- Demonstrating Ligandability of the LC3A and LC3B Adapter Interface
-
Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).
- Hartmann, Markus,Huber, Jessica,Kramer, Jan S.,Heering, Jan,Pietsch, Larissa,Stark, Holger,Odadzic, Dalibor,Bischoff, Iris,Fürst, Robert,Schr?der, Martin,Akutsu, Masato,Chaikuad, Apirat,D?tsch, Volker,Knapp, Stefan,Biondi, Ricardo M.,Rogov, Vladimir V.,Proschak, Ewgenij
-
p. 3720 - 3746
(2021/05/04)
-
- Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of schistosomiasis
-
Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, we chemically optimized our previously reported benzhydroxamate-based inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by the highly potent inhibitor 5o. Structure-based optimization of the novel inhibitors was carried out using the available crystal structures as well as docking studies on smHDAC8. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs (hHDAC). The in vitro and docking results were used for detailed structure activity relationships. The synthesized compounds were further investigated for their lethality against the schistosome larval stage using a fluorescence-based assay. The most promising inhibitor 5o showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
- Darwish, Salma,Erdmann, Frank,Ghazy, Ehab,Heimburg, Tino,Jung, Manfred,Lancelot, Julien,Pierce, Raymond,Robaa, Dina,Romier, Christophe,Schmidt, Matthias,Schmidtkunz, Karin,Shaik, Tajith B.,Simoben, Conrad V.,Sippl, Wolfgang,Truhn, Anne,Zeyen, Patrik
-
-
- Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors
-
The enzyme dihydrofolate reductase from M. tuberculosis (MtDHFR) has a high unexploited potential to be a target for new drugs against tuberculosis (TB), due to its importance for pathogen survival. Preliminary studies have obtained fragment-like molecule
- Dias, Marcio Vinícius Bertacine,Ferreira, Glaucio Monteiro,Kronenberger, Thales,Parise-Filho, Roberto,Pavan, Fernando Rogério,Poso, Antti,Ribeiro, Jo?o Augusto,Tavares, Maurício Temotheo,Trossini, Gustavo Henrique Goulart,da Silva Santos, Soraya,de Souza, Alfredo Danilo Ferreira
-
-
- Synthesis and comparative structure-activity study of carbohydrate-based phenolic compounds as α-glucosidase inhibitors and antioxidants
-
Twenty-one natural and unnatural phenolic compounds containing a carbohydrate moiety were synthesized and their structure-activity relationship (SAR) was evaluated for α-glucosidase inhibition and antioxidative activity. Varying the position of the galloyl unit on the 1,5-anhydro -D-glucitol (1,5-AG) core resulted in changes in the α-glucosidase inhibitory activity and notably, particularly strong activity was demonstrated when the galloyl unit was present at the C-2 position. Furthermore, increasing the number of the galloyl units significantly affected the α-glucosidase inhibition, and 2,3,4,6-tetra-galloyl-1,5-AG (54) and 2,3,4,6-tetra-galloyl-d-glucopyranose (61) exhibited excellent activities, which were more than 13-fold higher than the α-glucosidase inhibitory activity of acertannin (37). Moreover, a comparative structure-activity study suggested that a hemiacetal hydroxyl functionality in the carbohydrate core and a biaryl bond of the 4,6-O-hexahydroxydiphenoyl (HHDP) group, which are components of ellagitannins including tellimagrandin I, are not necessary for the α-glucosidase inhibitory activity. Lastly, the antioxidant activity increased proportionally with the number of galloyl units.
- MacHida, Shota,Mukai, Saki,Kono, Rina,Funato, Megumi,Saito, Hiroaki,Uchiyama, Taketo
-
-
- Hydrophobicity-oriented drug design (HODD) of new human 4-hydroxyphenylpyruvate dioxygenase inhibitors
-
Involved in the tyrosine degradation pathway, 4-hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for treating type I tyrosinemia. To discover novel HPPD inhibitors, we proposed a hydrophobicity-oriented drug design (HODD) strategy based on the interactions between HPPD and the commercial drug NTBC. Most of the new compounds showed improved activity, compound d23 being the most active candidate (IC50 = 0.047 μM) with about 2-fold more potent than NTBC (IC50 = 0.085 μM). Therefore, compound d23 is a potential drug candidate to treat type I tyrosinemia.
- Ndikuryayo, Ferdinand,Kang, Wei-Ming,Wu, Feng-Xu,Yang, Wen-Chao,Yang, Guang-Fu
-
-
- PIPERAZINE DERIVATIVES AS MAGL INHIBITORS
-
The invention provides new heterocyclic compounds having general Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1, R2, X, Y1 and Y2 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.
