24,168 results match your criteria Bioorg. Med. Chem. Lett.[Journal]


Synthesis and biological evaluation of thioadatanserin and its dialkylated products as partial 5-HTR agonists and 5-HTR antagonists for potential use in depression and anxiety disorders.

Bioorg Med Chem Lett 2020 Aug 17;30(16):127358. Epub 2020 Jun 17.

Department of Chemistry, Small Molecule X-ray Crystallography Facility, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.

Thionation of adatanserin hydrochloride (2) with Lawesson's reagent in toluene/triethylamine afforded novel compound, (3r,5r,7r)-N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)adamantane-1-carbothioamide (thioadatanserin, 3) in 84-90% isolated yield. Thioadatanserin underwent a tandem double alkylation with methyl iodide and benzyl bromide in NaH/THF to produce novel dialkylated products 6 and 7 respectively. The single X-ray crystal structure of 7 was determined to be 1-(2-((E- ((3r,5r,7r)-adamantan-1-yl)benzylthio)methylene)amino)ethyl)-1-benzyl-4- (pyrimidin-2-yl)piperazin-1-ium bromide showing that the piperazine ring adopts a chair-like configuration that is not co-planar with the pyrimidine ring. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127358DOI Listing

Structural basis for the stabilization of amyloidogenic immunoglobulin light chains by hydantoins.

Bioorg Med Chem Lett 2020 Aug 16;30(16):127356. Epub 2020 Jun 16.

Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:

Misfolding and aggregation of immunoglobulin light chains (LCs) leads to the degeneration of post-mitotic tissue in the disease immunoglobulin LC amyloidosis (AL). We previously reported the discovery of small molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which slow or stop the LC aggregation cascade at the outset. A predominant structural category of kinetic stabilizers emerging from the high-throughput screen are coumarins substituted at the 7-position, which bind at the interface between the two variable domains of the light chain dimer. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127356DOI Listing

Synthesis and biological evaluation of Schizandrin derivatives as tubulin polymerization inhibitors.

Bioorg Med Chem Lett 2020 Aug 16;30(16):127354. Epub 2020 Jun 16.

Centre for Natural Products & Traditional Knowledge, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address:

A series of oxime ester-derivatives were prepared by utilizing the schizandrin (1), a major compound isolated from Schisandra grandiflora, which is deployed in different traditional system of medicine. The in vitro antiproliferative activities of the synthesized compounds were assessed against a selected panel of human cancer cell lines (A549, RKO P3, DU145 and Hela) and normal cell (HEK293). Several of these derivatives were found more potent in comparison to parent compound, schizandrin (1). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127354DOI Listing

Improving NK1R-targeted gene delivery of stearyl-antimicrobial peptide CAMEL by conjugating it with substance P.

Bioorg Med Chem Lett 2020 Aug 15;30(16):127353. Epub 2020 Jun 15.

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China. Electronic address:

Specificity is a crucial condition that hampers the application of non-viral vectors for cancer gene therapy. In a previous study, we developed an efficient gene vector, stearyl-CAMEL, using N-terminal stearylation of the antimicrobial peptide CAMEL. Substance P (SP), an 11-residue neuropeptide, rapidly enters cells after binding to the neurokinin-1 receptor (NK1R), which is expressed in many cancer cell lines. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127353DOI Listing

Chemical constituents of Callistemon citrinus from Egypt and their antiausterity activity against PANC-1 human pancreatic cancer cell line.

Bioorg Med Chem Lett 2020 Aug 18;30(16):127352. Epub 2020 Jun 18.

Division of Natural Drug Discovery, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address:

Human pancreatic cancer is resistant to almost all conventional chemotherapeutic agents. It is known to proliferate aggressively within hypovascular tumor microenvironment by exhibiting remarkable tolerance to nutrition starvation,  a phenomenon termed as "austerity". Search for the new agents that eliminate the tolerance of cancer cells to nutrition starvation is a promising strategy in anticancer drug discovery. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127352DOI Listing

The synthesis and antituberculosis activity of 5-alkynyl uracil derivatives.

Bioorg Med Chem Lett 2020 Aug 13;30(16):127351. Epub 2020 Jun 13.

Department of Chemistry, Lomonosov Moscow State University, 1 Leninskie Gory, Moscow 119991, Russian Federation; Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severny proezd, Chernogolovka, Moscow Region 142432, Russian Federation.

