- Optimizing the structure of (salicylideneamino)benzoic acids: Towards selective antifungal and anti-staphylococcal agents
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An increasing resistance of human pathogenic bacteria and fungi has become a global health problem. Based on previous reports of 4-(salicylideneamino)benzoic acids, we designed, synthesised and evaluated their me-too analogues as potential antimicrobial agents. Forty imines derived from substituted salicylaldehydes and aminobenzoic acids, 4-aminobenzoic acid esters and 4-amino-N-phenylbenzamide were designed using molecular hybridization and prodrug strategies. The target compounds were synthesized with high yields and characterized by spectral methods. They were investigated against a panel of Gram-positive and Gram-negative bacteria, mycobacteria, yeasts and moulds. The most active imines were tested to determine their cytotoxicity and selectivity in HepG2 cells. Dihalogenosalicylaldehydes-based derivatives showed potent broad-spectrum antimicrobial properties, particularly against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (minimum inhibitory concentrations, MIC, from 7.81 μM) and Enterococcus faecalis (MIC of ≥15.62 μM), yeasts (MIC from 7.81 μM) and Trichophyton interdigitale mould (MIC of ≥3.90 μM). Methyl 4-[(2-hydroxy-3,5-diiodobenzylidene)amino]benzoate 4h exhibited excellent in vitro activity along with low toxicity to mammalian cells. This compound is selective for staphylococci, Candida spp. and Trichophyton interdigitale. In addition, this imine was evaluated as a potential inhibitor of Gram-positive biofilms. The successful approach used provided some promising derivatives with more advantageous properties than the parent 4-(salicylideneamino)benzoic acids.
- Krátky, Martin,Kone?ná, Klára,Broke?ová, Kate?ina,Maixnerová, Jana,Trejtnar, Franti?ek,Vin?ová, Jarmila
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- Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors
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The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, respectively. Among the known inhibitors for these proteases, we have described N4-benzyl-N2-phenylquinazoline-2,4-diamine (compound 7 in the original publication, 1a in this study), as a competitive cruzain inhibitor (Ki = 1.4 μM). Here, we describe the synthesis and biological evaluation of 22 analogs of 1a, containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring. The analogs demonstrate low micromolar inhibition of the target proteases and cidal activity against Trypanosoma cruzi with up to two log selectivity indices in counterscreens with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations. During the optimization of 1a, structure-based design and prediction of physicochemical properties were employed to maintain potency against the enzymes while removing colloidal aggregator characteristics observed for some molecules in this series.
- Barbosa Da Silva, Elany,Rocha, Débora A.,Fortes, Isadora S.,Yang, Wenqian,Monti, Ludovica,Siqueira-Neto, Jair L.,Caffrey, Conor R.,McKerrow, James,Andrade, Saulo F.,Ferreira, Rafaela S.
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p. 13054 - 13071
(2021/09/13)
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- HDAC/MIF dual inhibitor inhibits NSCLC cell survival and proliferation by blocking the AKT pathway
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Non-small-cell lung carcinoma (NSCLC) is one of the most common forms of lung cancer, and a leading cause of cancer death among human beings. There is an urgent demand for novel therapeutics for the treatment of NSCLC to enhance the efficacy of the currently applied Tyrosine kinase inhibitors (TKIs) therapy and to overcome therapy-resistance. Here, we report a novel small-molecule inhibitor that simultaneously targets histone deacetylase (HDAC) and macrophage migration inhibitory factor (MIF). The HDAC/MIF dual inhibitor proved to be toxic for EGFR mutated (H1650, TKI-resistant) or knock out (A549 EGFR?/?) NSCLC cell lines. Further experiments showed that HDAC inhibition inhibits cell survival and proliferation, while MIF inhibition downregulates pAKT or AKT expression level, which both interfere with cell survival. Furthermore, the combination treatment of TKI and HDAC/MIF dual inhibitor showed that the dual inhibitor enhanced TKI inhibitory efficacy, highlighting the advantages of HDAC/MIF dual inhibitor for more effective treatment of NSCLC.
- Cao, Fangyuan,Chen, Deng,Chen, Siwei,Dekker, Frank J.,Haisma, Hidde J.,Xiao, Zhangping,Zhao, Chunlong
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- Activated charcoal supported copper nanoparticles: A readily available and inexpensive heterogeneous catalyst for the N-arylation of primary amides and lactams with aryl iodides
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A novel heterogeneous copper catalyst has been developed by supporting copper nanoparticles on activated charcoal via in situ reducing copper(II) with aqueous hydrazine as reductant. The characterization of Cu/C catalyst showed that the Cu0 nano-particles were formed on the surface of charcoal. This catalyst displayed good catalytic activities toward the N-arylation of primary amides and lactams with aryl iodides.
