Abstract：
:During the syntheses and studies of natural iron chelators (mycobactins), we serendipitously discovered that a simple, small molecule, oxazoline-containing intermediate 3 displayed surprising anti-tuberculosis activity (MIC of 7.7 microM, average). Herein we report elaboration of SAR around this hit as well as the syntheses and evaluation of a hundred oxazoline- and oxazole-containing compounds derived from an efficient three step process: 1) formation of beta-hydroxy amides with serine or threonine; 2) cyclization to afford oxazolines; and 3) dehydration to give the corresponding oxazoles. A number of compounds prepared by this method were shown to possess impressive activity against Mycobacterium tuberculosis, extremely low toxicity and therefore high therapeutic indexes, as well as activity against even the more recalcitrant non-replicating form of M. tuberculosis. The uniqueness of their structures and their simplicity should allow them to be further optimized to meet ADME (absorption, distribution, metabolism, excretion) requirements. The syntheses of eight of the most potent in vitro compounds were scaled up and the compounds were tested in an in vivo mouse infection model to evaluate their efficacy before engaging upon more elaborate compound design and optimization.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Moraski GC,Chang M,Villegas-Estrada A,Franzblau SG,Möllmann U,Miller MJdoi
10.1016/j.ejmech.2009.12.074subject
Has Abstractpub_date
2010-05-01 00:00:00pages
1703-16issue
5eissn
0223-5234issn
1768-3254pii
S0223-5234(10)00043-7journal_volume
45pub_type
杂志文章abstract：:Invasion and metastasis are responsible for 90% of cancer-related mortality. Herein, we report on our quest for novel, clinically relevant inhibitors of local invasion, based on a broad screen of natural products in a phenotypic assay. Starting from micromolar chalcone hits, a predictive QSAR model for diaryl propenon...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2015.06.029
更新日期：2015-08-28 00:00:00
abstract：:A set of CB2R ligands, based on the thiophene scaffold, was synthesized and evaluated in in vitro assays. Compounds 8c-i, k, l, bearing the 3-carboxylate and 2-(adamantan-1-yl)carboxamido groups together with apolar alkyl/aryl substituents at 5-position or at 4- and 5-positions of the thiophene ring possess high CB2R ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2018.09.070
更新日期：2019-01-01 00:00:00
abstract：:Persistently activated signal transducer and activator of transcription 3 (STAT3) plays an important role in the development of multiple cancers, and therefore is a potential therapeutic target for cancer prevention. Herein, we report the rational design, synthesis, and biological evaluation of novel potent STAT3 inhi...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2020.112428
更新日期：2020-09-01 00:00:00
abstract：:Insulin resistance is a complex altered metabolic condition characterized by impaired insulin signaling and implicated in the pathogenesis of serious human diseases, such as diabetes, obesity, neurodegenerative pathologies. In pursuing our aim to identify new agents able to improve cellular insulin sensitivity, we hav...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2013.11.001
更新日期：2014-01-01 00:00:00
abstract：:A series of substituted 2-phenylthiazole-4-carboxamide derivatives were synthesized as potential cytotoxic agents and evaluated against three human cancer cell lines including T47D (Breast cancer), Caco-2 (Colorectal cancer) and HT-29 (Colon cancer). The SAR of the arylacetamido pendent connected to the para-position ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2010.08.063
更新日期：2010-11-01 00:00:00
abstract：:PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2019.06.021
更新日期：2019-09-15 00:00:00
abstract：:The following mini-review summarizes the basic literature data regarding synthesis, biological activity, structure-activity relationship, and discussion of the mechanisms of action of two major classes of nucleoside analogs with fused heterocyclic rings: (i) the ethenonucleosides and their related derivatives of the 5...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1016/j.ejmech.2014.12.026
更新日期：2015-06-05 00:00:00
abstract：:A series of [1,2,4]triazino[5,6-b]indol-3-ylthio-1,3,5-triazines and [1,2,4]triazino[5,6-b]indol-3-ylthio-pyrimidines were synthesized and screened for their in vitro antileishmanial activity against Leishmania donovani. Among all, 8 compounds have shown more than 90% inhibition against promastigotes and IC50 in the r...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2010.02.015
更新日期：2010-06-01 00:00:00