A series of new 5-alkynyl-substituted uracil and uridine derivatives were synthesised via palladium-catalysed Sonogashira cross-coupling reaction of 5-bromo-pyrimidine base with terminal acetylenes with good yields in DMF at room temperature. All obtained compounds were tested for antimycobacterial activity against Mycobacetrium bovis and Mycobacterium tuberculosis (H37Ra) at concentrations of 1-100 µg/ml using MABA test. Obtained results revealed that most of tested uracil derivatives exhibited high antimycobacterial activity (MIC = 1. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127351DOI Listing

A chalcone derivative binds a putative allosteric site of YopH: Inhibition of a virulence factor of Yersinia.

Bioorg Med Chem Lett 2020 Aug 12;30(16):127350. Epub 2020 Jun 12.

Centro de Biologia Molecular Estrutural, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Campus Trindade, Florianópolis, SC 88040-900, Brazil; Universidade Federal do Piauí, CPCE, Bom Jesus, PI 64900-000, Brazil. Electronic address:

Identification of allosteric inhibitors of PTPs has attracted great interest as a new strategy to overcome the challenge of discover potent and selective molecules for therapeutic intervention. YopH is a virulence factor of the genus Yersinia, validated as an antimicrobial target. The finding of a second substrate binding site in YopH has revealed a putative allosteric site that could be further exploited. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127350DOI Listing

Structure-activity relationship study of cytotoxic neolignan derivatives using multivariate analysis and computation-aided drug design.

Bioorg Med Chem Lett 2020 Aug 12;30(16):127349. Epub 2020 Jun 12.

Center of Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, Brazil. Electronic address:

Dehydrodieugenol B and five related natural neolignans were isolated from the Brazilian plant species Nectandra leucantha. Three of these compounds were shown to be active against murine (B16F10) and human (A2058) melanoma cells but non-toxic to human fibroblasts (T75). These results stimulated the preparation of a series of 23 semi-synthetic derivatives in order to explore structure-activity relationships and study the biological potential of these derivatives against B16F10 and A2058 cell lines. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127349DOI Listing

Direct monitoring of live human pluripotent stem cells by a highly selective pluripotency sensor.

Bioorg Med Chem Lett 2020 Aug 12;30(16):127347. Epub 2020 Jun 12.

School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, South Korea. Electronic address:

Human pluripotent stem cells (hPSCs) are a useful cell source for regenerative medicine. Despite having a potential of hPSCs for cell-based therapy, there is a need for a selective human pluripotency sensor for monitoring of live hPSCs. Here, we report the discovery of a novel pluripotency sensor (SHI5) from BODIPY-based library by high-throughput cell-based screening and describe the use of SHI5 to identify and isolate human embryonic stem cells and human induced pluripotent stem cells. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127347DOI Listing

Non-food bioactive products for insecticides (II): Investigation on stress responses of Tetranychus cinnabarinus Boisduval against a derivative of the alkaloid matrine.

Bioorg Med Chem Lett 2020 Aug 12;30(16):127346. Epub 2020 Jun 12.

College of Plant Protection, Northwest A&F University, Yangling 712100, Shaanxi Province, PR China; Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, College of Life Science, Huzhou University, Huzhou 313000, Zhejiang Province, PR China. Electronic address:

Besides structural modification of natural bioactive products to afford promising agrochemical candidates, investigation of their mechanisms of action against pests is also an important strategy to obtain novel potentially botanical pesticides. N-(p-Ethyl)phenylsulfonylmatrinic acid (2), derived from an natural alkaloid matrine (1), exhibited about 5.9-fold more pronounced acaricidal activity than 1 against the adult females of Tetranychus cinnabarinus Boisduval, and good control efficiency in the greenhouse. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127346DOI Listing

A dual-app nucleoside probe reports G-quadruplex formation and ligand binding in the long terminal repeat of HIV-1 proviral genome.

Bioorg Med Chem Lett 2020 Aug 12;30(16):127345. Epub 2020 Jun 12.

Department of Chemistry, Indian Institute of Science Education and Research (IISER), Pune Dr. Homi Bhabha Road, Pune 411008, India. Electronic address:

We have developed a dual-app nucleoside analog, 5-selenophene-modified 2'-deoxyuridine (dU), to probe the structure and ligand-binding properties of a G-rich segment present in the long terminal repeat (LTR) of the HIV-1 proviral DNA promoter region. The nucleoside probe is made of an environment-responsive fluorophore and X-ray crystallography phasing label (Se atom). dU incorporated into LTR-IV sequence, fluorescently reports the formation of G-quadruplex (GQ) structure without affecting the native fold. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127345DOI Listing

SAR of non-hydrolysable analogs of pyridoxal 5'-phosphate against low molecular weight protein tyrosine phosphatase isoforms.

Bioorg Med Chem Lett 2020 Aug 10;30(16):127342. Epub 2020 Jun 10.

