Alanine scan-guided synthesis and biological evaluation of analogues of culicinin D, a potent anticancer peptaibol.
Abstract Culicinin D (1), a 10 amino acid peptaibol originally isolated from Culicinomyces clavisporus, exhibits potent activity against a range of cancer cell lines. Building on our previous work exploring the structure-activity relationship (SAR) of the unusual (2S,4S,6R)-AHMOD residue, a series of analogues of culicinin D were prepared to further investigate the SAR of these peptaibols. Alanine scanning of a potent and readily accessible analogue 23 revealed the effect of each residue on antiproliferative activity, and a small panel of analogues were prepared to explore the SAR of the non-natural amino acid res...
Source: Bioorganic and Medicinal Chemistry Letters - March 23, 2020 Category: Chemistry Authors: Kavianinia I, Stubbing LA, Abbattista MR, Harris PWR, Smaill JB, Patterson AV, Brimble MA Tags: Bioorg Med Chem Lett Source Type: research

Cytotoxic and anti-inflammatory effects of lignans and diterpenes from Cupressus macrocarpa.
Abstract Cupressus macrocarpa is a windbreak tree and is reported to have various cytotoxic effects. A natural product study on the leaves of C. macrocarpa has yielded ten secondary metabolites, including three new diterpenoids (1-3), four known diterpenoids (4-7), and three known lignans (8-10). The structures of all isolated compounds were elucidated via the interpretation of spectroscopic methods, especially 2D NMR and mass analyses. In the cytotoxic assays, compounds 1-3 and 7-10 showed inhibition effect against HepG2, MDA-MB-231, and A549 cells with IC50 values ranging from 0.004 to 19.9 μg/mL. Moreov...
Source: Bioorganic and Medicinal Chemistry Letters - March 20, 2020 Category: Chemistry Authors: Al-Sayed E, Ke TY, Hwang TL, Chen SR, Korinek M, Chen SL, Cheng YB Tags: Bioorg Med Chem Lett Source Type: research

Discovery of heterocyclic carbohydrazide derivatives as novel selective fatty acid amide hydrolase inhibitors: design, synthesis and anti-neuroinflammatory evaluation.
Abstract Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat pain, inflammation, and other central nervous system disorders. Herein, a series of novel heterocyclic carbohydrazide derivatives were firstly designed by the classic scaffold-hopping strategy. Then, multi-steps synthesis and human FAAH enzyme inhibiting activity assays were conducted. Among them, compound 26 showedstrong inhibition against human FAAH with IC50 of 2.8 μM. Corresponding docking studies revealed that the acyl hydrazide group of compound 26 well-occupied the acyl-chain binding pocket. It als...
Source: Bioorganic and Medicinal Chemistry Letters - March 19, 2020 Category: Chemistry Authors: Shang Y, Hao Q, Jiang K, He M, Wang J Tags: Bioorg Med Chem Lett Source Type: research

The signal peptide as a new target for drug design.
Abstract Many current and potential drug targets are membrane-bound or secreted proteins that are expressed and transported via the Sec61 secretory pathway. They are targeted to translocon channels across the membrane of the endoplasmic reticulum (ER) by signal peptides (SPs), which are temporary structures on the N-termini of their nascent chains. During translation, such proteins enter the lumen and membrane of the ER by a process known as co-translational translocation. Small molecules have been found that interfere with this process, decreasing protein expression by recognizing the unique structures of the SPs...
Source: Bioorganic and Medicinal Chemistry Letters - March 17, 2020 Category: Chemistry Authors: Lumangtad LA, Bell TW Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and evaluation of anti-tumor activity of novel triazolo[1,5-a] pyrimidine on cancer cells by induction of cellular apoptosis and inhibition of epithelial-to-mesenchymal transition process.
In this study, a new protocol involves three-component condensation of the 3-amino-1,2,4-triazole as a 1,3-binucleophile, versatile aldehydes and N-methyl-1-(methylthio)-2-nitroethenamine as an enamine analogous in the presence of trichloroacetic acid as a Brønsted-Lowry acidic promoter leads to new functionalized N-alkyl-6-nitro-3,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine in moderate to good yields. The presence of five nitrogen heteroatoms in the product structure has gathered immense attention among chemists and biologists due to their biological values. Therefore, we evaluated the anti-tumor activity of ...
Source: Bioorganic and Medicinal Chemistry Letters - March 17, 2020 Category: Chemistry Authors: Safari F, Bayat M, Nasri S, Karami S Tags: Bioorg Med Chem Lett Source Type: research

Discovery of cyclic guanidine-linked sulfonamides as inhibitors of LMTK3 kinase.
Abstract Lemur tyrosine kinase 3 (LMTK3) is oncogenic in various cancers. In breast cancer, LMTK3 phosphorylates and modulates the activity of estrogen receptor-α (ERα) and is essential for the growth of ER-positive cells. LMTK3 is highly expressed in ER-negative breast cancer cells, where it promotes invasion via integrin β1. LMTK3 abundance and/or high nuclear expression have been linked to shorter disease free and overall survival time in a variety of cancers, supporting LMTK3 as a potential target for anticancer drug development. We sought to identify small molecule inhibitors of LMTK3 with th...
Source: Bioorganic and Medicinal Chemistry Letters - March 17, 2020 Category: Chemistry Authors: Ortiz MA, Michaels H, Molina B, Toenjes S, Davis J, Diletta Marconi G, Hecht D, Gustafson JL, Javier Piedrafita F, Nefzi A Tags: Bioorg Med Chem Lett Source Type: research

Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.
We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder. PMID: 32184044 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - March 10, 2020 Category: Chemistry Authors: Anderson NA, Cryan J, Ahmed A, Dai H, McGonagle GA, Rozier C, Benowitz AB Tags: Bioorg Med Chem Lett Source Type: research

Addition of ethylamines to the phenols of bithionol and synthetic retinoids does not elicit activity in gram-negative bacteria.
Abstract Our labs have demonstrated the activity of bithionol and synthetic retinoids against methicillin-resistant Staphylococcus aureus (MRSA), as well as their membrane-acting mechanism of action. However, the compounds lack activity in gram-negative species. Herein, we apply a known strategy for converting gram-positive agents into broad-spectrum therapies: addition of an alkylamine. By appending an alkylamine to the phenols of these known membrane disruptors, we test whether this approach is applicable to our compounds. Ultimately, biological testing in four MRSA strains and three gram-negative species showed...
Source: Bioorganic and Medicinal Chemistry Letters - March 9, 2020 Category: Chemistry Authors: Cheng AV, Schrank CL, Escobar IE, Mylonakis E, Wuest WM Tags: Bioorg Med Chem Lett Source Type: research

Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity.
Abstract A series of amino acid prodrugs of NVR3-778, a potent anti-HBV candidate currently under phase II clinical trial, were designed and synthesized as new anti-HBV agents. Except for 1e, all of them displayed roughly comparable anti-HBV activity (IC50, 0.28-0.56 µM) to NVR3-778 (IC50, 0.26 µM). Compound 1a, a l-valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC50 > 10 µM) than NVR3-778 (CC50, 4.81 µM). Moreover, 1a also exhibited acceptable PK prop...
Source: Bioorganic and Medicinal Chemistry Letters - March 9, 2020 Category: Chemistry Authors: Lv K, Li W, Wu S, Geng Y, Wang A, Yang L, Huang M, Chowdhury K, Li Y, Liu M Tags: Bioorg Med Chem Lett Source Type: research

Novel PDE5 inhibitors derived from rutaecarpine for the treatment of Alzheimer's disease.
Abstract A series of novel rutaecarpine derivatives were synthesized and subjected to pharmacological evaluation as PDE5 inhibitors. The structure-activity relationships were discussed and their binding conformation and simultaneous interaction mode were further clarified by the molecular docking studies. Among the 25 analogues, compound 8i exhibited most potent PDE5 inhibition with IC50 values about 0.086 μM. Moreover, it also produced good effects against scopolamine-induced cognitive impairment in vivo. These results might bring significant instruction for further development of potential PDE5 inhibitor...
Source: Bioorganic and Medicinal Chemistry Letters - March 7, 2020 Category: Chemistry Authors: Huang XF, Dong YH, Wang JH, Ke HM, Song GQ, Xu DF Tags: Bioorg Med Chem Lett Source Type: research

Chryso-lactams:Gold(I) derivatives of ampicillin with specific activity against Gram-positive pathogens.
n GLA PMID: 32173196 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - March 7, 2020 Category: Chemistry Authors: Michaut M, Steffen A, Contreras JM, Morice C, Paulen A, Schalk IJ, Plésiat P, Mislin GLA Tags: Bioorg Med Chem Lett Source Type: research

Semisynthesis and insecticidal bioactivities of benzoxazole and benzoxazolone derivatives of honokiol, a naturally occurring neolignan derived from Magnolia officinalis.
This study indicates that these honokiol derivatives could be used as leads for the further derivation and development of the potential pesticide candidates for crop protection. PMID: 32165043 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - March 5, 2020 Category: Chemistry Authors: Zhi XY, Jiang LY, Li T, Song LL, Wang Y, Cao H, Yang C Tags: Bioorg Med Chem Lett Source Type: research

Regioselective synthesis and evaluation of 2-amino 3-cyano chromene-chrysin hybrids as potential anticancer agents.
Abstract The first example of Ca(OH)2-activated p-regioselective synthesis of chrysin-fused chromene was reported through a cascade Michael/cyclization of chrysin and arylidenemalononitrile. The newly synthesized structurally diverse 2-amino 3-cyano chromene-chrysin hybrids 3 were evaluated for their in vitro anticancer activity, and some of the compounds showed stronger anti-proliferative activity against K562, PC-3, A549 and NCI-H1299 than parent compound chrysin, and demonstrated equipotent potency compared with the reference drug of cisplatin. In particular, compound 3h had the highest cytotoxicity towards K56...
Source: Bioorganic and Medicinal Chemistry Letters - March 4, 2020 Category: Chemistry Authors: Wang HJ, Zhou YY, Liu XL, Zhang WH, Chen S, Liu XW, Zhou Y Tags: Bioorg Med Chem Lett Source Type: research

