Synthesis of sydnonimine derivatives as potential trypanocidal agents

N‐(p‐Nitrophenoxy)carbonyl‐3‐morpholino‐sydnonimine (NCMS) has been prepared from 3‐morpholinosydnonimine hydrochloride. Using the Griess assay and the superoxide‐mediated reduction of ferricytochrome c, the nitric oxide (NO?) and superoxide anion (O₂?^‐) ‐ releasing properties in phosphate buffer pH 7.4 of this novel peroxynitrite donor was studied and compared with the known 3‐morpholino‐sydnonimine (SIN‐1). From compound NCMS, a series of N‐substituted sydnonimine derivatives were easily prepared that contain purine or melaminophenyl groups which specify a recognition by a trypanosomal purine transporter. The ability of these new sydnonimines to inhibit the uptake of [2³H]adenosine on Trypanosoma equiperdum was studied.     

14N NMR study of some sydnones,sydnonimines and related structures

¹⁴N NMR spectra indicate that the sydnones, their hydrochlorides, the N-acetylsydnonimines, their hydrochlorides and the sydnonimine hydrochlorides studied exist as such in solution. The sydnonimines themselves are involved in a more complicated equilibrium; neutral solutions contain only the corresponding isomeric alkyl-cyanomethyl-nitrosoamine molecules which upon acidification are turned into cyclic cations, representing true sydnonimine structure, protonated at the exocyclic N atom.     

Study of conjugation in sydnones and sydnonimines by the simple MO LCAO method with Pullman parameters

A number of sydnone and sydnonimine derivatives were calculated by the simple Huckel method with Pullman parameters. Several physical characteristics of the molecules are compared with the calculated data.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1456–1464, November, 1970.     

Synthesis of 1-amino-[1,2,3]oxadiazolo[4,3-α]phthalazin-4-ium chloride and substituted dihydro derivatives. New annelated sydnonimines

The sydnonimine 5 has been prepared by an original one-pot nitrosation and cyclisation procedure of the carbonyl chloride Reissert adduct 14 of phthalazine. This synthetic method could be extended to the preparation of dihydro derivatives 7a to 7f and represents a new access to annelated sydnonimines. The para anisoyl and ethoxycarbonyl derivatives of these sydnonimines were also prepared with analogy to molsidomine 1 or pirsidomine 2 .     

Sydnonimines as exogenous NO donors

Chemical oxidation of a series of sydnonimine derivatives followed by NO release was studied. Substances having alkylamine substituents in the position 3 were shown to be considerably more potent NO donors in comparison with those having alkyl or aralkyl substituents in the position 3. It was suggested that the effect is mainly due to lowering of the activation energy of NO release upon stabilization of the cation formed competitevely by the amino group.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2725–2729, December, 2004.     

Some peculiarities of the cyclization of N-polynitroalkyl-N-nitrosoaminoacetic acids and their nitriles to sydnones and sydnonimines

The cyclization of N-polynitroalkyl-N-nitrosoaminoacetic acids to sydnones occurs only under the influence of trifluoroacetic anhydride. Closing to a sydnonimine ring does not occur in the case of N-(2,2,2-trinitroethyl)-N-nitrosoaminoacetonitrile, but N-(2,2,2-trinitroethyl)-N-nitrosoiminoacetic acid imino ester is formed. Removal of the nitro groups in the γ position relative to the nitrosoamino group leads to normal occurrence of the reaction to give polynitroalkylsydnonimines.     

酶促药物衍生化的研究进展

介绍了近年来药物酶促衍生化研究的新进展, 包括酶促衍生化各种脂溶性药物. 水溶性药物和一些研究比较活跃的药物, 从而提高药物生物利用度, 同时针对药物不同基团的选择性衍生化进行阐述.     

3-哌啶甲酸及其衍生物的合成与应用研究进展

3-哌啶甲酸及其衍生物是重要的药物中间体, 具有很高的生物活性. 综述了3-哌啶甲酸及其羧基酯化、不饱和、不同位置取代与多取代衍生物的合成方法, 并对3-哌啶甲酸及其衍生物在合成γ-氨基丁酸(GABA)摄入抑制剂、抗肿瘤药、生长激素促分泌素、消炎药物、心血管药物、促智药物、抗流感病毒、骨疾病等药物中的应用进行了概述.     