abstract：:We synthesized a series of novel amide derivatives of 5-(p-tolyl)-1-(quinolin-2-yl)pyrazole-3-carboxylic acid and assessed their antiproliferative activities against three human cancer cell lines (Huh7, human liver; MCF7, breast and HCT116, colon carcinoma cell lines) with the sulforhodamine B assay. Compound 4j with ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2014.09.056
更新日期：2014-11-24 00:00:00
abstract：:Resistance to combretastatin A-4 is mediated by metabolic modification of the phenolic hydroxyl and ether groups of the 3-hydroxy-4-methoxyphenyl (B ring). Replacement of the B ring of combretastatin A-4 by a N-methyl-5-indolyl reduces tubulin polymerization inhibition (TPI) and cytotoxicity against human cancer cell ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2018.08.078
更新日期：2018-10-05 00:00:00
abstract：:Derived from the structures of the alkaloids rutaecarpine and dehydroevodiamine (DHED), and the long-known acetylcholinesterase (AChE) inhibitor tacrine, respectively, novel compounds were synthesised, including: 13-methyl-5,8-dihydro-6H-isoquino[1,2-b]quinazolin-13-ium chloride (12), (8Z)-5,6-dihydro-8H-isoquino[1,2-...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2004.12.003
更新日期：2005-03-01 00:00:00
abstract：:Several myrcenylhydroquinone derivatives have been evaluated for their cytotoxic activity against three neoplastic cell line cultures and compared with the activity previously observed on other neoplastic systems. Also a new series of this type of compounds has been prepared and the compounds synthesised have been eva...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/s0223-5234(01)01329-0
更新日期：2002-02-01 00:00:00
abstract：:Metal complexes of 2-methyl-1H-benzimidazole-5-carboxylic acid hydrazide (4a; L(1)) and its Schiff base 2-methyl-N-(propan-2-ylidene)-1H-benzimidazole-5-carbohydrazide (5a; L(2)) with transition metal ions e.g., copper, silver, nickel, iron and manganese were prepared. The complexes formed were 1:1 or 1:2 M:L complexe...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2008.07.013
更新日期：2009-04-01 00:00:00
abstract：:Structural modification of the frontline antitubercular isonicotinic acid hydrazide (INH) provides lipophilic adaptations (3-46) of the drug in which the hydrazine moiety of the parent compound has been chemically blocked from the deactivating process of N(2)-acetylation by N-arylaminoacetyl transferases. As a class, ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2009.05.009
更新日期：2009-10-01 00:00:00
abstract：:As a part of the research on the improvement of an alternative to conventional photodynamic therapy by light-induced formation of intercalators, we synthesized a series of novel heterocyclic compounds and their acyclic precursors. We now report details about their synthesis/characterization in respect to their potenti...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2006.03.012
更新日期：2006-08-01 00:00:00
abstract：:Oxovanadium(IV) complexes [VO(Fc-tpy)(acac)](ClO4) (1), [VO(Fc-tpy)(nap-acac)](ClO4) (2), [VO(Fc-tpy)(py-acac)](ClO4) (3) and [VO(Ph-tpy)(py-acac)](ClO4) (4) of 4'-ferrocenyl-2,2':6',2"-terpyridine (Fc-tpy) and 4'-phenyl-2,2':6',2"-terpyridine (Ph-tpy) having monoanionic acetylacetonate (acac), naphthylacetylacetonate...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2015.01.003
更新日期：2015-03-06 00:00:00
abstract：:Three series of novel 4-phenoxypyridine derivatives containing 4-methyl-6-oxo-1,6-dihydropyridazine- 3-carboxamide, 5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide and 4-methyl-3,5-dioxo-2,3,4,5- tetrahydro-1,2,4-triazine-6-carboxamide moieties were synthesized and evaluated for their in vitro inhibitory activitive...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2020.112244
更新日期：2020-05-15 00:00:00
abstract：:Anti-tubulin polymerization agents can disrupt tumor-vascular to exhibit anti-cancer potency. In this study, a series of substituted (2-(phenylamino)thieno[3,2-d]pyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone analogues were designed and synthesized as anti-tubulin polymerization agents that interact with colchicine ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2019.111679
更新日期：2019-12-01 00:00:00
abstract：:Various substituted 3-aryl-1-isoquinolinamines were designed and synthesized based on the previously constructed CoMFA model. Most of the synthesized compounds showed excellent potency in eight different human tumor cell lines as expected. In order to find the exact cytotoxic mechanism of these 3-aryl-1-isoquinolinami...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2010.08.042
更新日期：2010-11-01 00:00:00