Department of Chemistry, College of Saint Benedict, Saint John's University, St. Joseph, MN 56374, United States. Electronic address:

Kinases and phosphatases are key enzymes in cell signal transduction pathways. Imbalances in these enzymes have been linked to numerous disease states ranging from cancer to diabetes to autoimmune disorders. The two isoforms (IFA and IFB) of Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) appear to play a role in these diseases. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127342DOI Listing

Synthesis and anti-inflammatory activity of 2-oxo-2H-chromenyl and 2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates.

Bioorg Med Chem Lett 2020 Aug 10;30(16):127341. Epub 2020 Jun 10.

Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; AcSIR-Postal Staff College Area, Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201002, India. Electronic address:

Cycloaddition reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehydes (3a-g) and 4-chloro-2H-chromene-3-carbaldehydes (7a-h) with activated alkynes (4a-b) provided the 2-oxo-2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates (5a-n) and 2H-chromenyl-5-oxo-2,5-dihydrofuran-3-carboxylates (8a-p). All the prepared compounds were screened for anti-inflammatory activity. In vitro anti-inflammatory activity data demonstrated that the compounds 5g, 5i, 5k-l and 8f are effective among the tested compounds against TNF-α (1. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127341DOI Listing

Single-crystal structure and intracellular localization of Zn(II)-thiosemicarbazone complex targeting mitochondrial apoptosis pathways.

Bioorg Med Chem Lett 2020 Aug 9;30(16):127340. Epub 2020 Jun 9.

Medcine College of Pingdingshan University, Pingdingshan, Henan 467000, China. Electronic address:

Tracking of drugs in cancer cells is important for basic biology research and therapeutic applications. Therefore, we designed and synthesised a Zn(II)-thiosemicarbazone complex with photoluminescent property for organelle-specific imaging and anti-cancer proliferation. The Zn(AP44eT)(NO) coordination ratio of metal to ligand was 1:1, which was remarkably superior to 2-((3-aminopyridin-2-yl) methylene)-N, N-diethylhydrazinecarbothioamide (AP44eT·HCl) in many aspects, such as fluorescence and anti-tumour activity. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127340DOI Listing

Design, synthesis and biological activity evaluation of novel 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as potent transforming growth factor-β (TGF-β) type I receptor inhibitors.

Bioorg Med Chem Lett 2020 Aug 10;30(16):127339. Epub 2020 Jun 10.

Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address:

TGF-β type I receptor (also known as activin-like kinase 5 or ALK5) plays a critical role in the progression of fibrotic diseases and tumor invasiveness and metastasis, as well. The development of small inhibitors targeting ALK5 has been validated as a potential therapeutic strategy for fibrotic diseases and cancer. Here, we developed various 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as ALK5 inhibitors. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127339DOI Listing

Studies on the stereoselective synthesis and immunosuppressive activity of dihydroartemisinin-O-glycoside derivatives.

Bioorg Med Chem Lett 2020 Aug 10;30(16):127338. Epub 2020 Jun 10.

Shanghai Jiao Tong University School of Medicine, PR China; Shanghai University of Traditional Chinese Medicine, PR China. Electronic address:

Eight new dihydroartemisinin-O-glycosides were synthesized with their relative configurations were determined based on NMR spectrum. In vitro immunosuppressive assay showed that 10α-dihydroartemisinin-β-O-d-mannoside (19a) demonstrate 88% inhibition towards T cells proliferation and 98% reduction in IFN-γ levels in cell media. These results suggest that dihydroartemisinin-O-glycoside as a potential lead for further in vivo evaluation. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127338DOI Listing

Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors.

Bioorg Med Chem Lett 2020 Aug 12;30(16):127337. Epub 2020 Jun 12.

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11562, Egypt. Electronic address:

A novel series of 1,6-disubstituted pyrazolo[3,4-d]pyrimidin-7-one derivatives, 2a-h, 4a-d, 5 and 6, were successfully synthesized, which showed promising, and potent inhibition of phosphodiesterase 5 (PDE5). The inhibitory activities of 5, 4b, 2a, 2d, 2f, 4d and 4a against PDE5 were similar to that of sildenafil (100%). These compounds exhibited potent relaxant effects on isolated rat cavernosum tissue with pEC values ranging from 8. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127337DOI Listing

Chloroquine fumardiamides as novel quorum sensing inhibitors.

Bioorg Med Chem Lett 2020 Aug 9;30(16):127336. Epub 2020 Jun 9.