- -
-
Page/Page column 184
(2019/05/02)
-
- Substitution of terminal amide with 1H-1,2,3-triazole: Identification of unexpected class of potent antibacterial agents
-
3-Methoxybenzamide (3-MBA) derivatives have been identified as novel class of potent antibacterial agents targeting the bacterial cell division protein FtsZ. As one of isosteres for the amide group, 1,2,3-triazole can mimic the topological and electronic features of the amide, which has gained increasing attention in drug discovery. Based on these considerations, we prepared a series of 1H-1,2,3-triazole-containing 3-MBA analogues via isosteric replacement of the terminal amide with triazole, which had increased antibacterial activity. This study demonstrated the possibility of developing the 1H-1,2,3-triazole group as a terminal amide-mimetic element which was capable of both keeping and modulating amide-related bioactivity. Surprisingly, a different action mode of these new 1H-1,2,3-triazole-containing analogues was observed, which could open new opportunities for the development of antibacterial agents.
- Bi, Fangchao,Ji, Shengli,Venter, Henrietta,Liu, Jingru,Semple, Susan J.,Ma, Shutao
-
p. 884 - 891
(2018/02/15)
-
- Discovery of N-hydroxy-3-alkoxybenzamides as direct acid sphingomyelinase inhibitors using a ligand-based pharmacophore model
-
Acid sphingomyelinase (ASM) has been shown to be involved in many physiological processes, emerging to be a promising drug target. In this study, we constructed a ligand-based pharmacophore model of ASM inhibitors and applied this model to optimize the lead compound α-mangostin, a known inhibitor of ASM. 23 compounds were designed and evaluated in vitro for ASM inhibition, of these, 10 compounds were found to be more potent than α-mangostin. This high hit ratio confirmed that the presented model is very effective and practical. The most potent hit, 1c, was found to selectively and competitively inhibit the enzyme and inhibit the generation of ceramide in a dose-dependent manner. Furthermore, 1c showed favorable anti-apoptosis and anti-inflammatory activity. Interactions with key residues and the Zn2+ cofactor of 1c were found by docking simulation. These results provide promising leads and important guidance for further development of efficient ASM inhibitors and drug candidates.
- Yang, Kan,Nong, Keyi,Gu, Qinlan,Dong, Jibin,Wang, Jinxin
-
p. 389 - 400
(2018/04/12)
-
- Nhatrangin A: Total Syntheses of the Proposed Structure and Six of Its Diastereoisomers
-
A total synthesis of the proposed structure of nhatrangin A is described. This strategy relies on two aldol reactions to install the chiral centers at C3/C4 and C3′/C4′, a lithium-mediated coupling between an advanced intermediate alkyne and a Weinreb amide to complete the C1-C13 alkyl scaffold, and a Yamaguchi esterification to set the side chain. Discrepancies in the spectroscopic data between synthetic and natural nhatrangins led us to synthesize six more diastereoisomers of the proposed structure of nhatrangin A.
- Dias, Luiz C.,Polo, Ellen C.
-
p. 4072 - 4112
(2017/04/28)
-
- Benzoic hydroxamate-based iron complexes as model compounds for humic substances: Synthesis, characterization and algal growth experiments
-
A series of monomeric and dimeric FeIII complexes bearing benzoic hydroxamates as O,O-chelates has been prepared and characterized by elemental analysis, IR spectroscopy, UV-Vis spectroscopy, electrospray ionization mass spectrometry (ESI-MS), cyclic voltammetry, EPR spectroscopy and for some examples by X-ray diffraction analysis. The stability of the synthesized complexes in pure water and seawater was monitored over 24 h by means of UV-Vis spectrometry. The ability to release iron from the synthesized model complexes has been investigated with algae growth experiments.
- Orlowska, Ewelina,Roller, Alexander,Wiesinger, Hubert,Pignitter, Marc,Jirsa, Franz,Krachler, Regina,Kandioller, Wolfgang,Keppler, Bernhard K.
-
p. 40238 - 40249
(2016/05/24)
-
- Ring Opening of Bicyclo[3.1.0]hexan-2-ones: A Versatile Synthetic Platform for the Construction of Substituted Benzoates
-
Described is the development of a highly efficient 2πdisrotatory ring-opening aromatization sequence using bicyclo[3.1.0]hexan-2-ones. This unprecedented transformation efficiently proceeds under thermal conditions and allows facile construction of uniquely substituted and polyfunctionalized benzoates. In the presence of either amines or alcohols formation of substituted anilines or ethers, respectively, is achieved. Additionally, the utility of this method was demonstrated in a short synthesis of sekikaic acid methyl ester. Cracked open: A highly efficient thermal 2πdisrotatory ring-opening aromatization sequence of bicyclo[3.1.0]hexan-2-ones is described. The transformation proceeds in sulfolane to give uniquely substituted benzoates. In the presence of either amines or alcohols, formation of substituted anilines or ethers, respectively, is achieved.