abstract：:New series of quinoline-oxazolidinone hybrid molecules were synthesized based on the preliminary docking studies. All the newly synthesized compounds were characterized by spectral analyses. The newly synthesized compounds were screened for their antimycobacterial properties based on the promising preliminary antibact...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2011.07.049
更新日期：2011-10-01 00:00:00
abstract：:Thirty-six 6(7)-substituted-3-methyl- or 3-halogenomethyl-2-phenylthio-phenylsulphonyl-chloro-quinoxaline 1,4-dioxides belonging to series 3-6 were synthesised and submitted to a preliminary in vitro evaluation for antimycobacterial, anticandida and antibacterial activities. Antitubercular screening showed a generally...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/s0223-5234(02)01346-6
更新日期：2002-05-01 00:00:00
abstract：:Naphthoquinoidal compounds are of great interest in medicinal chemistry. In recent years, several synthetic routes have been developed to obtain bioactive molecules derived from lapachones. In this mini-review, we focus on the synthetic aspects and strategies used to design these compounds and on the biological activi...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1016/j.ejmech.2013.07.057
更新日期：2013-11-01 00:00:00
abstract：:The present works deals with simple and efficient method of improving therapeutic efficacy of racemic ibuprofen by retarding gastrointestinal side effects through masking of carboxylic group chemically. This is achieved by synthesis and evaluation of ester derivatives of ibuprofen as mutual prodrugs with naturally occ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2012.08.030
更新日期：2012-10-01 00:00:00
abstract：:Oral administration of 2-(4-[(2-hydroxybenzyl) amino]-phenyl amino-methyl)-phenol (HBPMP) (30 mg/kg) to Streptozotocin (STZ) rats produced significant antidiabetic activity after 6 h of HBPMP administration. Treatment of the STZ rats with HBPMP (30 mg/kg/day) for 30 days resulted in a significant decrease in their Fas...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2013.05.014
更新日期：2013-08-01 00:00:00
abstract：:Leukemia is the most common blood cancer, and its development starts at diverse points, leading to distinct subtypes that respond differently to therapy. This heterogeneity is rarely taken into account in therapies, so it is still essential to look for new specific drugs for leukemia subtypes or even for therapy-resis...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2016.02.047
更新日期：2016-05-04 00:00:00
abstract：:NOD1 and NOD2 are pattern recognition receptors that have important roles in innate immune responses. Although their overactivation has been linked to a number of diseases, NOD2 in particular remains a virtually unexploited target in this respect, with only one structural class of antagonist reported. To gain insight ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2020.112089
更新日期：2020-03-15 00:00:00
abstract：:Here, we describe the chemical characterization of the inclusion complex between diclofenac (DCF) and methyl-beta-cyclodextrin (M-beta-CD) in the presence or absence of monoethanolamine (MEA). Several techniques were used to analyze the complex both in solution and in the solid state. Solubility of DCF was increased b...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2010.05.068
更新日期：2010-09-01 00:00:00
abstract：:Oxindole has emerged as a valuable scaffold in medicinal chemistry possessing diverse range of pharmacological activities. Its value has further been increased by its natural occurrence as alkaloids in variety of plants. It was first extracted from the cat claw's plant Uncaria tomentosa found in the Amazon rainforest ...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1016/j.ejmech.2016.08.011
更新日期：2016-11-10 00:00:00
abstract：:Boronic acid (and ester) prodrugs targeting the overexpressed level of reactive oxygen species within tumor microenvironment represent a promising area for the discovery of new selective anticancer chemotherapy. This strategy that emerged only ten years ago is exponentially growing and could demonstrate its clinical u...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1016/j.ejmech.2020.112670
更新日期：2020-12-01 00:00:00
abstract：:A series of novel N(6)-alkyl(aryl)-2-alkyl(aryl)thioadenosines were synthesized, and their human antiplatelet aggregation activities were evaluated by the stimulation of adenosine 5'-diphosphate (ADP). Some of these compounds showed strong activity, among which compound 5b(11) displayed the highest activity with an IC...
journal_title：European journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1016/j.ejmech.2012.03.047
更新日期：2012-07-01 00:00:00
