Abstract：
:Every week, articles disclosing new antifungal leads reported as promising starting points for optimization projects are published. In many cases, the mechanism that accounts for their antifungal activity has not been fully elucidated. More significantly, the detrimental impact that could result from certain embedded chemical features has been underestimated or even overlooked. In the course of our research in the agrochemical area, we have concluded that in many cases such leads are actually nonoptimizable because they either contain what are now recognized as pan assay interference compounds (PAINS) or other promiscuous groups. This article is aimed at highlighting the pitfalls we have encountered and hopefully to steer other research groups away from them.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Pouliot M,Jeanmart Sdoi
10.1021/acs.jmedchem.5b00361subject
Has Abstractpub_date
2016-01-28 00:00:00pages
497-503issue
2eissn
0022-2623issn
1520-4804journal_volume
59pub_type
杂志文章,评审abstract：:The epigenetic regulator CBP/P300 presents a novel therapeutic target for oncology. Previously, we disclosed the development of potent and selective CBP bromodomain inhibitors by first identifying pharmacophores that bind the KAc region and then building into the LPF shelf. Herein, we report the "hybridization" of a v...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01372
更新日期：2017-12-28 00:00:00
abstract：:Conjugation of pleuromutilin is an attractive strategy for the development of novel antibiotics and the fight against multiresistant bacteria as the class is associated with low rates of resistance and cross-resistance development. Herein, the preparation of 35 novel (+)-pleuromutilin conjugates is reported. Their des...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01328
更新日期：2020-12-24 00:00:00
abstract：:The in vivo antitumor activity and in vitro metabolic dealkylation have been measured for an homologous series of 3-alkyl-1-(4-carbamoylphenyl)-3-methyltriazenes and have been compared with their partition coefficients. This investigation has shown that the extent of oxidative metabolism in vitro and the antitumor act...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00373a011
更新日期：1984-07-01 00:00:00
abstract：:The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00167a018
更新日期：1990-05-01 00:00:00
abstract：:New beta-adrenergic blocking agents, most of which do not contain an aromatic nucleus, were synthesized. They were derived either from alkylamino-aliphatic oxime ethers or alkylamino-aliphatic ethers. Most active among these are O-[3-(tert-butylamino)-2-hydroxypropyl]acetoxime (8; trachea pA2 = 7.65) and 1-isobutoxy-3...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00180a007
更新日期：1980-06-01 00:00:00
abstract：:Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)-4-oxobutyl]piperazine), a synthetic intermediate identified as a potential atypical antipsychotic, was selected as the starting point for pharmacological improvement. From 1, sequential structural variations were conducted in order to improve its potency and oral bio...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950894b
更新日期：1996-07-19 00:00:00
abstract：:From the whole plant of Euphorbia peplus L., five new diterpenes based on a jatrophane skeleton (pepluanins A-E, 1-5) were isolated, together with two known analogues (6 and 7), which served to divulge in detail the structure-activity relationships within this class of P-glycoprotein inhibitors. The results revealed t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030951y
更新日期：2004-02-12 00:00:00
abstract：:The pyridine C-nucleosides 5-beta-D-ribofuranosylnicotinamide and its N-methylpyridinium derivative (1 and 2), which are isosteric and isoelectronic, respectively, to nicotinamide nucleoside were synthesized. Condensation of 3-bromo-5-lithiopyridine with 2,4:3,5-di-O-benzylidene-D-aldehydoribose (7) afforded an allo/a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00388a030
更新日期：1987-05-01 00:00:00
abstract：:Structure-activity studies have been carried out on a series of imidazo[4,5-f]quinoline derivatives reported to have potent in vivo immunostimulatory activity. This activity has been confirmed, and subtle structure-activity relationships have been uncovered which resulted in the identification of novel analogs (pyrazo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00102a013
更新日期：1992-11-27 00:00:00
abstract：:A systematic exploration of bioisosteric replacements for furan and thiophene cores in a series of potent A2BAR antagonists has been carried out using the nitrogen-walk approach. A collection of 42 novel alkyl 4-substituted-2-methyl-1,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylates, which contain 18 differe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c00564
更新日期：2020-07-23 00:00:00
abstract：:Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00401a014
更新日期：1988-06-01 00:00:00
abstract：:N-Benzoyl-DL-phenylalanine (1) was found to possess hypoglycemic activity. A series of the analogues of compound 1 were prepared and evaluated for their blood glucose lowering activity. Both the steric effects of the phenylalanine moiety and the effects of variations in the acyl moiety were investigated. This study el...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00119a007
更新日期：1988-11-01 00:00:00
abstract：:Ergosterol, the predominant sterol of fungi, is postulated to have many cellular functions which include a bulk membrane role and a regulatory role. Studies with sterol auxotrophs show that, even in the presence of sterols which can fulfill the bulk membrane requirements, a small concentration of ergosterol is absolut...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9605851
更新日期：1996-12-20 00:00:00
