Novel Sulfonylurea Derivatives as Potential Antimicrobial Agents: Chemical Synthesis, Biological Evaluation, and Computational Study.

Methicillin-resistant Staphylococcus aureus (MRSA) is a worldwide health threat and has already tormented humanity during its long history, creating an urgent need for the development of new classes of antibacterial agents. In this study, twenty-one novel sulfonylurea derivatives containing phenyl-5-vinyl and pyrimidinyl-4-aryl moieties were designed and synthesized, among which, nine compounds exhibited inhibitory potencies against Gram-positive bacterial strains: MRSA (Chaoyang clinical isolates), S. aureus ATCC6538, vancomycin-resistant Enterococci-309 (VRE-309), and Bacillus subtilis ATCC 6633. Especially, 9i and 9q demonstrated inhibitory activities against the four bacterial strains with minimum inhibitory concentrations (MICs) of 0.78-1.56 µg/mL, and quite a few of other MRSA clinical strains with MICs of 0.78 µg/mL, superior to those of the positive controls vancomycin (MIC of 1 µg/mL) and methicillin (MIC of >200 µg/mL). This is the very first time that sulfonylurea derivatives have been identified as promising inhibitors against different MRSA clinical isolates. In addition, all the MIC values of the synthesized compounds against Candida albicans were greater than 100 µg/mL. Since the reported anti-Candida activities of sulfonylureas were due to acetohydroxyacid synthase (AHAS) inhibition, the molecular target against MRSA for the target sulfonylureas was thought to be a different mode of action. Density functional theory (DFT) calculations were finally performed to understand the structure-activity relationships, based on which, significant differences were observed between their HOMO maps for compounds with strong antibacterial activities and weak anti-MRSA effects. The present results hence provide valuable guidance for the discovery of novel agents to treat bacterial infections, especially against MRSA.

Chemical preparation, degradation analysis, computational docking and biological activities of novel sulfonylureas with 2,5-disubstituted groups.

Based on the previous finding that a substitution at 5-position of the benzene ring is favorable to enhance the degradation rates of sulfonylurea herbicides, a total of 16 novel 2,5-disubsituted sulfonylurea compounds were chemically synthesized and fully characterized by means of 1H NMR, 13C NMR, HRMS and X-ray diffraction. By using HPLC analysis, the degradation behavior of M03, a compound belonging to this family, was studied and confirmed that chlorsulfuron itself is not a degraded product of the 2,5-disubstituted sulfonylureas. Inhibition constants against plant acetohydroxyacid synthase (AHAS) were determined for selected compounds, among which SU3 showed seven times stronger activity against the mutant W574L enzyme than chlorsulfuron. Molecular docking suggested that the substituted group at 5-position of benzene ring is likely to interact with the surrounding residues Met200 and Asp376 of AtAHAS. From the greenhouse herbicidal assay and crop safety test, SU5 and SU6 are considered as herbicide candidates to control dicotyledon weeds in corn, while SU3 is likely to be a promising candidate to control dicotyledon weed species and barnyard grass in wheat. The present research has therefore provided some new insights to understand the structure-activity relationships of herbicidal sulfonylureas with di-substitutions at benzene ring.

Synthesis, herbicidal activity and soil degradation of novel 5-substituted sulfonylureas as AHAS inhibitors.

BACKGROUND: Chlorsulfuron, metsulfuron-methyl and ethametsulfuron can damage sensitive crops in rotation pattern as a result of their long persistence in soil. To explore novel sulfonylurea (SU) herbicides with favorable soil degradation rates, four series of SUs were synthesized through a structure-based drug design (SBDD) strategy. RESULTS: The target compounds, especially Ia, Id and Ie, exhibited prospective herbicidal activity against dicotyledon oil seed rape (Brassica campestris), amaranth (Amaranthus retroflexus), monocotyledon barnyard grass (Echinochloa crusgalli) and crab grass (Digitaria sanguinalis) at a concentration of 15 a.i. g ha-1 . Additionally, Ia, Id and Ig displayed excellent inhibitory effects against AtAHAS, with Kapp i values of 59.1, 34.5 and 71.8 µm, respectively, which were much lower than that of chlorsulfuron at 149.4 µm. The π-π stack and H-bonds between the Ia conformation and AtAHAS in the molecular docking results confirmed the series of compounds to be conventional AHAS inhibitors. In alkaline soil (pH = 8.46), compounds Ia-Ig revealed various degrees of acceleration in the degradation rate compared with chlorsulfuron. Besides, compound Ia showed considerable wheat and corn safety under postemergence at the concentration of 30, 60 and even 120 a.i. g ha-1 . CONCLUSION: Overall, based on the synthetic procedure, herbicidal activity, soil degradation and crop safety, the Ia sulfonylureas series were chosen to be investigated as prospective AHAS inhibitors. The 5-dimethylamino group on SUs accelerated the degradation rate at different levels in alkaline soils which seems to be controllable in conventional cropping systems in their further application. © 2022 Society of Chemical Industry.