Trans-Pd/Pt(II) saccharinate complexes with a phosphine ligand: Synthesis, cytotoxicity and structure-activity relationship.
Abstract New trans-[Pd(sac)2(PPhMe2)(DMSO)]·H2O (Pd) and trans-[Pt(sac)2(PPhMe2)2]·H2O (Pt) complexes (sac = saccharinate and PPhMe2 = dimethylphenylphosphine) were synthesized and characterized by elemental analysis, IR, NMR, ESI-MS spectral analyses and X-ray diffraction. The complexes were evaluated for their in vitro cytotoxicity against breast (MCF-7), colon (HCT116) and lung (A549) human cancer cell lines. The ATP viability assay displayed that Pd was biologically inactive, but Pt showed significant anticancer potency on MCF-7 cancer cells, similar to cisplatin. The results ...
Source: Bioorganic and Medicinal Chemistry Letters - March 4, 2020 Category: Chemistry Authors: Icsel C, Yilmaz VT, Aygun M, Ulukaya E Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and in vitro evaluation of antimycobacterial and cytotoxic activity of new α,β-unsaturated amide, oxazoline and oxazole derivatives from l-serine.
Synthesis and in vitro evaluation of antimycobacterial and cytotoxic activity of new α,β-unsaturated amide, oxazoline and oxazole derivatives from l-serine. Bioorg Med Chem Lett. 2020 Mar 02;:127074 Authors: Aguirre-Rentería SA, Carrizales-Castillo JJJ, Del Rayo Camacho Corona M, Hernández-Fernández E, Garza-González E, Rivas-Galindo VM, Arredondo-Espinoza E, Avalos-Alanís FG Abstract The synthesis of 19 compounds derived from l-serine and analogs of p-substituted cinnamic acid is reported. Oxazolines 9 and oxazoles 10 have high antitubercular activity wit...
Source: Bioorganic and Medicinal Chemistry Letters - March 2, 2020 Category: Chemistry Authors: Aguirre-Rentería SA, Carrizales-Castillo JJJ, Del Rayo Camacho Corona M, Hernández-Fernández E, Garza-González E, Rivas-Galindo VM, Arredondo-Espinoza E, Avalos-Alanís FG Tags: Bioorg Med Chem Lett Source Type: research

Discovery of 4-hydroxy-2-oxo-1,2-dihydroquinolines as potential inhibitors of Streptococcus pneumoniae, including drug-resistant strains.
Abstract New therapies for treating drug-resistant pneumococcal infections are urgently needed. The novel scaffold 6-hydroxy-4-oxo-1,2-dihydro-4H-quinoline was shown to have similar efficacies against all three different serotypes of S. pneumoniae, ATCC 49617™ (19F), ATCC BAA-1663™ (15B), and ATCC 700904™ (19A), in a resazurin-based high-throughput screen using the Korea Chemical Bank library. Further studies to identify a new lead with this scaffold, including tricyclic pyrrolo[3,2,1-ij]quinolone and pyrido[3,2,1-ij]quinolone derivatives, led to the identification of 6d, 7d and 12a. Compound 6d ...
Source: Bioorganic and Medicinal Chemistry Letters - February 29, 2020 Category: Chemistry Authors: Huddar S, Park CM, Kim HJ, Jang S, Lee S Tags: Bioorg Med Chem Lett Source Type: research

Water-soluble fluorescent sensor for Zn2+ with high selectivity and sensitivity imaging in living cells.
Abstract A new water-soluble 4-amino-1, 8-naphthalimide based fluorescent sensor, with iminoacetic acid and iminoethoxyacetic acid as receptor contained two different arms, was developed. Under physiological pH conditions, it demonstrates good water solubility, high selectivity and sensitivity for sensing Zn2+ with about 20-fold enhancement in aqueous solution, with a characteristic emission band of 4-amino-1, 8-naphthalimide with a green color centered at 550 nm. It was applied successfully to detect Zn2+ in living cells. PMID: 32139326 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicin...
Source: Bioorganic and Medicinal Chemistry Letters - February 29, 2020 Category: Chemistry Authors: Liu D, Zhang T, Zhang M, Shi J, Yin L, Shang Z, Zhu H, Yang G, He H Tags: Bioorg Med Chem Lett Source Type: research

Enantioselective synthesis of tetrahydrocarbazoles via trienamine catalysis and their anxiolytic-like activity.
mez C Abstract The first study about the anxiolytic activity of two chiral tetrahydrocarbazoles is presented. This new chiral compounds were prepared through an organocatalytic strategy via trienamine activation. The in situ ortho-quinodimethane species, formed by the condensation of the N-protected 2-methylindole acrylaldehyde with a sterically hindred diarylsilylprolinol ether derivative as catalyst, easily participate in a Diels-Alder reaction with the ethyl cyanophenyl acrylate as dienophile, in good yields and excellent stereoselectivity. These compounds showed activity against anxiety and mood disorders that...
Source: Bioorganic and Medicinal Chemistry Letters - February 27, 2020 Category: Chemistry Authors: Pawar TJ, Maqueda-Cabrera EE, Alonso-Castro AJ, Olivares-Romero JL, Cruz Cruz D, Villegas Gómez C Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and in-vitro anti-cancer evaluations of multi-methoxylated asymmetrical diarylpentanoids as intrinsic apoptosis inducer against colorectal cancer.
Abstract In the present study, a series of nine stable 3,4,5-methoxylphenyl-containing asymmetrical diarylpentanoids, derivatives of curcuminoids, have been synthesized, characterized and evaluated for their in-vitro anti-cancer potential against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, LoVo and SW620, HT29, RKO and NCI-H508, respectively. Structure-activity relationship study on cytotoxicity of tested compounds suggested that the presence of meta-hydroxyl and adjacent dimethoxyl groups are crucial for enhanced cytotoxicity of diarylpentanoids. Among the evaluated analogs, 8 ha...
Source: Bioorganic and Medicinal Chemistry Letters - February 26, 2020 Category: Chemistry Authors: Leong SW, Chia SL, Abas F, Yusoff K Tags: Bioorg Med Chem Lett Source Type: research