- Feierfeil, Johannes,Grossmann, Adriana,Magauer, Thomas
-
supporting information
p. 11835 - 11838
(2015/10/05)
-
- Identification of vitamin D3-based hedgehog pathway inhibitors that incorporate an aromatic A-ring isostere
-
Previous structure-activity relationship studies for vitamin D3 (VD3) inhibition of Hedgehog (Hh) signaling directed the design, synthesis, and evaluation of a series of VD3-based analogues that contain an aromatic A-ring mimic. Characterization of these
- Deberardinis, Albert M.,Banerjee, Upasana,Hadden, M. Kyle
-
supporting information
p. 590 - 595
(2013/07/26)
-
- Synthesis and antifungal properties of papulacandin derivatives
-
Derivatives of an antifungal agent that targets the β-(1,3)-D-glucan synthase, papulacandin D, were synthesized and tested for activity. The papulacandin D structure contains a challenging benzannulated spiroketal unit, which is introduced in a palladiumcatalyzed cross-coupling reaction of a glycal silanolate and an aryl iodide followed by an oxidative spiroketalization. Four different variants were made, differing in the nature of the acyl side chain with respect to the length, and in the number and stereochemistry of the double bonds. Moderate biological activity was observed for the derivatives with a side chain based on palmitic acid and linoleic acid.
- Van Der Kaaden, Marjolein,Breukink, Eefjan,Pieters, Roland J.
-
supporting information; experimental part
p. 732 - 737
(2012/07/14)
-
- 1,2,3,6-TETRAHYDROAZEPINO[4,5-B]INDOLE-5-CARBOXYLATE NUCLEAR RECEPTOR INHIBITORS
-
Provided are certain 1,2,3,6- tetrahydroazepino[4,5-b]indole-5-carboxylate compounds which are useful for modulating the activity of nuclear receptors, such as farnesoid X receptors, and/or for the treatment, prevention, or amelioration diseases or disorders related to the activity of these receptors.
- -
-
Page/Page column 55
(2010/04/27)
-
- CYCLIC TRIAZO AND DIAZO SODIUM CHANNEL BLOCKERS
-
Compounds of general structure in which X and Y are each N or C with at least one of X and Y being N; Z is a single bond or an optionally substituted linking group R1 is hydrogen or a substituent group; R2 is amino or a substituent group; N* is amino when RI is hydrogen or =NH when R1 is a substituent group; or N* is a group NRaRb where Ra and Rb are independently H or an alkyl group; or N* is an optionally substituted piperazinyl ring; and A is an optionally substituted heterocyclic or carbocyclic ring system which may be linked to the triazo/diazo ring through R2 to form a fused multicyclic ring; are indicated as suitable for treatment of disorders in mammals that are susceptible to sodium channel blockers and antifolates, and particularly disorders such epilepsy, multiple sclerosis, glaucoma and uevitis, cerebral traumas and cerebral ischaemias, stroke, head injury, spinal cord injury, surgical trauma, neurodegenerative disorders, motorneurone disease, Alzheimer's disease, Parkinson's disease, chronic inflammatory pain, neuropathic pain, migraine, bipolar disorder, mood, anxiety and cognitive disorders, schizophrenia and trigeminal autonomic cephalalgias; for treatment of mammalian cancers; and for treatment of malaria.
- -
-
Page/Page column 32-33
(2009/08/16)
-
- Synthesis and anti-proliterative in-vitro activity of two natural dihydrostilbenes and their analogues
-
A total synthetic route for two natural dihydrostilbenes with significant cytotoxicity toward human cancer cell lines, (3-(2-(7-methoxybenzo[d][1,3] dioxol-5-yl)ethyl)phenol 1a and 6-(3-hydroxyphenethyl)benzo[d][1,3]dioxol-4-ol 1b), which were isolated from Bulbophyllum odoratissimum Lind1, was developed via Wittig-Horner reaction. The natural products 1a and 1b were obtained in 28% and 20% overall yield, respectively. Additionally, nine analogues, 1c-1k, of the two natural dihydrostilbenes were synthesized and evaluated for their anti-proliferative activity against human SGC-7901, KB and HT-1080 cell lines by MTT assay. The activities of 1c and 1d were in the same range as those of the natural products 1a and 1b.