- Zhao, Rong,Dong, Wenwen,Teng, Jiangge,Wang, Zhiwei,Wang, Yunzhong,Yang, Jianguo,Jia, Qiang,Chu, Changhu
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supporting information
(2020/12/21)
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- Ligand-free Pd(0)/SiO2-catalyzed aminocarbonylation of aryl iodides to amides under atmospheric CO pressure
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An efficient and facile route for CO-based carbonylation of aryl iodides with amines to synthesize amides has been established by using SiO2 supported Pd(0) as the catalyst in a mild basic environment (K2CO3). This ligand-free heterogeneous reaction model can afford amide products in good to excellent yields (up to 99%) under atmospheric CO pressure and moderate temperature. The supported catalyst also displayed a broad substrate scope, good functional group tolerance and good recyclability. These features render the as-provided carbonylation approach sustainable and applicable in organic synthesis.
- Hu, Qinhua,Wang, Lele,Wang, Chen,Wu, Yubin,Ding, Zhengxin,Yuan, Rusheng
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p. 37200 - 37207
(2017/08/09)
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- arone and amide compound and its preparation and use in medicine
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The invention discloses a novel arone and arylamide compound represented by formula I, a cistrans isomer, physiologically acceptable salts, a solvate and a crystallizing form thereof, a preparation method of the compound, a medicine preparation containing the compound and clinical application of the compound in treating diseases related to protein tyrosine phosphatases 1B.
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Paragraph 0212; 0218; 0219
(2017/11/17)
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- Identification of Multiple Structurally Distinct, Nonpeptidic Small Molecule Inhibitors of Protein Arginine Deiminase 3 Using a Substrate-Based Fragment Method
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The protein arginine deiminases (PADs) are a family of enzymes that catalyze the post-translational hydrolytic deimination of arginine residues. Four different enzymologically active PAD subtypes have been characterized and exhibit tissue-specific expression and association with a number of different diseases. In this Article we describe the development of an approach for the reliable discovery of low molecular weight, nonpeptidic fragment substrates of the PADs that then can be optimized and converted to mechanism-based irreversible PAD inhibitors. The approach is demonstrated by the development of potent and selective inhibitors of PAD3, a PAD subtype implicated in the neurodegenerative response to spinal cord injury. Multiple structurally distinct inhibitors were identified with the most potent inhibitors having >10,000 min-1 M-1 kinact/KI values and ≥10-fold selectivity for PAD3 over PADs 1, 2, and 4. (Figure Presented).
- Jamali, Haya,Khan, Hasan A.,Stringer, Joseph R.,Chowdhury, Somenath,Ellman, Jonathan A.
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supporting information
p. 3616 - 3621
(2015/03/30)
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- Hypervalent iodine(III)-mediated oxidative dearomatizing cyclization of arylamines
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An oxidative dearomatizing cyclization of arylamines promoted by iodobenzene bis(trifluoroacetate) [PhI(CF3CO2) 2] has been explored, leading to a novel synthetic approach to functionalized spirocyclic building blocks containing the structurally unique dieniminium moiety. This unprecedented methodology, featuring oxidative dearomatization and carbon-carbon bond-forming cyclization, to some extent, not only expands the synthetic potential of hypervalent iodine chemistry, but also enriches the oxidation chemistry of arylamines.
- Jin, Cong-Yang,Du, Ji-Yuan,Zeng, Chao,Zhao, Xian-He,Cao, Ye-Xing,Zhang, Xiang-Zhi,Lu, Xin-Yun,Fan, Chun-An
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supporting information
p. 2437 - 2444
(2014/09/17)
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- β-Cyclodextrin-TiO2: Green Nest for reduction of nitroaromatic compounds
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In this paper, highly efficient photocatalytic reduction of nitroaromatic compounds was investigated using β-cyclodextrin (β-CD) and commercial nano-TiO2 as a host-guest system in water under sunlight irradiation. The nitroaromatic compounds solubilized in water through encapsulation in β-CD formed an inclusion complex which was attached to TiO2 under sunlight irradiation. This 'guest-host system' that we call 'Green Nest' showed high efficiency for the reduction of nitro compounds to the corresponding amines, and more interestingly, one pot reductive N-formylation and N-acylation from nitroaromatic compounds can be carried out in the presence of triethyl orthoformate, acetic and benzoic anhydride. The β-CD-TiO2 was characterized by transmission electron microscopy, UV-visible spectra, thermogravimetric analysis, Brunauer-Emmett-Teller measurements, UV-visible diffuse reflectance spectroscopy, and Raman spectroscopy.
