Spiropyrimidinetriones are a novel class of antibacterial agents that target the bacterial type II topoisomerase via a new mode of action. Compound ETX0914 is thus far the only drug from this class that is being evaluated in clinical trials. To improve the antibacterial activity and pharmacokinetic properties of ETX0914, we carried out systematic structural modification of this compound, and a number of compounds with increased potency were obtained. The most promising compound 33e, with incorporation of a spirocyclopropane at the oxazolidinone 5 position reduced metabolism, exhibited excellent antibacterial activity against Gram-positive pathogens and a good pharmacokinetic profile combined with high aqueous solubility. In addition, compound 33e exhibited good selectivity for Staphylococcus aureus gyrase over human Topo IIα. In a murine model of systemic methicillin-resistant S. aureus infection, 33e exhibited superior in vivo efficacy (ED50 = 3.87 mg/kg) compared to ETX0914 (ED50 = 11.51 mg/kg).
An improved process for the synthesis of YG-056SP, a potent oxazolidinone candidate against multi-drug resistant bacteria, is developed. Compared with the original synthetic route, this new approach is two steps shorter, and all of the steps involve simple purifications without column chromatography. More importantly, it avoids the use of explosive azide compounds and expensive metal catalysts. The new reaction conditions are mild and safe, which is more suitable for the scalable synthesis of YG-056SP for preclinical studies.
Amphotericin B (AMB, 1) is the most powerful antibiotic in treating potentially life-threatening invasive fungal infections (IFIs), though severe toxicity derived from self-aggregation greatly limits its clinical application. Herein, we applied a bisamidation strategy at the C16-COOH and C3'-NH2 to improve the therapeutic properties by suppressing self-aggregation. It was found that basic amino groups at the residue of C16 amide were beneficial to activity, while lipophilic fragments contributed to toxicity reduction. Additionally, N-methyl-amino acetyl and amino acetyl moieties at C3' amide could help keep the fungistatic effectiveness. The modification work culminated in the discovery of 36 (ED50 = 0.21 mg/kg), which exerted a 1.5-fold stronger antifungal efficacy than amphamide, the optimal derivative theretofore, in mice, low self-aggregation propensity, and thus low acute toxicity. With the improvement in therapeutic index and good PK profile, 36 is promising for further development as a second-generation polyene antifungal agent.
A new practical synthetic approach produced clinical drug candidate YT-14, improving the overall yield from 1.3% to 13.8%. Compared with the previous route, the new route is two steps shorter and all of the steps involve purifications without column chromatography. The advantages of this procedure include simple operating conditions and higher yields.
Natural products and their derivatives are a precious treasure in the pursuit of potent anti-inflammatory drugs. In this work, we measured the toxicity of 78 LA derivatives at 20 μM using MTT, then we evaluated the NO release of compounds without obvious toxicity in LPS-induced RAW.264.7 by Griess reagent, we identified three compounds, namely compounds 6, 19, 70, which exhibited promising anti-inflammatory potential. These compounds exhibited IC
Abstract Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds 5a , 5c , 5e , 6 , and 15j addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds 5a and 5c having ED 50 values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound 5e was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three‐dimensional quantitative structure–activity relationship (3D‐QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.
Background: The treatment of tuberculosis has been a serious medical and health problem that needs to be solved urgently. Streptomycin has been one of the important anti-tuberculosis drugs for decades; however, no systematic structural modification of streptomycin has been done, which means that the anti-tuberculosis ability of streptomycin derivatives deserves further exploration. Objective: In this study, we investigated the effect of systematic structural modification of the aldehyde groups in streptomycin on its anti-tuberculosis activity. Methods: Streptomycin was selected as the lead compound, and its aldehyde group was modified to obtain hydrazone, amino hydrazide, and sulfonyl hydrazide derivatives, respectively. In addition, siderophore fragments were introduced into streptomycin. The anti-tuberculosis activities of the new compounds against H37Rv were evaluated. Results: A total of 21 novel streptomycin derivatives have been designed and synthesized. All compounds were characterized with 1H NMR, 13C NMR, and HRMS. The preliminary bioactivity test showed that most analogues bearing hydrazine, acylhydrazine, or sulfonyl hydrazine, such as 12a, 13a-d, and 15a-f, possessed potent anti-tuberculosis activity with MIC value of 2 μg/mL, which was comparable to streptomycin, while secondary amine or siderophore derivatives caused a dramatic reduction in activity. Conclusion: The structural modification and structure-activity relationship of the aldehyde group of streptomycin were systematically studied for the first time. The results showed that the aldehyde group was not necessary for exhibiting its activity. It was well tolerated when the aldehyde group was converted into hydrazine, acylhydrazine, or sulfonyl hydrazine. These novel analogues provide potential lead structures for further modification in the future.
Abstract Recently, we reported the promising activity of a series of novel bicyclic pyridine derivatives as antiplatelet agents. Herein, we describe a modified and improved chemical synthesis of the lead compound, 1‐(3‐cyano‐5‐oxo‐5,7‐dihydrofuro[3,4‐b]pyridin‐2‐yl)‐4‐methyl‐N‐((4‐methylbenzyl)sulfonyl)piperidine‐4‐carboxamide ( 1 ), with the aim to produce from milligrams to 10 g of the pure compound that is necessary for the preclinical studies. This novel process is one step shorter and starts from cheap materials, achieving a sevenfold of the total yield from 0.7 % to 5 %. Additionally, it also avoids the use of palladium on carbon as well as all of the steps involve simple purifications without chromatography.
Cefiderocol is the first approved catechol-conjugated cephalosporin against multidrug-resistant Gram-negative bacteria, while its application was limited by poor chemical stability associated with the pyrrolidinium linker, moderate potency against
The thermodynamic analyses and actual applications of wet compression have demonstrated its benefits for power augment. An aerodynamic flow field simulation of the wet compression compressor cascade can give more information about the cascade internal flow patterns. In this paper, a stage of wet compression compressor is simulated with computational fluid dynamics software. Three dimensional, two phases flows are numerically investigated under different water injected amount, different water droplet diameter etc. The CFD results present the details of wet compression compressor cascade flows. And the flow fields of wet compression are compared with those of dry compression.
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