turned into alleviated in the mutants, indicating that vegetation that lack ADH1 or AOX1a are much less liable to the herbicides` phytotoxicity. The indiscriminate use of herbicides with the equal mechanism of movement brought about the upward push of the choice pressure resulting withinside the producing of ever more resistant weeds in present day years.…”