- Kakroudi, Mazaher Abdollahi,Kazemi, Foad,Kaboudin, Babak
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p. 52762 - 52769
(2015/01/16)
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- An efficient copper-catalyzed N-arylation of amides: Synthesis of N-arylacrylamides and 4-amido-N-phenylbenzamides
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Copper-catalyzed intermolecular C-N bond-forming reactions between aryl iodides and amides are described using sodium ascorbate, which is both cheap and nontoxic, as the additive. A variety of functionalized amides including some practical, unique secondary amides, such as N-arylacrylamides and 4-amido-N-phenylbenzamides, which are difficult to obtain by the classical methods, are prepared. Furthermore, some tertiary amides are prepared by using copper thiophenecarboxylate.
- Quan, Zheng-Jun,Xia, Hai-Dong,Zhang, Zhang,Da, Yu-Xia,Wang, Xi-Cun
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p. 8368 - 8374
(2013/09/02)
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- Copper-catalyzed amination of aryl halides with aqueous ammonia under mild conditions
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A Cu(I) generated in situ from CuSO4·5H 2O/sodium ascorbate catalyzed cross-coupling reaction of aryl halides with aqueous ammonia for the synthesis of primary aromatic amines has been developed. Key to the success included the application of aqueous ammonia under a homogeneous condition. A Cu(I) generated in situ from CuSO4· 5H2O/sodium ascorbate catalyzed cross-coupling reaction of aryl halides with aqueous ammonia for the synsthesis of primary aromatic amines has been developed. Key to the success included the application of aqueous ammonia under a homogeneous condition.
- Quan, Zhengjun,Xia, Haidong,Zhang, Zhang,Da, Yuxia,Wang, Xicun
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p. 501 - 506
(2013/08/25)
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- Design, synthesis, and biological activity of a novel series of human sirtuin-2-selective inhibitors
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Selective inhibitors of human sirtuin 2 (SIRT2), a deacetylase, are candidate therapeutic agents for neurodegenerative diseases such as Parkinson's disease and Huntington's disease as well as potential tools for elucidating the biological functions of SIRT2. On the basis of homology models of SIRT1 and SIRT2, we designed and prepared a series of 2-anilinobenzamide analogues. Enzyme assays using recombinant SIRT1 and SIRT2 revealed that 3'-phenethyloxy-2- anilinobenzamide analogues such as 33a and 33i are potent and selective SIRT2 inhibitors, showing more than 3.5-fold greater SIRT2-inhibitory activity and more than 35-fold greater SIRT2-selectivity compared with AGK2 (3), a previously reported SIRT2-selective inhibitor. Compound 33a also induced a dose-dependent selective increase of α-tubulin acetylation in human colon cancer HCT116 cells, indicating selective inhibition of SIRT2 in the cells. These 3'-phenethyloxy-2-anilinobenzamide derivatives represent an entry into a new class of SIRT2-selective inhibitors.
- Suzuki, Takayoshi,Khan, Mohammed Naseer Ahmed,Sawada, Hideyuki,Imai, Erika,Itoh, Yukihiro,Yamatsuta, Katsura,Tokuda, Natsuko,Takeuchi, Jun,Seko, Takuya,Nakagawa, Hidehiko,Miyata, Naoki
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experimental part
p. 5760 - 5773
(2012/07/28)
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- Design, synthesis, and biological activity of urea derivatives as anaplastic lymphoma kinase inhibitors
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In anaplastic large-cell lymphomas, chromosomal translocations involving the kinase domain of anaplastic lymphoma kinase (ALK), generally fused to the 5' part of the nucleophosmin gene, produce highly oncogenic ALK fusion proteins that deregulate cell cycle, apoptosis, and differentiation in these cells. Other fusion oncoproteins involving ALK, such as echinoderm microtubule-associated protein-like 4-ALK, were recently found in patients with non-small-cell lung, breast, and colorectal cancers. Recent research has focused on the development of inhibitors for targeted therapy of these ALK-positive tumors. Because kinase inhibitors that target the inactive conformation are thought to be more specific than ATP-targeted inhibitors, we investigated the possibility of using two known inhibitors, doramapimod and sorafenib, which target inactive kinases, to design new urea derivatives as ALK inhibitors. We generated a homology model of ALK in its inactive conformation complexed with doramapimod or sorafenib in its active site. The results elucidated why doramapimod is a weak inhibitor and why sorafenib does not inhibit ALK. Virtual screening of commercially available compounds using the homology model of ALK yielded candidate inhibitors, which were tested using biochemical assays. Herein we present the design, synthesis, biological activity, and structure-activity relationships of a novel series of urea compounds as potent ALK inhibitors. Some compounds showed inhibition of purified ALK in the high nanomolar range and selective antiproliferative activity on ALK-positive cells.
