Design,Synthesis and Evaluation of Rhodanine Derivatives as Aldose Reductase Inhibitors

Aldose reductase (ALR) enzyme plays a significant role in conversion of excess amount of glucose into sorbitol in diabetic condition, inhibitors of which decrease the secondary complication of diabetes mellitus. To understand the structural interaction of inhibitors with ALR enzyme and develop more effective ALR inhibitors, a series of substituted 5-phenylbenzoate containing N-substituted rhodanine derivatives were synthesized and evaluated for their in vitro ALR inhibitory activity. Docking studies of these compounds were carried out, which revealed that the 5-phenylbenzoate moiety deeply influenced the key π-π stacking while 4-oxo-2-thioxothiazolidines contributed in hydrogen bond interactions. The phenyl ring of benzylidene system occupied in specific pocket constituted from Phe115, Phe122, Leu300 and Cys303 while the rhodanine ring forms a tight net of hydrogen bond with Val47 at anionic binding site of the enzyme. The structural insights obtained from the docking study gave better understanding of rhodanine and macromolecular interaction and will help us in further designing and improving of ALR inhibitory activity of rhodanine analogs.     

培氟沙星C-3(绕丹宁不饱和酮)酰胺的合成及抗肿瘤活性

为发现将抗菌药氟喹诺酮转化为抗肿瘤药的结构修饰新策略,用酰氨基和绕丹宁不饱和酮分别作为培氟沙星(1)C-3羧基的等排体和修饰基,设计合成了12个新的培氟沙星C-3(绕丹宁不饱和酮)酰胺类目标化合物(6a~6l),其结构经元素分析和光谱数据确证。体外抗增殖活性结果显示,目标化合物对Hep-3B、Capan-1和L1210 3种肿瘤细胞株的活性显著高于母体培氟沙星,含芳杂环或氟苯基化合物的活性与对照抗肿瘤药阿霉素相当。由此推测酰氨基绕丹宁不饱和酮杂合骨架替代C-3羧基有利于提高氟喹诺酮的抗肿瘤活性。     

Design,synthesis, biological evaluation,and molecular modeling studies of rhodanine derivatives as pancreatic lipase inhibitors

A series of rhodanine‐3‐acetic acid derivatives were synthesized via Knoevenagel condensation of rhodanine‐3‐acetic acid with various substituted aromatic aldehydes. The synthesized derivatives were screened in vitro for understanding the inhibitory potential towards pancreatic lipase (PL), a key enzyme responsible for the digestion of dietary fats. Derivative 8f exhibited a potential inhibitory activity towards PL (IC₅₀ = 5.16 µM), comparable to that of the standard drug, orlistat (0.99 µM). An increase in the density of the aromatic ring resulted in potential PL inhibition. The enzyme kinetics of 8f exhibited a reversible competitive‐type inhibition, similar to that of orlistat. Derivative 8f exhibited a MolDock score of ‐125.19 kcal/mol in docking studies, and the results were in accordance with their PL inhibitory potential. Furthermore, the reactive carbonyl group of 8f existed at a distance adjacent to Ser152 (≈3 Å) similar to that of orlistat. Molecular dynamics simulation (10 ns) of the 8f ‐PL complex revealed a stable binding conformation of 8f in the active site of PL (maximum root mean square displacement of ≈2.25 Å). The present study identified novel rhodanine‐3‐acetic acid derivatives with promising PL inhibitory potential, and further lead optimization might result in potent PL inhibitors.     

Pharmacophoric features for a very potent 5‐spirofluorenehydantoin inhibitor of cancer efflux pump ABCB1, based on X‐ray analysis

In order to extend knowledge about pharmacophoric features responsible for ABCB1 inhibitory properties of imidazolidin‐2,4‐dione derivatives, 1′‐[4‐(4‐(o‐methoxyphenyl)‐piperazin‐1‐yl)butyl]‐3′‐methyl‐spiro(fluoren‐9,5′‐imidazolidine)‐2′,4′‐dione ( 3 ) and its salt ( 4 ) with rhodanine‐3‐acetic acid ( RA ) were prepared and investigated by X‐ray diffraction method, as well as their efflux modulating effects in cancer cells (mouse T‐lymphoma), cytotoxic and antiproliferative activities were evaluated in vitro. The molecular geometry, intermolecular interactions, and crystal packing of base and acid forms of 3 were analyzed to see, if conformational changes influence the biological activities. The geometry of 2‐methoxyphenylpiperazine and 5‐spirofluorenehydantoin moieties was compared with other crystal structures containing these fragments. Our results indicated a very potent inhibitory action on ABCB1 pump, and significant cytotoxic and antiproliferative properties of 3 in T‐lymphoma, even more potent in the case of multidrug resistance cells. Furthermore, the compound 3 converted into the salt 4 of inactive acid ( RA ) has maintained both, the efflux pump inhibitory and antiproliferative activities, showing strong synergism with doxorubicin. A comparison of geometry of 3 in both crystal structures ( 3 and 4 ) shows a significant difference in the arrangement of piperazine ring with respect to the aliphatic linker.     

