Synthesis of a number of derivatives of alkaloids and of nitrogen-containing heterocycles and their anticholinesterase activities

N-Methyl- and N-phenylcarbamates based on a number of alkaloids and nitrogen-containing heterocycles have been synthesized, and they have proved to be weak irreversible inhibitors of acetylcholinesterase and butyrylcholinesterase. It has been shown that the choline fragments of the above-mentioned carbamates and their -methylcholine analogs are reversible inhibitors of both cholinesterases and make a substantial contribution to the anticholinesterase activity. Selective inhibitors of ACE and BuCE have been found among the compounds synthesized.A. S. Sadykov Institute of Bioorganic Chemistry, Academy of Sciences of the Uzbek SSR, Tashkent. Translated from Khimiya Prirodynkh Soedinenii, No. 6, pp. 825–831, November–December, 1988.     

Synthesis of lupinine esters and their interaction with cholinesterases

A number of lupinine esters of carboxylic acids and their hydrochlorides and methiodides have been synthesized. It has been shown that these compounds are reversible inhibitors of human blood erythrocyte acetylcholinesterase and horse blood serum butyryl cholinesterase. Noncompetitive inhibitors of these enzymes have been found among the compounds synthesized.A. S. Sadykov Institute of Bioorganic Chemistry, Academy of Sciences of the Uzbek SSR, Tashkent. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 75–79, January–February, 1990.     

Synthesis of bisindolylmaleimides related to GF109203x and their efficient conversion to the bioactive indolocarbazoles

From a structure-activity relationship perspective, the new indolocarbazoles 11 and 12 have been synthesized and evaluated biologically as novel Chk1 inhibitors. Compounds 11 and 12 were synthesized in high yield from indole via bisindolylmaleimides 18 and 24.     

Design,synthesis and anti-diabetic activity of chromen-2-one derivatives

DPP-IV inhibitors have been immersed as promising pathway to treat Type 2 diabetes. Here we have reported designing of coumarin derivatives as DPP-IV inhibitors. Designed compounds have been studied for their binding with DPP-IV enzyme through molecular docking followed by synthesis. All synthesized compounds have been fully characterized and screened for DPP-IV inhibition activity. Two compounds showed very good inhibition at 10 μM concentration.     

芳酰基吡咯里嗪衍生物的设计与合成

COX和5-LOX双重抑制剂通过同时阻断炎症介质前列腺素和白三烯的形成, 产生协同的抗炎作用, 可以提高疗效, 同时避免COX抑制剂引发的副作用. 以芳基吡咯里嗪为先导物, 设计合成了2类15个5或6位芳酰基取代的7-芳基-2,3-二氢-1H-吡咯里嗪衍生物进行抗炎活性研究; 也可以其为模板进行结构修饰与优化, 设计合成更好的COX/5-LOX双重抑制剂. 同时分析了同分异构体III和IV的波谱学性质, 并确证了化合物的结构.     

Diketene analogs as beta-lactamase inhibitor

Compounds having a structural analogy with diketene have been synthesized and their potencies as beta-lactamase inhibitors have been studied. Among six compounds so far tested, alpha-phenyl-beta-benzylidene-3-propanolide was shown to be an irreversible inhibitor of the enzyme. The availability of simple monocyclic compounds as beta-lactamase inhibitors is discussed.     

Rapid and efficient microwave-assisted synthesis of aryl aminobenzophenones using Pd-catalyzed amination

Substituted aryl aminobenzophenone p38 MAP kinase inhibitors were synthesized in good to excellent yields using palladium-catalyzed aryl amination under conditions of microwave irradiation. Various ligands have been screened, and the reaction conditions were optimized. These coupling reactions are suitable for various anilines and aryl bromides that bear a variety of functional groups. Some leaving groups (iodides, chlorides, triflates, and tosylates) other than bromides have also been investigated. By this method, a large number of aryl aminobenzophenone p38 MAP kinase inhibitors were prepared in short order.     

Piperidines: a new class of urease inhibitors

A variety of piperidines (2-12, 14-26) with variable substituents at N-atoms have been synthesized and evaluated as urease inhibitors. The synthesized compounds showed varying degree of urease inhibitory activity ranging from 31.97 to 254 microM. The size and electron-donating or -withdrawing effects of substituents influence the activity, which lead to the formation of urease inhibitors.     

Design and synthesis of inhibitors of adenosine and AMP deaminases

Nucleosides and nucleotides which are able to undergo covalent hydration in the aglycone ring system are potential inhibitors of the enzymes adenosine deaminase (ADA) and AMP deaminase, respectively. Calculations of the enthalpy of covalent hydration and of enzyme binding energy have been used to design new inhibitors of ADA. The ribosyl triazolotriazine 16, which was synthesized as a result of these calculations, exists predominantly as the covalent hydrate 18 in water and is a potent inhibitor of mammalian ADA (IC(50) 50 nM).     

N-alkyl-3-decarboxy-3-hydroxymethylsiastatin B, a new family of glycosidase inhibitors of gem-diamine 1-N-iminosugars

N-Alkyl-3-decarboxy-3-hydroxymethylsiastatin B, N-alkyl analogues of gem-diamine 1-N-iminosugars, is a new family of glycosidase inhibitors that have been synthesized from siastatin B isolated from Streptomyces culture. These compounds were evaluated as glycosidase inhibitors.     