University of Zagreb, Faculty of Pharmacy and Biochemistry, HR 10000 Zagreb, Croatia. Electronic address:

Quorum sensing inhibitors (QSIs) that specifically interfere with bacterial cell-to-cell communication are considered as an alternative approach to conventional antibacterial therapy. In our study, a set of twenty-six fumardiamides with a quinoline head-group were evaluated as potential QSIs. Two strains of Gram-negative Chromobacterium violaceum (violacein-producing strain ATCC31532 and violacein-negative, mini-Tn5 mutant derivative CV026) were used as QS reporters for testing anti-QS and bactericidal activity of various quinoline fumardiamides. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127336DOI Listing

Synthesis and antiproliferative activity of C- and N-terminal analogues of culicinin D.

Bioorg Med Chem Lett 2020 Aug 9;30(16):127331. Epub 2020 Jun 9.

School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland 1010, New Zealand; The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1010, New Zealand; School of Biological Sciences, The University of Auckland, 3A Symonds St, Auckland 1010, New Zealand. Electronic address:

Culicinin D (1), a 10 amino acid peptaibol containing several unusual residues, has been shown to exhibit potent anticancer activity. Previous work in our group towards developing a structure-activity relationship (SAR) for this peptaibol has concentrated on replacement of the synthetically challenging AHMOD (3) and AMD (4) residues, resulting in the discovery of analogues with equivalent or better potency and simplified synthesis. The SAR of this peptaibol is extended in this work by investigating the effect of the N-terminal lipid tail and C-terminal amino alcohol, revealing the key contribution of each of these moieties on antiproliferative activity in a panel of breast and lung cancer cell lines. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127331DOI Listing

Exploring the newer oxadiazoles as real inhibitors of human SIRT2 in hepatocellular cancer cells.

Bioorg Med Chem Lett 2020 Aug 11;30(16):127330. Epub 2020 Jun 11.

Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.

A novel series of indazole tethered oxadiazoles (OTDs) derivatives were synthesized, characterized and screened for their anti-proliferative activity against hepatocellular carcinoma (HCC) cells. OTDs structure was further confirmed by Single-crystal X-ray diffraction studies. Among the tested OTDs, compound 2-(4-methoxyphenyl)-5-(1-methyl-1H-indazol-3-yl)-1,3,4-oxadiazole was found to inhibit the catalytical activity of SIRT2 and brings about apoptosis as shown by western blot analysis and flow cytometry data. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127330DOI Listing

Design, synthesis and biological evaluation of novel pteridinone derivatives possessing a hydrazone moiety as potent PLK1 inhibitors.

Bioorg Med Chem Lett 2020 Aug 8;30(16):127329. Epub 2020 Jun 8.

School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Yangtze River Pharmaceutical Group Pharmaceutical Co., Ltd, 1 South Yangtze River Road Taizhou, Jiangsu 225321, China. Electronic address:

A series of novel pteridinone derivatives possessing a hydrazone moiety were designed, synthesized and evaluated for their biological activity. Most of the synthesized compounds demonstrated moderate to excellent activity against A549, HCT116 and PC-3 cancer cell lines. In particular, compound L exhibited the most potent antiproliferative effects on three cell lines with IC values of 3. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127329DOI Listing

Design, synthesis and biological evaluation of 2-methyl-(1,1'-biphenyl)-pyrimidine conjugates.

Bioorg Med Chem Lett 2020 Aug 10;30(16):127328. Epub 2020 Jun 10.

Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, China. Electronic address:

Small molecule inhibitors of biphenyl structure as core backbone have shown a significant effect on PD-1/PD-L1 axis, and 2-amino-pyrimidine structure is a promising privileged scaffold in medicinal chemistry and drug discovery. We designed by combination principles and synthesized 27 novel compounds with N-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrimidin-2-amine as a basic skeletal structure, and their anti-cancer activity was evaluated. Among compounds, 15a-d and 16b displayed strong anti-cancer effects on 9 tested cancer cell lines, in particular, the 16b did the highest inhibitive activity, but against HepG2 cells, and possessed the lowest IC value of 2. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127328DOI Listing

Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation.

Bioorg Med Chem Lett 2020 Aug 9;30(16):127327. Epub 2020 Jun 9.

Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address:

The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127327DOI Listing

Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[C]methoxyphenethyl)pyridazin-3(2H)-one, a C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

Bioorg Med Chem Lett 2020 Aug 9;30(16):127326. Epub 2020 Jun 9.

Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States. Electronic address:

Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer's patients with early phase. Herein we report the synthesis and preliminary evaluation of a C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127326DOI Listing

Anticonvulsant and analgesic in neuropathic pain activity in a group of new aminoalkanol derivatives.

Bioorg Med Chem Lett 2020 Aug 7;30(16):127325. Epub 2020 Jun 7.