依帕司他的合成

对醛搪还原酶抑制剂依帕司他的合成工艺作了改进，使中间体绕丹宁乙酸的收率提高到７６．４％。     

Rhodanine as a scaffold in drug discovery: a critical review of its biological activities and mechanisms of target modulation

Introduction: Rhodanine-based compounds have been associated with numerous biological activities. After many years of research in drug discovery, they have gained a reputation as being pan assay interference compounds (PAINS) and frequent hitters in screening campaigns. Rhodanine-based compounds are also aggregators that can non-specifically interact with target proteins as well as Michael acceptors and interfere photometrically in biological assays due to their color.

Areas covered: The authors review the recently reported biological activities of rhodanine-based compounds. Furthermore, the article provides details of their synthesis and occurrence in compound libraries through high-throughput screening (HTS) and virtual high-throughput screening (VHTS). Additionally, the authors provide the reader with possible mechanisms of non-specific target modulation, analysis of the crystal structures of enzyme–rhodanine complexes and a comparison of rhodanine and thiazolidine-2,4-dione moieties.

Expert opinion: The biological activity of compounds possessing a rhodanine moiety should be considered very critically despite the convincing data obtained in biological assays. In addition to the lack of selectivity, unusual structure–activity relationship profiles and safety and specificity problems mean that rhodanines are generally not optimizable.     

Rhodanine derivatives as selective protease inhibitors against bacterial toxins

In this study, we analyzed a series of rhodanine derivatives, as potential inhibitors of bacterial toxins, namely the proteases anthrax lethal factor and the botulinum neurotoxin type A. Conducting an extensive structure-activity relationship study on rhodanine derivatives, we profiled their selectivity against the two bacterial toxins and two related human metalloproteases using in vitro assays. In addition, we examined initial in vitro ADME-Tox properties of selected compounds and their ability to protect lethal factor-induced cell death of macrophages. These data allowed the selection of one additional drug candidate for which preliminary in vivo efficacy studies against anthrax spores were conducted. Integration of these results with our structure-activity relationship studies provides a framework for the development of potential drug candidates against anthrax and botulinum.     

The Rhodadyns,a New Class of Small Molecule Inhibitors of Dynamin GTPase Activity

相似文献   

玫瑰红银分光光度法测定纳米银胶体溶液中的痕量银

目的:建立纳米银胶体溶液中银的含量测定方法。方法:以浓硝酸作溶剂溶解纳米粒沉淀后,在表面活性剂作用下,与对二甲氨基苄基罗丹宁(玫瑰红银试剂)反应生成橙红色络合物,采用紫外分光光度法,于475nm波长处检测银含量。结果:测得银离子在0.05～1.50mg.L-1范围内,吸光度与浓度呈良好线性关系(r=0.999 9);平均回收率为96.04%(n=9,RSD为1.82%)。结论:上述方法操作简便,便于开展,方法灵敏,适用于测定纳米银胶体溶液中主要成分的含量测定。     

Viral membranes: an emerging antiviral target for enveloped viruses?

Evaluation of: Wolf MC, Freiberg AN, Zhang T et al. A broad-spectrum antiviral targeting entry of enveloped viruses. Proc. Natl Acad. Sci. USA 107, 3157–3162 (2010).

The emergence and re-emergence of viruses and the widespread antiviral resistance calls for the development of a broad-spectrum strategy for viral infection. The article under review describes an approach to achieve this goal by developing an antiviral rhodanine derivative effective against enveloped viruses targeting the viral lipid membrane. By intercalating into the viral membrane, the compound irreversibly inactivates the virions with virucidal effects. Potential toxic effects on hosts could be minimized by continuous regeneration of cellular membranes. The present strategy exploits the therapeutic window that exists between static viral membranes and biogenic cellular membranes and provides a useful guideline for future research endeavors towards broad-spectrum antiviral approaches for enveloped viruses. Developing a formulation that ensures efficient delivery and pharmacokinetic properties while minimizing systemic toxicity on cell membranes remains a challenge. The advantages and disadvantages of a viral membrane-targeting approach for the control of emerging and re-emerging viruses will be discussed.