- Zhang, Wei-Ge,Zhao, Rui,Ren, Jian,Ren, Li-Xiang,Lin, Jin-Guang,Liu, Dai-Lin,Wu, Ying-Liang,Yao, Xin-Sheng
-
p. 244 - 250
(2008/02/09)
-
- Synthesis and characterization of a series of novel phenol- and polyphenol-based glycerolipids
-
A building block approach was used to design a modular synthetic route for the preparation of novel glycerolipids with phenolic and polyphenolic headgroups. Based on this scheme, it is possible to vary the substitution pattern of the headgroup, the stereo
- Schmidt, Rolf,Carrigan, Joseph G.,DeWolf, Christine E.
-
p. 1411 - 1415
(2007/10/03)
-
- PHENYL-[4-(3-PHENYL-1H-PYRAZOL-4-YL)-PYRIMIDIN-2-YL]-AMINE DERIVATIVES AS IGF-IR INHIBITORS
-
The present invention relates to a compound of formula (I) and derivatives thereof. Furthermore, the invention relates to the use of such compounds as medicaments. In addition, the invention relates to the use of such compounds for manufacturing a medicament useful for treating proliferative diseases.
- -
-
Page/Page column 37
(2008/06/13)
-
- Synthesis and in vitro leishmanicidal activity of some hydrazides and their analogues
-
Twenty-one hydrazides were synthesized by treating different esters with hydrazine hydrate. Substituted hydrazides were obtained by treating hydrazides with alkyl/aryl/acyl halides. Some of these compounds exhibit potential in vitro leishmanicidal activity. The structures of all the synthesized compounds were confirmed by spectroscopic analysis.
- Khan, Khalid Mohammad,Rasheed, Maimona,Ullah, Zia,Hayat, Safdar,Kaukab, Farhana,Choudhary, M. Iqbal,Ur-Rahman, Atta,Perveen, Shahnaz
-
p. 1381 - 1387
(2007/10/03)
-
- Treatment of parasitic diseases by inhibition of cysteine proteases of the papain superfamily
-
The present invention relates to compounds and pharmaceutical compositions which inhibit proteases, such as cysteine proteases. In particular, the present invention relates to compounds and pharmaceutical compositions which inhibit cysteine proteases of the papain superfamily. The compounds and pharmaceutical compositions of the present invention are useful for treating diseases, particularly parasitic diseases, which are mediated by such proteases. In particular, the present invention relates to a method of treating malaria by inhibiting the cysteine protease falcipain.
- -
-
-
- 4,5-dipheny-oxazole derivatives and their use as platelet aggregation inhibitors
-
Heterocyclic compounds of the formula: ???whereinR1 is carboxy or esterified carboxy,R2 is phenyl or (C1-C6)alkylphenyl,R3 is phenyl or (C1-C6)alkylphenyl,R4 is hydrog
- -
-
-
- PROTEASE INHIBITORS
-
Disclosed herein is a compound of the formula STR1 known as 2-[N-(N-benzyloxycarbonyl-L-leucinyl)]-2'-[N'-[4-(N,N-dimethylaminomethyl) benzyloxy]carbonyl-L-leucinyl]carbohydrazide; and pharmaceutically acceptable salts, hydrates and solvates thereof.
- -
-
-
- Structure-based design of cathepsin K inhibitors containing a benzyloxy- substituted benzoyl peptidomimetic
-
Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid- based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.
- Thompson, Scott K.,Smith, Ward W.,Zhao, Baoguang,Halbert, Stacie M.,Tomaszek, Thaddeus A.,Tew, David G.,Levy, Mark A.,Janson, Cheryl A.,D'Alessio, Karla J.,McQueney, Michael S.,Kurdyla, Jeff,Jones, Christopher S.,Desjarlais, Renee L.,Abdel-Meguid, Sherin S.,Veber, Daniel F.
-
p. 3923 - 3927
(2007/10/03)
-
- Pharmacologically active 4-[2-hydroxy-4-(substituted)phenyl]naphthalen-2(1H)-ones and 2-ols, derivatives thereof and intermediates therefor
-
Compounds having the formula STR1 wherein STR2 R1 is hydrogen, benzyl or alkanoyl, X is C2-4 alkylene; and Z-W is alkyl, phenylalkyl or pyridylalkyl which can have an oxygen atom as part of the alkyl chain and their use as CNS agents, antidiarrheals and antiemetics. Processes for their preparation and intermediates therefor are described.
- -
-
-