abstract：:Following earlier work on cystine-bridged peptides, cyclic phosphopeptides containing nonreducible mimics of cystine were synthesized that show high affinity and specificity toward the Src homology (SH2) domain of the growth factor receptor-binding protein (Grb2). Replacement of the cystine in the cyclic heptapeptide ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9811007
更新日期：1999-03-25 00:00:00
abstract：:A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared. Their affinity for the AT1 receptor was determined in a binding assay on rat adrenal cortical membranes. Th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00024a008
更新日期：1995-11-24 00:00:00
abstract：:Analogues of luliberin containing an alpha-azaamino acid in position 6, 9, or 10 (I--XIV) have been synthesized by the solution method of peptide synthesis. Two nonaza analogues, [D-Phe6]- and [D-Ser(But)6,des-Gly-NH2(10),Pro-ethylamide9]luliberin, were also synthesized for comparison. The ovulation-inducing activity ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00208a004
更新日期：1978-10-01 00:00:00
abstract：:A series of cis- and trans-dihydroxycotahydrobenzo[f]quinoline congeners of dopamine has been prepared, in which the N substitutent is H, ethyl, or n-propyl. The trans isomers include the dopamine moiety held rigidly in an antiperiplanar diposition which is believed to be necessary for certian central and peripheral d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00190a002
更新日期：1979-04-01 00:00:00
abstract：:The medicinal chemistry community has directed considerable efforts toward the discovery of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK), given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We h...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501998m
更新日期：2015-05-14 00:00:00
abstract：:The neutral endopeptidase inhibitor (2R)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]pentanoic acid 2 is metabolized to acyl glucuronide 3. Unprecedentedly, at pH 7.4, 3 does not undergo the O-acyl migration characteristic of acyl glucuronides but rapid, eliminative cyclization (t1/2 at 37...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0706766
更新日期：2007-11-29 00:00:00
abstract：:A series of antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3'-processing. These strand transfer selective inhibitors also inhibited H...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5001503
更新日期：2014-04-24 00:00:00
abstract：:Fourteen structurally diverse Annonaceous acetogenins, representing the three main classes of bis-adjacent, bis-nonadjacent, and single-THF ring(s), were tested for their ability to inhibit the growth of adriamycin resistant human mammary adenocarcinoma (MCF-7/Adr) cells. This cell line is resistant to treatment with ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9700169
更新日期：1997-06-20 00:00:00
abstract：:In order to investigate the structural requirements for gastroprotective activity in 6-[[1(S)-(3(S),4-dihydro-8- hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-4(S),5(S)-dihydroxy 6-oxo-3(S)-ammoniohexanoate [AI-77-B, 1], a product of Bacillus pumilus AI-77, nine derivatives were prepared and then tested for...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00364a007
更新日期：1983-10-01 00:00:00
abstract：:A new series of zinc(II) phthalocyanine derivatives have been synthesized and characterized. These macrocycles exhibited a sharp absorption band in the red visible region in DMF, which indicated that they were dissolved well and almost did not aggregate in this solvent. Compared with the unsubstituted zinc(II) phthalo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm400722d
更新日期：2013-07-25 00:00:00
abstract：:A previously outlined general procedure for preparing various 3-substituted cephalosporins from the penicillin nucleus has been used, with modifications where required, to prepare a series of analogues of cephalexin with various substituents in the 3-methyl group. The 3-substituents most conducive to broad-spectrum an...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00218a019
更新日期：1977-08-01 00:00:00
abstract：:The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01681
更新日期：2020-03-12 00:00:00
abstract：:We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pum...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301499r
更新日期：2013-02-28 00:00:00
abstract：:Molecular modeling methods have been used to design a novel series of conformationally constrained cyclic peptide inhibitors of human renin. Three goals were defined: enhanced inhibitory potency, high specificity for renin, and increased metabolic stability. Three cyclic compounds were synthesized with ring sizes 10, ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00397a003
更新日期：1988-02-01 00:00:00
abstract：:HIV-1 replication has been inhibited by using a compound able to target the human cellular cofactor DEAD-box ATPase DDX3, essential for HIV-1 RNA nuclear export. This compound, identified by means of a computational protocol based on pharmacophoric modeling and molecular docking calculations, represents the first smal...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm8008844
更新日期：2008-11-13 00:00:00
abstract：:Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this l...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5013352
更新日期：2015-01-08 00:00:00
abstract：:A novel series of nonsteroidal heterocycles was discovered which display cell-type selective, high-affinity (nanomolar) binding to the progesterone receptors from TE85 osteosarcoma cells but > 1 microM binding affinity to the progesterone receptors from T47D and ZR75 human breast carcinoma cells. Structure-activity re...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00025a004
更新日期：1995-12-08 00:00:00