Jagiellonian University Medical College, Faculty of Pharmacy, Chair of Organic Chemistry, Department of Bioorganic Chemistry, Medyczna 9, 30-688 Kraków, Poland. Electronic address:

As part of the presented research, thirteen new aminoalkanol derivatives were designed and obtained by chemical synthesis. In vivo studies (mice, i.p. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127325DOI Listing

Design and synthesis of potent inhibitors of bc complex based on natural product neopeltolide.

Bioorg Med Chem Lett 2020 Aug 8;30(16):127324. Epub 2020 Jun 8.

Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Chemical Biology Center, Central China Normal University, Wuhan 430079, PR China; Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300071, PR China. Electronic address:

Neopeltolide, a natural product isolated from deep-water sponge specimen of the family neopeltidae, has been proven to be a novel inhibitor of cytochrome bc. In this study, a series of neopeltolide derivatives was designed by replacing the 14-membered macrolactone with indole ring and confirmed by H NMR, C NMR, and HRMS. Based on the binding mode of 12h with bc complex, the IC values of compounds 16a-f (ranging from 0. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127324DOI Listing

Discovery of ASP5286: A novel non-immunosuppressive cyclophilin inhibitor for the treatment of HCV.

Bioorg Med Chem Lett 2020 Aug 4;30(16):127308. Epub 2020 Jun 4.

Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.

Evidence indicates that hepatitis C virus (HCV) utilizes cellular cyclophilin proteins in its replication, and cyclophilin inhibitors represent a new class of anti-HCV agents. We have established an efficient synthetic methodology to generate FR901459 derivatives via N, O-acyl migration reaction while avoiding total synthesis. Through a detailed structure-activity relationship study, we improved anti-HCV activity while decreasing immunosuppressive activity. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127308DOI Listing

Decaturenol A and known oxalicine related meroterpenoids isolated from Penicillium decaturense RO050, and their new biological activities.

Bioorg Med Chem Lett 2020 Aug 5;30(16):127307. Epub 2020 Jun 5.

Laboratory of Medical Microbiology, School of Pharmacy, Nihon University, 7-7-1, Narashinodai, Funabashi 274-8555, Chiba, Japan.

Decaturenol A (1), a new oxalicine related meroterpenoid, has been isolated from Penicillium decaturense RO050 along with seven known compounds (2-8). The structure of 1 was elucidated by spectroscopic data. The effects of isolated compounds (1-8) on endoplasmic reticulum (ER) stress-induced cell death in HT22 hippocampal nerve cells and on the interleukin 10 (IL-10)-induced expression of CD163, a M2 phenotype marker, in human monocyte-derived macrophages were evaluated. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127307DOI Listing

T-UCRs with digestive and respiratory diseases.

Bioorg Med Chem Lett 2020 Aug 2;30(16):127306. Epub 2020 Jun 2.

School of Traditional Chinese Materia Medica, Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address:

From the perspective of histoembryology, the lung, gaster, and intestines that derived from the endoderm of the gastrula are structurally homologous. The interplay of intestines and lung in many pathologic changes is called the gut-lung axis. RNAs transcribed from ultraconserved regions (T-UCRs) are highly evolutionarily conserved in many mammalian genomes and have been found to be important in the pathogenesis and diagnosis of many diseases. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127306DOI Listing

Synthesis and dopamine receptor pharmacological evaluations on ring C ortho halogenated 1-phenylbenzazepines.

Bioorg Med Chem Lett 2020 Aug 4;30(16):127305. Epub 2020 Jun 4.

Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Program in Chemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA; Program in Biochemistry, CUNY Graduate Center, 365 5(th) Avenue, New York, NY 10016, USA. Electronic address:

A series of 1-phenylbenzazepines containing bromine or chlorine substituents at the ortho position of the appended phenyl ring (2'-monosubstituted or 2',6'- disubstituted patterns) were synthesized and evaluated for affinity towards dopamine DR, DR and DR. As is typical of the 1-phenylbenzazepine scaffold, the compounds displayed selectivity towards DR and DR; analogs generally lacked affinity for DR. Interestingly, 2',6'-dichloro substituted analogs showed modest DR versus DR selectivity whereas this selectivity was reversed in compounds with a 2'-halo substitution pattern. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127305DOI Listing

Synthesis and anti-proliferative activity of a novel 1,2,3-triazole tethered chalcone acetamide derivatives.

Bioorg Med Chem Lett 2020 Aug 4;30(16):127304. Epub 2020 Jun 4.