Artemisinin and Derivatives-Based Hybrid Compounds: Promising Therapeutics for the Treatment of Cancer and Malaria

Cancer and malaria are major health conditions around the world despite many strategies and therapeutics available for their treatment. The most used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multi-drug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. The currently ongoing preclinical studies have demonstrated that combination therapy is a potent approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to exhibit potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria.     

Chemical and Biological Aspects of Peptide Catecholamine Conjugates

Polymeric derivatives of D-isoproterenol have been prepared by diazotization to water-soluble, random copolypeptides of hydroxypropylglutamine and p-aminophenylalanine, molecular weight 1500, 3000, and 9600. The polymeric isoproterenol derivatives were purified by gel chromatography which reduced contamination by the parent catecholamine to undetectable levels (i. e., less than 0.01 wt %) and by 6-aminoisoproterenol (a possible decomposition product) to less than 0.4%. The derivatives were found to elicit positive chronotropic responses in isolated perfused guinea pig hearts, with mean effective doses (ED₅₀) which were between 1.3 and 2.0 orders of magnitude (for the 1500 and 9600 molecular weight derivatives, respectively) less than the ED50 for D-isoproterenol. Inotropic response decay times in isolated cat papillary muscles following washouts suggest that the polymer-bound drug does not diffuse into muscle tissues. In vivo biological studies (in conscious dogs) indicate that the polymeric drugs have significantly prolonged durations of action of between 5.5 ± 0.4 min for the derivative of highest (9600) molecular weight and 27.4 ± 4.9 min for the derivative of lowest (1500) molecular weight compared with 4.5 ± 0.14 min for a comparable dose of free isoproterenol. Possible explanations for the inverse relationship between the molecular weights of the derivatives and their in vivo durations of action are suggested. Our findings demonstrate that under controlled conditions isoproterenol can retain biological activity while covalently bound to a soluble polymeric support. The in vivo biological data suggest that the tethering of drugs to polymers may provide a means of maximizing the therapeutic utility of drugs with short half-lives.     

Targeting SARS-CoV-2 Polymerase with New Nucleoside Analogues

Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2.     

神经氨酸酶与三羟基甲氧基黄酮衍生物相互作用的分子模拟

以5,7,4'-三羟基-8-甲氧基黄酮(MF)为先导物, 以现有的神经氨酸酶(NA)抑制剂类药物的结构特征为参考, 设计了一系列的三羟基甲氧基黄酮衍生物, 并运用分子对接与分子动力学相结合的方法进行了筛选及作用机制分析. 分子对接结果表明, 功能团(羧基及胍基/氮-乙酰氨基)的引入并未影响衍生物在酶活性腔中的结合位置, 衍生物的结构与相互作用能之间存在一定的联系. 将羧基和胍基作为替代基团引入到MF的C7及C5位上所得的新化合物(9)在所合成的衍生物中具有最好的结合能力(-1172.52 kJ/mol), 远远优于现有先导药物4-(氮-乙酰氨基)-5-胍基-3-(3-戊氧基)安息香酸(BA)和MF与NA的结合能力(-672.12和-347.44 kJ/mol). 进一步的作用机制分析发现, 在神经氨酸酶活性腔中, 化合物9的羧基和胍基的空间取向与现有药物中这两个基团的空间取向一致, 且化合物9与先导药物MF一样, 能与活性腔内保守残基Asp151和Glu227发生较强的相互作用. 因此可认为化合物9是一种具有应用潜质的新型神经氨酸酶抑制剂. 本研究结果为实验研究和设计抗流感药物提供了可行性思路.     

壳聚糖及其衍生物应用于肥胖治疗的研究进展

肥胖是并发高血脂、脂肪肝、糖尿病和心脑血管损害等疾病的主要危险因子,减肥药物（食品）是一种有效的控制体重的手段。壳聚糖对脂肪和胆固醇具有良好的吸附性能,正在成为一种新型的减肥药物（食品）。结合本课题研究方向,综述了药用壳聚糖及其衍生物在治疗肥胖及其并发症方面应用的研究进展。通过在壳聚糖C6住-OH上改性制备了水溶性、油溶性和两亲性良好的壳聚糖衍生物,并通过动物试验研究了其减肥功效。     

Comparative study of degree-based molecular descriptors of cyclodextrins through M-polynomial and NM-polynomial

Cyclodextrins are natural oligosaccharides used to increase the solubility of drugs. It has numerous applications in drug discovery, food storage and other fields. Loftsson et al. explained about applications of Cyclodextrins(CDs) in administrating the drugs through various ways. Jansook et al. has given insights into the structure, physicochemical properties and pharmaceutical applications of CDs. In the present work, cyclodextrin and its derivatives such as α, β, γ CDs are studied for which various degree and neighborhood degree-based topological indices are computed through M-polynomial and NM-polynomial respectively and the comparison of the indices for all three types of cyclodextrins are presented which are of great importance in QSPR/QSAR studies.     