- Boijeaf Gennaes, Gustav,Mologni, Luca,Ahmed, Shaheen,Rajaratnam, Mohanathas,Marin, Oriano,Lindholm, Niko,Viltadi, Michela,Gambacorti-Passerini, Carlo,Scapozza, Leonardo,Yli-Kauhaluoma, Jari
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experimental part
p. 1680 - 1692
(2012/01/06)
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- METHOD OF MANUFACTURING BIPYRIDINIUM COMPOUND AND SYNTHETIC INTERMEDIATE OF THE SAME, METHOD OF MANUFACTURING DYE COMPOUND, AND NOVEL BIPYRIDINIUM COMPOUND AND NOVEL DYE COMPOUND COMPRISING THE SAME
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Provided is a method of manufacturing a bipyridinium compound denoted by general formula (A). In general formula (A), Ar1 and Ar2 each independently denote an optionally substituted (hetero)aryl group, R3 and R4 each independently denote a substituent that may form a ring with a pyridine ring to which the substituent substitutes, m3 and m4 each independently denote an integer ranging from 0 to 4, X denotes a halogen atom or RSO3, and R denotes an optionally substituted aryl group or alkyl group. The method can manufacture a 4,4′-bipyridinium compound under mild reaction conditions in an integrated manner without separation of intermediates.
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Page/Page column 29-30
(2009/04/24)
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- Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. Design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor
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Although cyclooxygenase-1 (COX-1) inhibition is thought to be a major mechanism of gastric damage by nonsteroidal anti-inflammatory drugs (NSAIDs), some COX-1-selective inhibitors exhibit strong analgesic effects without causing gastric damage. However, it is not clear whether their analgesic effects are attributable to COX-1-inhibitory activity or other bioactivities. Here, we report that N-(5-amino-2-pyridinyl)-4-(trifluoromethyl)benzamide (18f, TFAP), which has a structure clearly different from those of currently available COX-1-selective inhibitors, is a potent COX-1-selective inhibitor (COX-1 IC 50 = 0.80 ± 0.05 μM, COX-2 IC50 = 210 ± 10 μM). This compound causes little gastric damage in rats even at an oral dose of 300 mg/kg, though it has an analgesic effect at as low a dose as 10 mg/kg. Our results show that COX-1-selective inhibitors can be analgesic agents without causing gastric damage.
- Kakuta, Hiroki,Zheng, Xiaoxia,Oda, Hiroyuki,Harada, Shun,Sugimoto, Yukio,Sasaki, Kenji,Tai, Akihiro
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p. 2400 - 2411
(2008/12/22)
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- New bis(2-aminoimidazoline) and bisguanidine DNA minor groove binders with potent in vivo antitrypanosomal and antiplasmodial activity
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A series of 75 guanidine and 2-aminoimidazoline analogue molecules were assayed in vitro against Trypanosoma brucei rhodesiense STIB900 and Plasmodium falciparum K1. The dicationic diphenyl compounds exhibited the best activities with IC50 values against T. b. rhodesiense and P. falciparum in the nanomolar range. Five compounds (7b, 9a, 9b, 10b, and 14b) cured 100% of treated mice upon ip administration at 20 mg/kg in the difficult to cure T. b. rhodesiense STIB900 mouse model. Overall, the compounds that bear the 2-aminoimidazoline cations benefit from better safety profiles than the guanidine counterparts. The observation of a correlation between DNA binding affinity at AT sites and trypanocidal activity for three series of compounds supported the view of a mechanism of antitrypanosomal action due in part to the formation of a DNA complex. No correlation between antiplasmodial activity and in vitro inhibition of ferriprotoporphyrin IX biomineralisation was observed, suggesting that additional mechanism of action is likely to be involved.
- Rodríguez, Fernando,Rozas, Isabel,Kaiser, Marcel,Brun, Reto,Nguyen, Binh,Wilson, W. David,García, Rory Nelson,Dardonville, Christophe
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p. 909 - 923
(2008/12/22)
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- Structure-activity relationships in the binding of chemically derivatized CD4 to gp120 from human immunodeficiency virus
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The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction.
- Xie, Hui,Ng, Danny,Savinov, Sergey N.,Dey, Barna,Kwong, Peter D.,Wyatt, Richard,Smith III, Amos B.,Hendrickson, Wayne A.