Fluoro-Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India. Electronic address:

A new series of 1,2,3-triazole tethered chalcone acetamide derivatives (7a-c &8a-r) have been synthesized in excellent yields and their structures were determined by analytical and spectral (FT-IR, H NMR, C NMR & HRMS) studies. The newly synthesized derivatives were evaluated for their cytotoxic activity against four human cancer cell lines, such as HeLa (Human cervical cancer), A549 (Human alveolar adenocarcinoma), MCF-7 (Human breast adenocarcinoma) and SKNSH (Human brain cancer). Among them, compound 7c exhibited good anti-proliferation activity with HeLa (IC 7. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127304DOI Listing

Synthesis of paramagnetic ligands that target the C-terminal binding site of Hsp90.

Bioorg Med Chem Lett 2020 Aug 2;30(16):127303. Epub 2020 Jun 2.

Department of Chemistry and Biochemistry, University of Notre Dame, IN, USA. Electronic address:

Identification of a ligand binding site represents the starting point for a structure-based drug development program. Lack of a binding site hampers the development of improved ligands that modulate the protein of interest. In this letter, we describe the development of chemical tools that will allow for elucidation of the Hsp90 C-terminal ligand binding site. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127303DOI Listing

N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide as a new inhibitor of mitochondrial complex III: Synthesis, biological evaluation and computational simulations.

Bioorg Med Chem Lett 2020 Aug 3;30(16):127302. Epub 2020 Jun 3.

Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China.

Mitochondrial complex III is one of the most promising targets for a number of pharmaceuticals and fungicides. Due to the wide-spreaduse of complex III-inhibiting fungicides, a considerable increase of resistance has occurred worldwide. Therefore, inhibitors with novel scaffolds and potent activity against complex III are still in great demand. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127302DOI Listing

Short chain α-pyrones capable of potentiating penicillin G against Pseudomonas aeruginosa.

Bioorg Med Chem Lett 2020 Aug 2;30(16):127301. Epub 2020 Jun 2.

Department of Chemistry, University of North Carolina Asheville, One University Heights, Asheville, NC 28804, United States. Electronic address:

The dramatic increase in bacterial resistance over the past three decades has greatly reduced the effectiveness of nearly all clinical antibiotics, bringing infectious disease to the forefront as a dire threat to global health. To combat these infections, adjuvant therapies have emerged as a way to reactivate known antibiotics against resistant pathogens. Herein, we report the evaluation of simplified α-pyrone adjuvants capable of potentiating penicillin G against Pseudomonas aeruginosa, a Gram-negative pathogen whose multidrug-resistant strains have been labeled by the Centers for Disease Control and Prevention as a serious threat to public health. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127301DOI Listing

Discovery of phenanthridine analogues as novel chemical probes disrupting the binding of DNA to ΔFosB homodimers and ΔFosB/JunD heterodimers.

Bioorg Med Chem Lett 2020 Aug 6;30(16):127300. Epub 2020 Jun 6.

Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address:

The transcription factor ΔFosB accumulates in response to chronic insults such as drugs of abuse, L-3,4-dihydroxyphenylalanine (l-DOPA) or stress in specific regions of the brain, triggering long lasting neural and behavioral changes that underlie aspects of drug addiction, dyskinesia, and depression. Thus, small molecule chemical probes are urgently needed to investigate biological functions of ΔFosB. Herein we describe the identification of a novel phenanthridine analogue ZL0220 (27) as an active and promising ΔFosB chemical probe with micromolar inhibitory activities against ΔFosB homodimers and ΔFosB/JunD heterodimers. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127300DOI Listing

Design, synthesis, and biological evaluation of spiroindolines as novel inducers of oligodendrocyte progenitor cell differentiation-Use of a conformation-based hypothesis to facilitate compound design.

Bioorg Med Chem Lett 2020 Aug 2;30(16):127299. Epub 2020 Jun 2.

Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.

Inducing oligodendrocyte progenitor cell (OPC) differentiation is a novel therapeutic strategy for the treatment of demyelinating diseases such as multiple sclerosis (MS). In the preceding article, we detailed the discovery of compound 1, a potent inducer of OPC differentiation possessing a characteristic spiroindoline structure. Also, we found that N-methylation and des-carbonyl compound 1 (4) led to a loss in potency. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127299DOI Listing

Discovery of the potent non-steroidal glucocorticoid receptor modulator BAY 1003803 as clinical candidate.

Bioorg Med Chem Lett 2020 Aug 1;30(16):127298. Epub 2020 Jun 1.

Open Innovation, Research & Development, Pharmaceuticals, Bayer AG, D-13353 Berlin, Germany.

We report on the discovery of the new clinical candidate BAY 1003803 as glucocorticoid receptor agonist for the topical treatment of psoriasis or severe atopic dermatitis. In the course of optimizing the amino alcohol series as a highly potent new non-steroidal lead structure, considerations were made as to how physicochemical properties and safety concerns relate to structural motifs. BAY 1003803 demonstrates strong anti-inflammatory activity in vitro paired with a pharmacokinetic profile suitable for topical application. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127298DOI Listing

Signaling pathways associated with macrophage-activating polysaccharide isolated from the fermentation liquor of Rhizopus nigricans.