Study on structure-activity relationship of vitamin K derivatives: Conversion of the naphthoquinone part into another aromatic ring and evaluation of their neuronal differentiation-inducing activity.
Abstract We synthesized novel vitamin K derivatives by converting the naphthoquinone group to benzene derivatives and benzoquinone. We evaluated their neuronal differentiation activities to investigate the effect of the quinone moiety on this process. We observed that the 1,4-quinone as well as the side chain part play important roles in neuronal differentiation. We also performed QSAR analysis to predict the compounds which would have higher differentiation activity. PMID: 32127260 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - February 24, 2020 Category: Chemistry Authors: Yoshimura H, Hirota Y, Soda S, Okazeri M, Takagi Y, Takeuchi A, Tode C, Kamao M, Osakabe N, Suhara Y Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and biological evaluation of isoliquiritigenin derivatives as a neuroprotective agent against glutamate mediated neurotoxicity in HT22 cells.
Abstract Glutamate-induced neurotoxicity is characterized by cellular Ca2+ uptake, which is upstream of reactive oxygen species (ROS)-induced apoptosis signaling and MAPKs activation. In the present study, we synthesized isoliquiritigenin analogs with electron-donating and electron-withdrawing functional groups. These analogs were evaluated for neuroprotective effect against glutamate-induced neurotoxicity in HT22 cells. Among these analogs, compound BS11 was selected as a potent neuroprotective agent. Cellular Ca2+ concentration, ROS level, MAPKs activation and AIF translocation to the nucleus were increased upon...
Source: Bioorganic and Medicinal Chemistry Letters - February 24, 2020 Category: Chemistry Authors: Selvaraj B, Kim DW, Huh G, Lee H, Kang K, Lee JW Tags: Bioorg Med Chem Lett Source Type: research

Discovery of 4-((1-(1H-imidazol-2-yl)alkoxy)methyl)pyridines as a new class of Trypanosoma cruzi growth inhibitors.
Abstract The identification of a new series of growth inhibitors of Trypanosoma cruzi, the causative agent of Chagas' disease, is described. In vitro screening of a subset of compounds from our in-house compound collection against the parasite led to the identification of hit compound 1 with low micromolar inhibition of T. cruzi growth. SAR exploration on the hit compound led to the identification of compounds that show nanomolar parasite growth inhibition (T. cruzi EC50 ≤ 100 nM) and no cytotoxicity in human cells (HeLa CC50 > 50 μM). Further investigation identified CYP51 i...
Source: Bioorganic and Medicinal Chemistry Letters - February 22, 2020 Category: Chemistry Authors: Ponzi S, Bresciani A, Kaiser M, Nardi V, Nizi E, Ontoria JM, Pace P, Paonessa G, Summa V, Harper S Tags: Bioorg Med Chem Lett Source Type: research

Discovery of sulfonamides and 9-oxo-2,8-diazaspiro[5,5]undecane-2-carboxamides as human kynurenine aminotransferase 2 (KAT2) inhibitors.
;inen J Abstract Human kynurenine aminotransferase 2 (KAT2) inhibitors could be potentially used to treat the cognitive deficits associated with bipolar disease and schizophrenia. Although, there has been active drug research activity by several industrial and academic groups in developing KAT2 inhibitors over the years, no such compound has proceeded to the clinics. Here, we report two different chemical series of reversible KAT2 inhibitors with sub-micromolar activities. The first series was identified by a high-throughput screening of a diverse random library and the second one by structure-based virtual screen...
Source: Bioorganic and Medicinal Chemistry Letters - February 22, 2020 Category: Chemistry Authors: Kalliokoski T, Rummakko P, Rantanen M, Blaesse M, Augustin M, Ummenthala GR, Choudhary S, Venäläinen J Tags: Bioorg Med Chem Lett Source Type: research

Anilinopyrazines as potential mitochondrial uncouplers.
In this study, we report the structure-activity relationship profile of the pyrazine scaffold bearing substituted aniline rings. Our work indicates that a trifluoromethyl group is best at the para position while the trifluoromethoxy group is preferred in the meta position of the aniline rings of 2,3-substituted pyrazines. As proton transport and cycling requires the formation of a negative charge that has to traverse the mitochondrial membrane, a stabilizing internal hydrogen bond is a key feature for efficient mitochondrial uncoupling activity. PMID: 32113842 [PubMed - as supplied by publisher] (Source: Bioorganic an...
Source: Bioorganic and Medicinal Chemistry Letters - February 21, 2020 Category: Chemistry Authors: Murray JH, Hargett S, Hoehn KL, Santos WL Tags: Bioorg Med Chem Lett Source Type: research

Identification of C10 nitrogen-containing aporphines with dopamine D1 versus D5 receptor selectivity.
Abstract New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT1A and 5-HT2A receptors and at human dopamine D1, D2 and D5 receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D5 receptor, thus attaining D1 versus D5 selectivity. Compound 20c was the most potent D1 ligand identified. Docking studies at D1 ...
Source: Bioorganic and Medicinal Chemistry Letters - February 20, 2020 Category: Chemistry Authors: Karki A, Juarez R, Namballa HK, Alberts I, Harding WW Tags: Bioorg Med Chem Lett Source Type: research

Fluorogenic glycopolymers available for determining the affinity of lectins by intermolecular FRET.
Abstract A convenient assembly of fluorogenic glycopolymers having various polymer compositions was accomplished from the corresponding glycomonomer and dansyl monomer by means of radical polymerization, and the water-soluble glycopolymers gave typical fluorescence spectroscopic profiles due to the dansyl moieties on the glycopolymer in aqueous media. Biological evaluation of the polymer against wheat germ agglutinin (WGA) was accomplished on the basis of fluorescence changes due to tryptophan residues on WGA, and the affinities between the glycopolymers and WGA were estimated to be 4.7 × 105 to 9....
Source: Bioorganic and Medicinal Chemistry Letters - February 19, 2020 Category: Chemistry Authors: Matsuoka K, Suzuki Y, Koyama T, Matsushita T, Hatano K Tags: Bioorg Med Chem Lett Source Type: research