A dataset of diversity and distribution of rodents and shrews in China.

The rodents and shrews are important reservoirs for a large number of zoonotic pathogens. Here by performing a literature review, we determined the occurrence and distribution of rodents and shrews in China at three scales including province, city, and county levels. The peer-reviewed papers published in English and Chinese were collected, standard procedures were applied in reference books, field surveys and websites to remove duplicates, and information on recorded locations of rodents and shrews was extracted. The dataset contains 13,911 records of geo-referenced occurrences for 364 rodents and shrews distributed over 1,663 locations distinguished. As pathogens continue to emerge from rodents and shrews, this dataset could assist efforts to put preliminary bounds around a variety of spatial analyses of rodents and shrews, facilitate a better understanding of the transmission risk of the pathogens they carry, and be helpful for assessing the risk of future emergence of rodent-borne zoonoses.

Degradation of 5-Dialkylamino-Substituted Chlorsulfuron Derivatives in Alkaline Soil.

Sulfonylurea herbicides are widely used as acetolactate synthase (ALS) inhibitors due to their super-efficient activity. However, some sulfonylurea herbicides show toxicity under crop rotation due to their long degradation time, for example, chlorsulfuron. Our research goal is to obtain chlorsulfuron-derived herbicides with controllable degradation time, good crop safety and high herbicidal activities. Based on our previously reported results in acidic soil, we studied the degradation behaviors of 5-dialkylamino-substituted chlorsulfuron derivatives (NL101-NL108) in alkaline soil (pH 8.39). The experimental data indicate that addition of the 5-dialkylamino groups on the benzene ring of chlorsulfuron greatly accelerated degradation in alkaline soil. These chlorsulfuron derivatives degrade 10.8 to 51.8 times faster than chlorsulfuron and exhibit excellent crop safety on wheat and corn (through pre-emergence treatment). With a comprehensive consideration of structures, bioassay activities, soil degradation and crop safety, it could be concluded that 5-dialkylamino-substituted chlorsulfuron derivatives are potential green sulfonylurea herbicides for pre-emergence treatment on both wheat and corn. The study also provides valuable information for the discovery of new sulfonylurea herbicides for crop rotation.

Human infections with neglected vector-borne pathogens in China: A systematic review.

Background: Emerging vector-borne pathogens (VBPs) pose a continuous background threat to the global health. Knowledge of the occurrence, distributions and epidemiological characteristics of VBP are lacking in many countries. Outbreaks of novel VBP are of increasing global interest including those arising in China. Methods: A systematic review of published literature was undertaken to characterize the spectrum of VBPs causing human illness in China. We searched five databases for VBP-related articles in English and Chinese published between January 1980 and June 2021, that excluded those listed in the National Notifiable Diseases Surveillance System of China. The study is registered with PROSPERO, CRD42021259540. Findings: A total of 906 articles meeting the selection criteria were included in this study. A total of 44,809 human infections with 82 species of VBPs including 40 viruses, 33 bacteria (20 Rickettsiales bacteria, eight Spirochaetales bacteria, and five other bacteria) and nine parasites, were identified in China. Rickettsiales bacteria were the most common and widely distributed pathogens with 18,042 cases reported in 33 provinces by 347 reviewed articles, followed by Spirochaetales bacteria with 15,745 cases in 32 provinces (299 articles), viruses with 8455 cases in 30 provinces (139 articles), other bacteria with 2053 cases in 19 provinces (65 articles), parasites with 514 cases in 17 provinces (44 articles), and multiple pathogens with 3626 cases in 14 provinces (23 articles). Coxiella burnetii, Bartonella henselae and Rickettsia sibirica were the most frequently reported pathogens. A total of 18 new pathogens were reported in China during this period (these also represented their first identification globally). Based on 419 articles with clinical information, a meta-analysis revealed that flu-like illness was the most common manifestation among infections with VBPs. Interpretation: This review helps improve the understanding of VBPs in China, demonstrating the need to consider a wider surveillance of VBPs in many different settings, thus helping to inform future research and surveillance efforts. Funding: Natural Science Foundation of China.