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p. 4898 - 4908
(2008/03/11)
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- Selective reduction of aromatic nitro groups in the presence of amide functionality
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Pressure mediated selective reduction of aromatic nitro groups in the presence of amide functionality has been achieved by use of hydrazine hydrate.
- Deka, Dibakar Chandra,Kakati, Hari Sankar
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p. 223 - 224
(2007/10/03)
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- Novel lead structures for antimalarial farnesyltransferase inhibitors
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Through the combination of nitrophenylfurylacryloyl moiety which has been designed to occupy an aryl binding site of farnesyltransferase with several AA(X)-peptidomimetic substructures some novel farnesyltransferase inhibitors were obtained. Evaluation of their antimalarial activity and some initial modifications yielded a 4-benzophenone- and a sulfonamid-based novel lead for antimalarial farnesyltransferase inhibitors.
- Kettler,Sakowski,Wiesner,Ortmann,Jomaa,Schlitzer, Martin
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p. 323 - 327
(2007/10/03)
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- Zinc-catalyzed ammonium formate reductions: Rapid and selective reduction of aliphatic and aromatic nitro compounds
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Aliphatic and aromatic nitro compounds are selectively and rapidly reduced to their corresponding amino derivatives in good yields using ammonium formate and commercial zinc dust. This system is found to be compatible with several sensitive functionalities such as halogens, -OH, -OCH3, -CHO, -COCH3, -COC6H5, -COOH, COOC2H5, -CONH2, -CN, -CH=CH-COOH, -NHCOCH3. The reduction can be carried out not only with HCOONH4 but also with HCOOH.
- Gowda, D. Channe,Mahesh, B.,Gowda, Shankare
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- Synthesis and Antiviral Activity of Sulfonamidobenzophenone Oximes and Sulfonamidobenzamides
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To find antiviral agents, various sulfonamidobenzophenone oximes (II) were synthesized from the appropriate m-sulfonamidobenzophenones by hydroxylamine reaction.The reaction products were generally obtained as syn/anti mixtures which were separable by fractional crystallization.The anti isomer had more potent antipoliovirus activity than the syn isomer.Various sulfonamidobenzamides (III) which were structurally related to II were synthesized by the reaction of amino-substituted benzamides with sulfuryl chloride or amines with (aminosulfonyl)benzoyl chloride.Antiviral activity was examined by the plaque-inhibition test.Compounds 5, 36, and 69 exhibited strong antipicornavirus activity.The structure-activity relationships are discussed.
- Ogata, Masaru,Matsumoto, Hiroshi,Shimizu, Sumio,Kida, Shiro,Wada, Toru,et al.
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p. 417 - 423
(2007/10/02)
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- Anticonvulsant activity of some 4-aminobenzamides
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A series of 4-aminobenzamides of some simple primary and secondary amines were prepared and evaluated for anticonvulsant effects. The compounds were tested in mice against seizures induced by electroshock and pentylenetetrazole (metrazole) and in the rotorod assay for neurologic deficit. For those N-alkyl amides tested, 4-amino-N-amylbenzamide was the most potent against maximal electroshock seizures (MES): ED50=42.98 mg/kg; however, the N-cyclohexylbenzamide showed the greatest protective index (PI=TD50/ED50), 2.8. The introduction of a second aromatic ring produced more potent compounds, with d,l-4-amino-N-(α-methylbenzyl)-benzamide showing the highest level of activity. This compound has an anti-MES ED50 of 18.02 mg/kg in mice when administered intraperitoneally (ip) and a TD50 of 170.78 mg/kg (PI=9.5) in the same species. These data compare quite favorably with those for phenobarbital and phenytoin in the same assays.
- Clark,Wells,Sansom,et al.
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p. 779 - 782
(2007/10/02)
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- Method of suppressing body odor with aminobenzoic acid amides
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This invention is directed to a cosmetic deodorant composition comprising: (a) from about 0.1 to 5 percent by weight, based on the weight of the total composition, of aminobenzoic acid amides of the formula STR1 wherein R1 and R2, which may be the same or different, each represent hydrogen, an alkyl of from 1 to 12 carbon atoms; a hydroxyalkyl of from 2 to 4 carbon atoms; an aryl; an aralkyl or carboxyalkyl with from 1 to 3 carbon atoms in the alkyl moiety; or an alkoxyalkyl with from 1 to 8 carbon atoms in the alkoxy moiety and from 1 to 3 carbon atoms in the alkyl moiety, or R1 and R2 together with the amide nitrogen form an optionally substituted heterocyclic ring; and (b) the remainder conventional cosmetic deodorant composition compounds.
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- Anti-convulsant
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New amino-benzamides and their use for the treatment of epilepsy.
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