Novel cilengitide-based cyclic RGD peptides as αvβ3 integrin inhibitors.
Novel cilengitide-based cyclic RGD peptides as αvβ3 integrin inhibitors. Bioorg Med Chem Lett. 2020 Feb 17;:127039 Authors: Meena CL, Singh D, Weinmüller M, Reichart F, Dangi A, Marelli UK, Zahler S, Sanjayan GJ Abstract In this letter, we report a series of five new RGD-containing cyclic peptides as potent inhibitors to αvβ3 integrin protein. We have incorporated various unnatural lipophilic amino acids into the cyclic RGD framework of cilengitide, which is selective for αvβ3 integrin. All the newly synthesized cyclic peptides were evaluated in vitrosolid phase b...
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2020 Category: Chemistry Authors: Meena CL, Singh D, Weinmüller M, Reichart F, Dangi A, Marelli UK, Zahler S, Sanjayan GJ Tags: Bioorg Med Chem Lett Source Type: research

Development of 2-(4-pyridyl)-benzimidazoles as PKN2 chemical tools to probe cancer.
Abstract Kinases are signalling proteins which have proven to be successful targets for the treatment of a variety of diseases, predominantly in cancers. However, only a small proportion of kinases (
Source: Bioorganic and Medicinal Chemistry Letters - February 17, 2020 Category: Chemistry Authors: Scott F, Fala AM, Pennicott LE, Reuillon TD, Massirer KB, Elkins JM, Ward SE Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and efficacy of pyrvinium-inspired analogs against tuberculosis and malaria pathogens.
Abstract Herein, we report the synthesis and evaluation of pyrvinium-based antimalarial and antitubercular compounds. Pyrvinium is an FDA approved drug for the treatment of pinworm infection, and it has been reported to have antiparasitic and antimicrobial activities. Pyrvinium contains quinoline core coupled with pyrrole. We replaced the pyrrole with various aryl or heteroaryl substituents to generate pyrvinium analogs. The profiling of these compounds against malaria parasite P. falciparum 3D7 revealed analogs with better antimalarial activity than pyrvinium pamoate. Compound 14 and 16 showed IC50 of 23 nM ...
Source: Bioorganic and Medicinal Chemistry Letters - February 14, 2020 Category: Chemistry Authors: Gaikwad VR, Karale UB, Govindarajalu G, Adhikari N, Krishna EV, Krishna VS, Misra S, Sriram D, Sijwali PS, Rode HB Tags: Bioorg Med Chem Lett Source Type: research

Novel 1,3,4-oxadiazole thioether derivatives containing flexible-chain moiety: Design, synthesis, nematocidal activities, and pesticide-likeness analysis.
Abstract Seventy-two novel 1,3,4-oxadiazole thioether derivatives containing different flexible-chain moieties were designed and synthesized. The nematicidal activities of all the title compounds were evaluated, and some compounds showed excellent nematicidal activities against citrus nematodes. The compounds 15, 16, 18, 27, 41, 42, 44, 53, and 71 had the mortality to citrus nematodes of 92.5, 93.7, 90.3, 91.5, 92.6, 92.8, 93.5, 91.3, and 91.0% at the concentration of 100 mg/L, which were better than the control agent of avermectin (85.9%). After the test concentration was reduced to 50 mg/L, the nematic...
Source: Bioorganic and Medicinal Chemistry Letters - February 13, 2020 Category: Chemistry Authors: Chen J, Wei C, Wu S, Luo Y, Wu R, Hu D, Song B Tags: Bioorg Med Chem Lett Source Type: research

Diarylheptanoids with NO production inhibitory activity from Amomum kravanh.
Abstract Seven new diarylheptanoids, kravanhols C-I (1-7), along with two known analogues (8 and 9), were isolated from the fruits of Amomum kravanh. The structures of compounds 1-7 were elucidated by analysis of spectroscopic data, and the absolute configurations of selective ones were determined by time-dependent density functional theory (TD-DFT) based electronic circular dichroism (ECD) calculations. All compounds were evaluated for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in murine RAW264.7 macrophage cells. Compounds 2, 5, 6 and 9 exhibited moderate inh...
Source: Bioorganic and Medicinal Chemistry Letters - February 13, 2020 Category: Chemistry Authors: Zhang JS, Cao XX, Yu JH, Yu ZP, Zhang H Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and biological evaluation of novel pyrazolo[3,4-b]pyridines as cis-restricted combretastatin A-4 analogues.
Abstract Twenty-six novel pyrazolo[3,4-b]pyridine-bridged analogues of combretastatin A-4 possessing 3,4,5-trimethoxylphenyl groups, were synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. Preliminary biological evaluation demonstrated that some of the target compounds displayed significant antiproliferative effectagainst four different cell lines including MCF-7, MDA-MB-231, HeLa and Kyse150. The most active analogue 6n was found to induce HeLa cells arrest in the G2/M phase in a dose-dependent manner. Molecular modeling studies indicated that derivative 6n mos...
Source: Bioorganic and Medicinal Chemistry Letters - February 11, 2020 Category: Chemistry Authors: Jian XE, Yang F, Jiang CS, You WW, Zhao PL Tags: Bioorg Med Chem Lett Source Type: research