Bioorg Med Chem Lett 2020 Aug 1;30(16):127297. Epub 2020 Jun 1.

School of Life Science, Shandong University, Qingdao 266000, China; National Glycoengineering Rechearch Center, Shandong University, Qingdao 266000, China. Electronic address:

Our previous reports showed that the structural features and immunologic enhancement of polysaccharide (EPS1-1) from Rhizopus nigricans. However, the molecular mechanism in cellular immunomodulatory of EPS1-1 remains unclear. Here the experiments for the molecular mechanisms of EPS1-1 on the peritoneal macrophages were performed. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127297DOI Listing

Novel anticancer drug curaxin CBL0137 impairs DNA methylation by eukaryotic DNA methyltransferase Dnmt3a.

Bioorg Med Chem Lett 2020 Aug 1;30(16):127296. Epub 2020 Jun 1.

Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, Russia.

Novel DNA intercalating anticancer drug curaxin CBL0137 significantly inhibited in vitro DNA methylation by eukaryotic DNA methyltransferase Dnmt3a catalytic domain (Dnmt3a-CD) at low micromolar concentrations (IC 3-9 µM). CBL0137 reduced the binding affinity of Dnmt3a-CD to its DNA target, causing up to four-fold increase in the K of the enzyme/DNA complex. Binding of CBL0137 to Dnmt3a-CD was not observed. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127296DOI Listing
August 2020
2.420 Impact Factor

Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition.

Bioorg Med Chem Lett 2020 Aug 30;30(16):127293. Epub 2020 May 30.

Department of Chemistry, Emory University, Atlanta, GA 30322, United States. Electronic address:

LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127293DOI Listing

Targeting the TS dimer interface in bifunctional Cryptosporidium hominis TS-DHFR from parasitic protozoa: Virtual screening identifies novel TS allosteric inhibitors.

Bioorg Med Chem Lett 2020 Aug 30;30(16):127292. Epub 2020 May 30.

Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address:

Effective therapies are lacking to treat gastrointestinal infections caused by the genus Cryptosporidium, which can be fatal in the immunocompromised. One target of interest is Cryptosporidium hominis (C. hominis) thymidylate synthase-dihydrofolate reductase (ChTS-DHFR), a bifunctional enzyme necessary for DNA biosynthesis. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127292DOI Listing

Synthesis and biological evaluation of a novel photo-activated histone deacetylase inhibitor.

Bioorg Med Chem Lett 2020 Aug 30;30(16):127291. Epub 2020 May 30.

Department of Medicine, Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia. Electronic address:

Hydroxamic acid-based histone deacetylase inhibitors (HDACi) are a class of epigenetic agents with potentially broad therapeutic application to several disease states including post angioplasty mediated neointimal hyperplasia (NIH). Precise spatiotemporal control over the release of HDACi at the target blood vessel site is required for the safe and successful therapeutic use of HDACi in the setting of drug eluting balloon catheter (DEBc) angioplasty treatment of NIH. We aimed to develop and characterise a novel photoactive HDACi, as a potential coating agent for DEBc. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127291DOI Listing

Design, synthesis and biological evaluation of new Myo-inositol derivatives as potential RAS inhibitors.

Bioorg Med Chem Lett 2020 Aug 29;30(16):127290. Epub 2020 May 29.

Discipline of Chemistry, IIT Gandhinagar, Palaj, Gandhinagar 382355, India. Electronic address:

Ras is a small family of GTPases that control numerous cellular functions like cell proliferation, growth, survival, gene expression, and is closely engaged in cancer pathogenesis. The ras-targeted methodology entails a holy grail in oncology. Nevertheless, there are no specific molecules reported targeting the same, although it is a known oncogene for more than three decades. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127290DOI Listing

Hybrid molecules based on fullerene C60 and 5Z,9Z-dienoic acids: Synthesis and cytotoxic activity.

Bioorg Med Chem Lett 2020 Aug 28;30(16):127289. Epub 2020 May 28.

Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 ProspektOktyabrya, 450075 Ufa, Russian Federation.

The present research project details synthesis of new hybrid methanofullerenes based on acetylene and triazole esters of malonic acid containing 5Z,9Z-dienoic acids and fullerene C under Bingel-Hirsch conditions, including study of the cytotoxic activity with respect to Jurkat, K562, U937 and HL60 tumor cell lines. Hybrid methanofullerenes containing acetylenic fragments, unlike triazole substituents, were found to exhibit higher cytotoxicity, but are characterized by lower selectivity of action in relation to healthy cells. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127289DOI Listing

Potent dual EGFR/Her4 tyrosine kinase inhibitors containing novel (1,2-dithiolan-4-yl)acetamides.