A dataset of distribution and diversity of blood-sucking mites in China.

Mite-borne diseases, such as scrub typhus and hemorrhagic fever with renal syndrome, present an increasing global public health concern. Most of the mite-borne diseases are caused by the blood-sucking mites. To present a comprehensive understanding of the distributions and diversity of blood-sucking mites in China, we derived information from peer-reviewed journal articles, thesis publications and books related to mites in both Chinese and English between 1978 and 2020. Geographic information of blood-sucking mites' occurrence and mite species were extracted and georeferenced at the county level. Standard operating procedures were applied to remove duplicates and ensure accuracy of the data. This dataset contains 6,443 records of mite species occurrences at the county level in China. This geographical dataset provides an overview of the species diversity and wide distributions of blood-sucking mites, and can potentially be used in distribution prediction of mite species and risk assessment of mite-borne diseases in China.

Controllable Soil Degradation Rate of 5-Substituted Sulfonylurea Herbicides as Novel AHAS Inhibitors.

Chlorsulfuron has been applied in wheat fields as a recognized herbicide worldwide, yet it was officially banned in China since 2014 for its soil persistence problem. On the basis of our previous research that 5-dimethylamino distinctively accelerated degradation rate in soils, a modified amino moiety (Ia-c) and monosubstituted amino group (Id-e) were introduced onto the fifth position of the benzene ring in sulfonylurea structures, as well as heterocyclic amino substituents (If-g) to seek a suitable soil degradation rate during such an in situ crop rotation system. Referring to the biological data and ScAHAS inhibition and ScAHAS docking results, they turned out to be AHAS inhibitors with high potent herbicidal activities. The various influence on soil degradation rate along with crop safety indicated that different substituents on the fifth position have exerted an apparent impact. Their united study of structure-activity-safety-degradation relationship has great potential to provide valuable information for further development of eco-friendly agrochemicals.

Research on the controllable degradation of N-methylamido and dialkylamino substituted at the 5th position of the benzene ring in chlorsulfuron in acidic soil.

Owing to the lengthy residual problems associated with chlorsulfuron, metsulfuron-methyl, and ethametsulfuron, which prevents them from being used in the "annual multi-crop planting system", the application of these sulfonylurea herbicides (SU) has regrettably been terminated in China since 2014. In this field, we were the first to discover that the 5th position of the benzene ring in chlorsulfuron is a key point for influencing its degradation rate and the amino moiety at this position showed faster degradation rates and maintained their original potent bioactivity. In this study, we further elaborated on N-methylamido and dialkylamino substituents at the same position in chlorsulfuron to obtain 18 novel structures as M and N series. Their half-life degradation (DT50) values were faster, to varying degrees, than chlorsulfuron in acidic soil. It was found that most of the titled structures also retained their potent herbicidal activity and the crop safety of the M series towards corn greatly increased. Based on these data, a comprehensive graph describing the structure/degradation relationship was established first. Relating to the new molecules, their herbicidal activity (A), degradation rates (D), and crop safety (S) relationship were correlated and we used this approach to predict and explore the most preferable molecule, which coincided to the corresponding experimental data. The new concept of controllable degradation will provide us with more insight when searching for new ecological bioactive molecules in the future.

Syntheses and biological evaluation of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib.

Three novel series of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib were prepared and evaluated in vitro for their cytostatic effects against a human chronic myeloid leukemia (K562), acute myeloid leukemia (HL60), and human leukemia stem-like cell line (KG1a). The structure-activity relationship was analyzed by determining the inhibitory rate of each imatinib analog. Benzene and piperazine rings were necessary groups in these compounds for maintaining inhibitory activities against the K562 and HL60 cell lines. Introducing a trifluoromethyl group significantly enhanced the potency of the compounds against these two cell lines. Surprisingly, some compounds showed significant inhibitory activities against KG1a cells without inhibiting common leukemia cell lines (K562 and HL60). These findings suggest that these compounds are able to inhibit leukemia stem-like cells.