Structural determinants of affinity and selectivity in the binding of inhibitors to histone deacetylase 6.
Abstract Histone deacetylase 6 (HDAC6) is associated with multiple neurological disorders as well as aggressive cancers, making its selective inhibition highly desirable for therapeutic purposes. The basic molecular design of an effective HDAC6 inhibitor consists of a zinc-binding group, a linker, and a capping group capable of making interactions at the mouth of the active site. To date, more than 50 high-resolution X-ray crystal structures of HDAC6-inhibitor complexes have been reported, many of which reveal intermolecular interactions that contribute to isozyme affinity and selectivity. Here, we review the key ...
Source: Bioorganic and Medicinal Chemistry Letters - February 11, 2020 Category: Chemistry Authors: Osko JD, Christianson DW Tags: Bioorg Med Chem Lett Source Type: research

Recent advances in TRPV4 agonists and antagonists.
Abstract TRPV4 is a ubiquitously expressed, non-selective cation channel activated by a range of stimuli including hypotonicity, temperature, pH, stretch and endogenous ligands. Agents that modulate TRPV4 are sought as potential therapeutics for the treatment of many diseases including osteoarthritis, respiratory illnesses, gastrointestinal disorders, pain and congestive heart failure. In recent years, significant advances in TRPV4 drug discovery have been realized as at least seven novel TRPV4 agonist or antagonist templates were reported and the first selective TRPV4 antagonist was evaluated in early clinical tr...
Source: Bioorganic and Medicinal Chemistry Letters - February 8, 2020 Category: Chemistry Authors: Lawhorn BG, Brnardic EJ, Behm DJ Tags: Bioorg Med Chem Lett Source Type: research

Synthesis and biological evaluation of chepraecoxin A derivatives as α-glucosidase inhibitors.
Synthesis and biological evaluation of chepraecoxin A derivatives as α-glucosidase inhibitors. Bioorg Med Chem Lett. 2020 Feb 06;:127020 Authors: Yang XT, Geng CA, Li TZ, Deng ZT, Chen JJ Abstract The ent-kaurane diterpenoid chepraecoxin A (CA) obtained in our previous study showed a potential inhibitory activity on α-glucosidase (IC50 274.5 ± 12.5 μM). In order to figure out the structure-activity relationships (SARs), twenty-two derivatives of chepraecoxin A were synthesized by modifying the ester, allyl, double bond and carboxyl groups, and assayed for their &al...
Source: Bioorganic and Medicinal Chemistry Letters - February 6, 2020 Category: Chemistry Authors: Yang XT, Geng CA, Li TZ, Deng ZT, Chen JJ Tags: Bioorg Med Chem Lett Source Type: research

Discovery and optimization of 4-oxo-2-thioxo-thiazolidinones as NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inhibitors.
Abstract Aberrant activation of NLRP3 inflammasome is present in a subset of acute and chronic inflammatory diseases. The NLRP3 inflammasome has been recognized as an attractive therapeutic target for developing novel and specific anti-inflammatory inhibitors. Cellular structure-activity relationship-guided optimization resulted in the identification of 4-oxo-2-thioxo-thiazolidinone derivative 9 as a selective and direct small-molecule inhibitor of NLRP3 with IC50 of 2.4 μM, possessing favorable ex vivo and in vivo pharmacokinetic properties. Compound 9 may represent a lead for the development of anti-infl...
Source: Bioorganic and Medicinal Chemistry Letters - February 6, 2020 Category: Chemistry Authors: Chen Y, He H, Jiang H, Li L, Hu Z, Huang H, Xu Q, Zhou R, Deng X Tags: Bioorg Med Chem Lett Source Type: research

Design, synthesis and biological evaluation of HIV-1 protease inhibitors with morpholine derivatives as P2 ligands in combination with cyclopropyl as P1' ligand.
Abstract A series of novel HIV-1 protease inhibitors has been designed and synthesized, which contained morpholine derivatives as the P2 ligands and hydrophobic cyclopropyl as the P1' ligand at the meantime in this study, with the aim of improving the interactions between the active sites of HIV-1 protease and the inhibitors. Twenty-eight compounds were synthesized and assessed, among which inhibitors m18 and m1 exhibited excellent inhibitory effect on the activity of HIV-1 protease with IC50 value of 47 nM and 53 nM, respectively. The molecular modeling of m1 revealed possible hydrogen bondings or van d...
Source: Bioorganic and Medicinal Chemistry Letters - February 5, 2020 Category: Chemistry Authors: Dou Y, Zhu M, Dong B, Wang JX, Zhang GN, Zhang F, Wang YC Tags: Bioorg Med Chem Lett Source Type: research

Catenulisporidins A and B, 16-membered macrolides of the hygrolidin family produced by the chemically underexplored actinobacterium Catenulispora species.
Abstract Two new macrolide metabolites of the hygrolidin family, catenulisporidins A and B (1 and 2), together with a known compound hygrolidin (3), were isolated from the culture broth of the rare actinobacterium Catenulispora sp. KCB13F192. Their structures were elucidated on the basis of HRESIMS spectrometric and NMR spectroscopic analyses. Catenulisporidins A and B are the first example of natural hygrolidin and bafilomycin derivatives featuring a modified macrolide ring, and catenulisporidin A possesses a tetrahydrofuran ring through an ether linkage between C-7 and C-10. In cell-based fluorescent imaging and...
Source: Bioorganic and Medicinal Chemistry Letters - February 3, 2020 Category: Chemistry Authors: Son S, Jang M, Lee B, Lee JS, Hong YS, Kim BY, Ko SK, Jang JH, Ahn JS Tags: Bioorg Med Chem Lett Source Type: research