Mapping of stereoselective recognition sites on human serum transferrin by capillary electrophoresis and molecular modelling

Stereoselective recognition of chiral compounds can be used for mapping of surface interaction sites on proteins. Iron-free human serum transferrin is a suitable chiral selector in capillary electrophoresis used in native form in solution. Separation of optical isomers of tryptophan-methylester, tryptophan-ethylester and tryptophan-butylester and various drugs were studied in capillary zone electrophoresis applying a distinct transferrin zone prior to sample injection. Changes in the electrophoretic patterns (i.e., in the migration properties) of the molecules reflected the possible interactions with the protein. The tryptophan derivatives and eight drugs possessed stereoselective interactions, seven drugs showed interactions without appreciable chiral separation, and the others did not present any direct complexation with the protein molecules. Molecular modelling was performed to characterize the binding areas at the iron binding site of iron-free transferrin. The docking of tryptophan derivatives on transferrin showed that the R-enantiomers possess a stronger complexation with transferrin, whereas the S-enantiomers are bound by weaker interactions, which is in excellent agreement with the capillary electrophoresis results, where the R-enantiomers were always retarded stronger by transferrin. A ranking of drugs by the lipo score parameter of the docking shows an accordance with the stereoselective interactions by the protein.     

Bio-Organometallic Derivatives of Antibacterial Drugs

Overuse and misuse of antibacterial drugs has resulted in bacteria resistance and in an increase in mortality rates due to bacterial infections. Therefore, there is an imperative necessity of new antibacterial drugs. Bio-organometallic derivatives of antibacterial agents offer an opportunity to discover new active antibacterial drugs. These compounds are well-characterized products and, in several examples, their antibacterial activities have been studied. Both inhibition of the antibacterial activity and strong increase in the antibiotic activity of the parent drug have been found. The synthesis of the main classes of bio-organometallic derivatives of these drugs, as well as examples of the use of structure–activity relation (SAR) studies to increase the activity and to understand the mode of action of bio-organometallic antimicrobial peptides (BOAMPs) and platensimicyn bio-organometallic mimics is presented in this article.     

卟啉类第二代光敏剂的发展

本文对目前用于光动力治疗的以卟啉为基础的第二代光敏剂进行了综述, 这些光敏剂中的大部分已进入临床或临床前试验, 光物理性质研究表明它们是很有前途的光动力药物. 本文同样介绍了连接生物分子和硼烷的卟啉衍生物, 作为光疗剂, 它们具有非常光明的前途.     

Antiviral Potential of Naphthoquinones Derivatives Encapsulated within Liposomes

HSV infections, both type 1 and type 2, are among the most widespread viral diseases affecting people of all ages. Their symptoms could be mild, with cold sores up to 10 days of infection, blindness and encephalitis caused by HSV-1 affecting immunocompetent and immunosuppressed individuals. The severe effects derive from co-evolution with the host, resulting in immune evasion mechanisms, including latency and growing resistance to acyclovir and derivatives. An efficient alternative to controlling the spreading of HSV mutations is the exploitation of new drugs, and the possibility of enhancing their delivery through the encapsulation of drugs into nanoparticles, such as liposomes. In this work, liposomes were loaded with a series of 2-aminomethyl- 3-hydroxy-1,4-naphthoquinones derivatives with n-butyl (compound 1), benzyl (compound 2) and nitrobenzene (compound 3) substituents in the primary amine of naphthoquinone. They were previously identified to have significant inhibitory activity against HSV-1. All of the aminomethylnaphthoquinones derivatives encapsulated in the phosphatidylcholine liposomes were able to control the early and late phases of HSV-1 replication, especially those substituted with the benzyl (compound 2) and nitrobenzene (compound 3), which yields selective index values that are almost nine times more efficient than acyclovir. The growing interest of the industry in topical administration against HSV supports our choice of liposome as a drug carrier of aminomethylnaphthoquinones derivatives for formulations of in vivo pre-clinical assays.