Discovery of Novel Pyrazole Acyl Thiourea Skeleton Analogue as Potential Herbicide Candidates.

To discover novel transketolase (TKL, EC 2.2.1.1) inhibitors with potential herbicidal applications, a series of pyrazole acyl thiourea derivatives were designed based on a previously obtained pyrazolamide acyl lead compound, employing a scaffold hopping strategy. The compounds were synthesized, their structures were characterized, and they were evaluated for herbicidal activities. The results indicate that 7a exhibited exceptional herbicidal activity against Digitaria sanguinalis and Amaranthus retroflexus at a dosage of 90 g ai/ha, using the foliar spray method in a greenhouse. This performance is comparable to that of commercial products, such as nicosulfuron and mesotrione. Moreover, 7a showed moderate growth inhibitory activity against the young root and stem of A. retroflexus at 200 mg/L in the small cup method, similar to that of nicosulfuron and mesotrione. Subsequent mode-of-action verification experiments revealed that 7a and 7e inhibited Setaria viridis TKL (SvTKL) enzyme activity, with IC50 values of 0.740 and 0.474 mg/L, respectively. Furthermore, they exhibited inhibitory effects on the Brassica napus acetohydroxyacid synthase enzyme activity. Molecular docking predicted potential interactions between these (7a and 7e) and SvTKL. A greenhouse experiment demonstrated that 7a exhibited favorable crop safety at 150 g ai/ha. Therefore, 7a is a promising herbicidal candidate that is worthy of further development.

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

Transketolase (TK) was identified as a new target for the development of novel herbicides. In this study, a series of naphthalimide-aroyl hybrids were designed and prepared based on TK as a new target and tested for their herbicidal activities. In vitro bioassay showed that compounds 4c and 4w exhibited stronger inhibitory effects against Digitaria sanguinalis (DS) and Amaranthus retroflexus (AR) with the inhibition over 90% at 200 mg/L and around 80% at 100 mg/L. Also, compounds 4c and 4w exhibited excellent postemergence herbicidal activity against DS and AR with the inhibition around 90% at 90 g [active ingredient (ai)]/ha and 80% at 50 g (ai)/ha in the greenhouse, which was comparable with the activity of mesotrione. The fluorescent quenching experiments of At TK revealed the occurrence of electron transfer from compound 4w to At TK and the formation of a strong exciplex between them. Molecular docking analyses further showed that compounds 4w exhibited profound affinity with At TK through the interaction with the amino acids in the active site, which results in its strong inhibitory activities against TK. These findings demonstrated that compound 4w is potentially a lead candidate for novel herbicides targeting TK.

Single-molecule visualization of human RECQ5 interactions with single-stranded DNA recombination intermediates.

RECQ5 is one of five RecQ helicases found in humans and is thought to participate in homologous DNA recombination by acting as a negative regulator of the recombinase protein RAD51. Here, we use kinetic and single molecule imaging methods to monitor RECQ5 behavior on various nucleoprotein complexes. Our data demonstrate that RECQ5 can act as an ATP-dependent single-stranded DNA (ssDNA) motor protein and can translocate on ssDNA that is bound by replication protein A (RPA). RECQ5 can also translocate on RAD51-coated ssDNA and readily dismantles RAD51-ssDNA filaments. RECQ5 interacts with RAD51 through protein-protein contacts, and disruption of this interface through a RECQ5-F666A mutation reduces translocation velocity by ∼50%. However, RECQ5 readily removes the ATP hydrolysis-deficient mutant RAD51-K133R from ssDNA, suggesting that filament disruption is not coupled to the RAD51 ATP hydrolysis cycle. RECQ5 also readily removes RAD51-I287T, a RAD51 mutant with enhanced ssDNA-binding activity, from ssDNA. Surprisingly, RECQ5 can bind to double-stranded DNA (dsDNA), but it is unable to translocate. Similarly, RECQ5 cannot dismantle RAD51-bound heteroduplex joint molecules. Our results suggest that the roles of RECQ5 in genome maintenance may be regulated in part at the level of substrate specificity.