Pro-apoptotic carboxamide analogues of natural fislatifolic acid targeting Mcl-1 and Bcl-2.
Abstract A library of 26 novel carboxamides deriving from natural fislatifolic acid has been prepared. The synthetic strategy involved a bio-inspired Diels-Alder cycloaddition, followed by functionalisations of the carbonyl moiety. All the compounds were evaluated on Bcl-xL, Mcl-1 and Bcl-2 proteins. In this series of cyclohexenyl chalcone analogues, six compounds behaved as dual Bcl-xL/Mcl-1 inhibitors in micromolar range and one exhibited sub-micromolar affinities toward Mcl-1 and Bcl-2. The most potent compounds evaluated on A549 and MCF7 cancer cell lines showed moderate cytotoxicities. PMID: 32035700 [Pu...
Source: Bioorganic and Medicinal Chemistry Letters - February 3, 2020 Category: Chemistry Authors: Gapil Tiamas S, Daressy F, Abou Samra A, Bignon J, Steinmetz V, Litaudon M, Fourneau C, Hoong Leong K, Ariffin A, Awang K, Desrat S, Roussi F Tags: Bioorg Med Chem Lett Source Type: research

The fluorescent markers based on oxazolopyridine unit for imaging organelles.
Abstract Bioactive oxazolopyridine unit was used in the synthesis of fluorescent markers for specific organelles in this paper. The compounds 1a-c are linked with double bond between oxazolopyridine ring and photogenic precursors (3a-c). Compound 1a showed higher fluorescence yield (0.86 in THF), compounds 1b-c showed larger stokes shifts in DMSO. In lipid vesicles environment, they also showed good optical properties. In addition, the three compounds are biomarkers with lower cytotoxicity. Among them, compound 1a based on oxazolopyridine and coumarin unit is a dual targetable fluorescent marker for mitochondria a...
Source: Bioorganic and Medicinal Chemistry Letters - January 29, 2020 Category: Chemistry Authors: Wang YN, Xu B, Qiu LH, Sun R, Xu YJ, Ge JF Tags: Bioorg Med Chem Lett Source Type: research

Radiosynthesis of [thiocarbonyl-11C]disulfiram and its first PET study in mice.
Abstract [Thiocarbonyl-11C]disulfiram ([11C]DSF) was synthesized via iodine oxidation of [11C]diethylcarbamodithioic acid ([11C]DETC), which was prepared from [11C]carbon disulfide and diethylamine. The decay-corrected isolated radiochemical yield (RCY) of [11C]DSF was greatly affected by the addition of unlabeled carbon disulfide. In the presence of carbon disulfide, the RCY was increased up to 22% with low molar activity (Am, 0.27 GBq/μmol). On the other hand, [11C]DSF was obtained in 0.4% RCY with a high Am value (95 GBq/μmol) in the absence of carbon disulfide. The radiochemical purity of [11C]...
Source: Bioorganic and Medicinal Chemistry Letters - January 28, 2020 Category: Chemistry Authors: Ishii H, Yamasaki T, Yui J, Zhang Y, Hanyu M, Ogawa M, Nengaki N, Tsuji AB, Terashima Y, Matsushima K, Zhang MR Tags: Bioorg Med Chem Lett Source Type: research

Design, synthesis and evaluation of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors.
Abstract A series of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors (AChEIs) were designed and synthesized, Furthermore, their inhibitory activities against acetylcholinesterase in vitro were tested by Ellman spectrophotometry, and the results of inhibitory activity test showed that most of them had a certain acetylcholinesterase inhibitory activity in vitro. Moreover, the IC50 value of compound 4f was to 0.66 μM, which was higher than that of Rivastigmine and Huperzine-A as reference compounds, and it had a weak inhibitory effect on butyrylcholinesterase. The potential binding m...
Source: Bioorganic and Medicinal Chemistry Letters - January 24, 2020 Category: Chemistry Authors: Xu Y, Jian MM, Han C, Yang K, Bai LG, Cao F, Ma ZY Tags: Bioorg Med Chem Lett Source Type: research

Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity.
Abstract Toll-like receptors 7 and 8 (TLR7/8) agonists are potent immunostimulants that are attracting considerable interest as vaccine adjuvants. We recently reported the synthesis of a new series of 2-O-butyl-8-oxoadenines substituted at the 9-position with various linkers and N-heterocycles, and showed that TLR7/8 selectivity, potency and cytokine induction could be modulated by varying the alkyl linker length and the N-heterocyclic ring. In the present study, we further optimized the oxoadenine scaffold by investigating the effect of different substituents at the 2-position of the oxoadenine on TLR7/8 potency/...
Source: Bioorganic and Medicinal Chemistry Letters - January 22, 2020 Category: Chemistry Authors: Bazin HG, Bess LS, Livesay MT, Li Y, Cybulski V, Miller SM, Johnson DA, Evans JT Tags: Bioorg Med Chem Lett Source Type: research

Screening for tyrosinase inhibitors from actinomycetes; identification of trichostatin derivatives from Streptomyces sp. CA-129531 and scale up production in bioreactor.
Abstract In the course of a primary screening of 614 microbial actinomycete extracts for the discovery of tyrosinase inhibitors, the EtOAc extract of the fermentation broth of the strain Streptomyces sp. CA-129531 isolated from a Martinique sample, exhibited in cell free and cell-based assays the most promising activity (IC50 value of 63 μg/mL). Scaled-up production in a bioreactor led to the isolation of one new trichostatic acid analogue, namely trichostatic acid B (1), along with six known trichostatin derivatives (2-7), four diketopiperazines (8-11), two butyrolactones (12-13) and one hydroxamic acid s...
Source: Bioorganic and Medicinal Chemistry Letters - January 21, 2020 Category: Chemistry Authors: Georgousaki K, Tsafantakis N, Gumeni S, Gonzalez I, Mackenzie TA, Reyes F, Lambert C, Trougakos IP, Genilloud O, Fokialakis N Tags: Bioorg Med Chem Lett Source Type: research