Bioorg Med Chem Lett 2020 Aug 28;30(16):127288. Epub 2020 May 28.

Aurigene Discovery Technology Ltd. Bollaram Road, Miyapur, Hyderabad, 500 049 Telangana, India.

Modifications at C and C positions of 3-cyanoquinolines 6 and 7 led to potent inhibitors of the ErbB family of kinases particularly against EGFR and Her4 enzymes in the radioisotope filter binding assay. The lead (4, SAB402) displayed potent dual biochemical activities with EGFR/Her4 IC ratio of 80 due to its potent inhibition of Her4 activity (IC 0.03 nM), however, the selectivity towards activating mutations (EGFR, EGFR) was decreased. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127288DOI Listing

Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7.

Bioorg Med Chem Lett 2020 Aug 26;30(16):127287. Epub 2020 May 26.

Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China. Electronic address:

In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 reverse transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC = 42 nM) in MT-4 cells, and sub-micromole (EC = 0.308 μM) to inhibit HIV-1 NL4-3 strain in TZM-bl cells. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127287DOI Listing

Synthesis and biological evaluation of novel isothiazoloquinoline quinone analogues.

Bioorg Med Chem Lett 2020 Aug 26;30(16):127286. Epub 2020 May 26.

School of Pharmaceutical Sciences, Central South University, Changsha 410013, China. Electronic address:

Natural quinones and their analogues have attracted growing attention because of their novel anticancer activities. A series of novel isothiazoloquinoline quinone analogues were synthesized and evaluated for antitumor activities against four different kind of cancer cells. Among them, isothiazoloquinolinoquinones inhibited cancer cells proliferation effectively with IC values in the nanomolar range, and isothiazoloquinolinoquinone 13a induced the cell apoptosis. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127286DOI Listing

Potent antiviral activity of novel multi-substituted 4-anilinoquin(az)olines.

Bioorg Med Chem Lett 2020 Aug 27;30(16):127284. Epub 2020 May 27.

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Screening a series of 4-anilinoquinolines and 4-anilinoquinazolines enabled identification of potent novel inhibitors of dengue virus (DENV). Preparation of focused 4-anilinoquinoline/quinazoline scaffold arrays led to the identification of a series of high potency 6-substituted bromine and iodine derivatives. The most potent compound 6-iodo-4-((3,4,5-trimethoxyphenyl)amino)quinoline-3-carbonitrile (47) inhibited DENV infection with an EC = 79 nM. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127284DOI Listing

C2-substituted quinazolinone derivatives exhibit A and/or A adenosine receptor affinities in the low micromolar range.

Bioorg Med Chem Lett 2020 Aug 22;30(16):127274. Epub 2020 May 22.

Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.

Antagonists of the adenosine receptors (A and A subtypes) are widely researched as potential drug candidates for their role in Parkinson's disease-related cognitive deficits (A subtype), motor dysfunction (A subtype) and to exhibit neuroprotective properties (A subtype). Previously the benzo-α-pyrone based derivative, 3-phenyl-1H-2-benzopyran-1-one, was found to display both A and A adenosine receptor affinity in the low micromolar range. Prompted by this, the α-pyrone core was structurally modified to explore related benzoxazinone and quinazolinone homologues previously unknown as adenosine receptor antagonists. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127274DOI Listing

N-[F]-Fluoroacetylcrizotinib: A potentially potent and selective PET tracer for molecular imaging of non-small cell lung cancer.

Bioorg Med Chem Lett 2020 Aug 2;30(16):127257. Epub 2020 Jun 2.

Vanderbilt Center for Molecular Probes, United States; Vanderbilt University, Institute of Imaging Science, United States; Vanderbilt University Medical Center, United States; Department of Radiology, Vanderbilt University Medical Center, United States. Electronic address:

N-[F]fluoroacetylcrizotinib, a fluorine-18 labeled derivative of the first FDA approved tyrosine kinase inhibitor (TKI) for the treatment of Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), crizotinib, was successfully synthesized for use in positron emission tomography (PET). Sequential in vitro biological evaluation of fluoracetylcrizotinib and in vivo biodistribution studies of [F]fluoroacetylcrizotinib demonstrated that the biological activity of the parent compound remained unchanged, with potent ALK kinase inhibition and effective tumor growth inhibition. These results show that [F]fluoroacetylcrizotinib has the potential to be a promising PET ligand for use in NSCLC imaging. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127257DOI Listing