Synthesis and Biological Activity of Pyrazolo[5,1-d] [1,2,3,5]-Tetrazine-4-ones

It is reported that benzo[1,2,3]-triazine-4-ones have widespread use, for instance, as diuretics, sedatives, tranquilizers and inflammation inhibitors and pyrazolo[1,5-a]-1,3,5-triazines are potent inhibitors of xanthine oxidase. So far,the herbicidal activities of above fused ring compounds and their analogues have not been studied. According to the principle of bioisotherism, pyrazolo[5,1-d] [1,2,3,5]-tetrazine-4-ones (2) have been developed and synthesized.     

Synthesis and biological evaluation of potential bisubstrate inhibitors of protein farnesyltransferase. Design and synthesis of functionalized imidazoles

A novel series of compounds, derived from 2,5-functionalized imidazoles, have been synthesized as potential bisubstrate inhibitors of protein farnesyltransferase (FTase) using structure-based design. These compounds have a 1,4-diacid chain and a tripeptide connected by an imidazole ring. The synthetic strategy relies on the functionalization at the C-2 position of the heterocycle with the diacid side chain and peptide coupling at the C-5 position. Several new compounds were synthesized in good yields. Kinetic experiments on the most active compounds revealed different binding modes depending on the diacid chain length.     

Medicinal Chemical Studies of Anti-Inflammatory and Analgesic Natural Products

Following the discovery of salicylates and its conversion to aspirin, natural products research has provided many promising leads for further modification as anti-inflammatory and analgesic agents. Recent studies have focused on biosynthesis inhibitors of eicosanoids and receptor antagonists of the platelet activating factor, including a new class of dual functional inhibitors derived from neolignans. The highly potent analgesic alkaloid epibatidine from the frog skin has been synthesized and recharacterized as a very strong acetylcholine nicotinic receptor agonist. Some novel epibatidine analogs have shown promise as potential CNS drugs and research probes for clarifying the anti-addictive property of the African alkaloid ibogaine.     

Total synthesis of psammaplysenes A and B, naturally occurring inhibitors of FOXO1a nuclear export

[reaction: see text] Two inhibitors of FOXO1a-mediated nuclear export, psammaplysenes A and B, have been synthesized by a flexible and efficient route. A common starting material, 4-iodophenol, was used to prepare both halves of these pseudosymmetric dibromotyrosine-derived metabolites.     

N1-Benzyl Tryptamine Pan-SHIP1/2 Inhibitors: Synthesis and Preliminary Biological Evaluation as Anti-Tumor Agents

Inhibition of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP) with small molecule inhibitors leads to apoptosis in tumor cells. Inhibitors that target both SHIP1 and SHIP2 (pan-SHIP1/2 inhibitors) may have benefits in these areas since paralog compensation is not possible when both SHIP paralogs are being inhibited. A series of tryptamine-based pan-SHIP1/2 inhibitors have been synthesized and evaluated for their ability to inhibit the SHIP paralogs. The most active compounds were also evaluated for their effects on cancer cell lines.     

Aziridine-2-carboxylic acid derivatives and its open-ring isomers as a novel PDIA1 inhibitors

Chemistry of Heterocyclic Compounds - Acyl derivatives of aziridine-2-carboxylic acid have been synthesized and tested as PDIA1 inhibitors. Calculations of charge value and distribution in...     

Synthesis of antimicrobial natural products targeting FtsZ: (+/-)-dichamanetin and (+/-)-2' '-hydroxy-5' '-benzylisouvarinol-B

[chemical structure: see text]. Two natural products have been synthesized using a ZnCl2-mediated benzylic coupling reaction. Both are potent inhibitors of the GTPase activity of FtsZ, a highly conserved protein that is essential for bacterial cytokinesis.     

Synthesis,structure, and anticholinesterase activity of some organophosphorus derivatives of anabasine

Anabasine derivatives based on methylphosphonothoic acid have been synthesized. It has been shown by PMR spectroscopy that in solution O-alkyl O-[β-(anabasin-1-yl)ethyl] methylphosphonothioates exist in two stereomeric forms, which is due to the influence of the optically active anabasine residue. It has been shown that these compounds are competitive reversible inhibitors of acetylcholinesterase and of butyrylcholinesterase.     

Design,Synthesis, and Structure–Activity Relationship Study of Potent MAPK11 Inhibitors

Huntington’s disease (HD) is a rare single-gene neurodegenerative disease, which can only be treated symptomatically. Currently, there are no approved drugs for HD on the market. Studies have found that MAPK11 can serve as a potential therapeutic target for HD. Regrettably, no MAPK11 small molecule inhibitors have been approved at present. This paper presents three series of compounds that were designed and synthesized based on the structure of skepinone-L, a known MAPK14 inhibitor. Among the synthesized compounds, 13a and 13b, with IC₅₀ values of 6.40 nM and 4.20 nM, respectively, displayed the best inhibitory activities against MAPK11. Furthermore, the structure–activity relationship (SAR) is discussed in detail, which is constructive in optimizing the MAPK11 inhibitors for better activity and effect against HD.     

Interception of quorum sensing in Staphylococcus aureus: a new niche for peptidomimetics

Pathogenesis in Staphylococcus aureus is dependent on local cell density and is regulated in part by small macrocyclic peptides. Natural and artificial peptide inhibitors of this quorum sensing response have been synthesized and evaluated in structure-activity relationship studies. These investigations have illuminated the quorum sensing mechanism and set the stage for the design of biostable, peptidomimetic inhibitors that could be developed ultimately as therapeutics.