Design and biological evaluation of a novel type of potential multi-targeting antimicrobial sulfanilamide hybrids in combination of pyrimidine and azoles.
Abstract This work explored a novel type of potential multi-targeting antimicrobial three-component sulfanilamide hybrids in combination of pyrimidine and azoles. The hybridized target molecules were characterized by 1H NMR, 13C NMR and HRMS spectra. Some of the developed target compounds exerted promising antimicrobial activity in comparison with the reference drugs norfloxacin and fluconazole. Noticeably, sulfanilamide hybrid 5c with pyrimidine and indole could effectively inhibit the growth of E. faecalis with MIC value of 1 μg/mL. The active molecule 5c showed low cell toxicity and did not obviously tr...
Source: Bioorganic and Medicinal Chemistry Letters - January 20, 2020 Category: Chemistry Authors: Sui YF, Li D, Wang J, Bheemanaboina RRY, Ansari MF, Gan LL, Zhou CH Tags: Bioorg Med Chem Lett Source Type: research

Discovery of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors.
Abstract Herein, we report the discovery of a series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as a new class of ROCK inhibitors. Structure-activity relationship studies of these compounds led to the identification of the most potent compound, 3-(3-methoxybenzyl)-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)thieno[2,3-d]pyrimidin-4(3H)-one (8k), which showed IC50 values of 0.004 μM and 0.001 μM against ROCK Ⅰ and ROCK Ⅱ, respectively. In vitro, 8k significantly reduced the phosphorylation level of ROCK downstream signaling protein and induce changes in cell morphology and migration. Overall, this stu...
Source: Bioorganic and Medicinal Chemistry Letters - January 15, 2020 Category: Chemistry Authors: Miao Z, Sun YM, Zhao LY, Li YS, Wang YF, Nan JS, Qiao ZE, Li LL, Yang SY Tags: Bioorg Med Chem Lett Source Type: research

A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor ROR γt.
A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor RORγt. Bioorg Med Chem Lett. 2020 Jan 15;:126967 Authors: Jiang X, Dulubova I, Reisman SA, Hotema M, Lee CI, Liu L, McCauley L, Trevino I, Ferguson DA, Eken Y, Wilson AK, Wigley WC, Visnick M Abstract Inhibition of the nuclear receptor Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a promising strategy for the treatment of autoimmune diseases. In this paper, we describe a series of allosteric, cysteine-dependent, inverse agonists of RORγt. Site-directed mutagenesis and molecu...
Source: Bioorganic and Medicinal Chemistry Letters - January 15, 2020 Category: Chemistry Authors: Jiang X, Dulubova I, Reisman SA, Hotema M, Lee CI, Liu L, McCauley L, Trevino I, Ferguson DA, Eken Y, Wilson AK, Wigley WC, Visnick M Tags: Bioorg Med Chem Lett Source Type: research

Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors.
Abstract Herein we report an efficient method for the synthesis of a highly functionalized 2-pyrrolidinone, tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylate, from readily available starting materials. Utility of this compound was demonstrated in the synthesis of a novel series of macrocyclic Tyk2 inhibitors, leading to the identification of a potent and selective macrocyclic Tyk2 inhibitor (26). PMID: 31980341 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry Letters)
Source: Bioorganic and Medicinal Chemistry Letters - January 13, 2020 Category: Chemistry Authors: Sasaki Y, Tokuhara H, Ohba Y, Okabe A, Nakayama M, Nakagawa H, Skene R, Hoffman I, Zou H, Yoshida M Tags: Bioorg Med Chem Lett Source Type: research

Inhibitors of the Zika virus protease NS2B-NS3.
Abstract In recent years, the Zika virus has emerged from a neglected flavivirus to a health-threatening pathogen that causes epidemic outbreaks associated with neurological disorders and congenital malformations. In addition to vaccine development, the discovery of specific antiviral agents has been pursued intensely. The Zika virus protease NS2B-NS3 catalyses the processing of the viral precursor polyprotein as an essential step during viral replication. Since the epidemic Zika virus outbreak in the Americas, several inhibitors of this protease have been reported. Substrate-derived peptides revealed important st...
Source: Bioorganic and Medicinal Chemistry Letters - January 11, 2020 Category: Chemistry Authors: Voss S, Nitsche C Tags: Bioorg Med Chem Lett Source Type: research

Photo effect on the CD1d-binding ability of azobenzene-attached analogues of α-GalCer.
Photo effect on the CD1d-binding ability of azobenzene-attached analogues of α-GalCer. Bioorg Med Chem Lett. 2020 Jan 11;:126960 Authors: Kanamori T, Numata T, Kuwabara S, Ishii Y, Watarai H, Yuasa H Abstract α-Galactosylceramide (α-GalCer) is recognized by the CD1d proteins on antigen-presenting cells at the ceramide moiety and the galactose moiety is presented to iNKT cells, which stimulates the immune responses. However, the immune suppression by repeated injections of α-GalCer has discouraged its development as an anti-cancer agent. To overcome the shortcoming by spatiotemp...
Source: Bioorganic and Medicinal Chemistry Letters - January 11, 2020 Category: Chemistry Authors: Kanamori T, Numata T, Kuwabara S, Ishii Y, Watarai H, Yuasa H Tags: Bioorg Med Chem Lett Source Type: research