Abstract：
:Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention toward that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Rueda-Zubiaurre A,Yahiya S,Fischer OJ,Hu X,Saunders CN,Sharma S,Straschil U,Shen J,Tate EW,Delves MJ,Baum J,Barnard A,Fuchter MJdoi
10.1021/acs.jmedchem.9b00898subject
Has Abstractpub_date
2020-03-12 00:00:00pages
2240-2262issue
5eissn
0022-2623issn
1520-4804journal_volume
63pub_type
杂志文章abstract：:The synthesis and testing of potential multisubstrate inhibitors of tyrosine-specific protein kinases are described. One of the substrates, ATP, was mimicked by the known kinase inhibitor 5'-[4-(fluorosulfonyl)benzoyl]adenosine, which was covalently linked via the sulfonyl moiety to tyrosine mimics. The resulting mult...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00117a015
更新日期：1988-09-01 00:00:00
abstract：:Chemical probes are small molecules designed to bind to a specific protein and disrupt the proteins function. Although many inhibitors are reported for human carbonic anhydrase (CA) enzymes, few may be considered useful as chemical probes as they exhibit broad action against the 12 catalytically active CA isozymes. In...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01228
更新日期：2015-09-24 00:00:00
abstract：:The preparation of stable complexes between the N7-[2-(2-pyridyl)ethyl] and N7-(2-piperazinylethyl) derivatives of mitomycin C and metal ions such as Cu(II), Zn(II), and Pt(II) was accomplished. Mitomycin C did not form stable complexes, but it rearranged to a mitosene capable of complex formation. Some of these compl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00151a023
更新日期：1986-01-01 00:00:00
abstract：:The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200808v
更新日期：2011-10-27 00:00:00
abstract：:Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by inve...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01888
更新日期：2020-09-24 00:00:00
abstract：:The leukotrienes, metabolites of arachidonic acid produced through the action of the enzyme 5-lipoxygenase, are important mediators of immediate hypersensitivity and inflammation. Among the variety of diseases in which the leukotrienes may play a symptomatic or causative role is the dermatological condition psoriasis,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00165a005
更新日期：1990-03-01 00:00:00
abstract：:4-(2-Methoxyphenyl)-2-[4(5)-methyl-5(4)-imidazolylmethyl]thiazole (5) is a highly potent member of a structurally novel series of selective serotonin-3 receptor antagonists. The synthesis of tritiated 5 and its binding profile in neuroblastoma-glioma 108-15 cells are described. Furthermore, in vivo studies in rat with...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00173a017
更新日期：1990-11-01 00:00:00
abstract：:Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which afte...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501573b
更新日期：2015-01-22 00:00:00
abstract：:Dispiro-1,2,4,5-tetraoxanes and 1,2,4-trioxolanes represent attractive classes of synthetic antimalarial peroxides due to their structural simplicity, good stability, and impressive antimalarial activity. We investigated the reactivity of a series of potent amide functionalized tetraoxanes with Fe(II)gluconate, FeSO(4...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm200768h
更新日期：2011-10-13 00:00:00
abstract：:The synthesis and evaluation of a refined series of alpha-ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explore...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800136b
更新日期：2008-08-14 00:00:00
abstract：:A series of 2-substituted methyl 2,3-dihydroimidazo[1, 2-c]quinazolin-5(6H)-ones (4), 3-substituted methyl 2, 3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (5), 3-substituted methyl 2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-ones (15a,b), 3-substituted methyl 2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ones (16a,b), 3-su...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970159v
更新日期：1998-08-13 00:00:00
abstract：:In this article we introduce a molecular docking algorithm called MolDock. MolDock is based on a new heuristic search algorithm that combines differential evolution with a cavity prediction algorithm. The docking scoring function of MolDock is an extension of the piecewise linear potential (PLP) including new hydrogen...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm051197e
更新日期：2006-06-01 00:00:00
abstract：:125I-labeled (E)-18-iodo-17-octadecenoic acid (13) has been prepared and evaluated in rats to determine the myocardial uptake and retention and degree of in vivo deiodination of this model iodovinyl-substituted fatty acid, which contains no structural perturbation to inhibit metabolism. This new agent was prepared by ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00367a021
更新日期：1984-01-01 00:00:00
abstract：:Novel 3,5-bis(benzylidene)-1-[3-(2-hydroxyethylthio)propanoyl]piperidin-4-ones (3a-e) display potent cytotoxicity and a preferential lethality toward various neoplasms compared to some normal cells. The corresponding sulfonic acid analogues 5a-e and an isostere 4 demonstrated substantially lower activity. The leads 3d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101595p
更新日期：2011-05-12 00:00:00
abstract：:Four new 2-(2-piperidinoethyl)benzocycloalkanone derivatives, 20-23, were prepared and evaluated as potential antipsychotic agents in receptor binding assays for dopamine (DA) and 5-HT2A receptors and in functional and behavioral screens. Their affinities for D2 receptors (Ki's in the nanomolar range: 46.7-70.7) and D...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00042a009
更新日期：1994-08-05 00:00:00
abstract：:Phenacyl-riphenylphosphorane (1a) and several analogs substituted in the meta position of the phenacyl group lowered blood glucose levels in 48-hr fasted rats. The corresponding phosphonium salts had comparable hypoglycemic activity. Two compounds (1a and 1b) were also hypoglycemic in fed rats, but hypoglycemia could ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00243a021
更新日期：1975-09-01 00:00:00
abstract：:Imaging serotonin transporters (SERT) is an emerging research tool potentially useful to cast light on the mechanisms of drug action as well as to monitor the treatment of depressed patients. We have prepared two new derivatives of 3, 2-(2-(dimethylaminomethyl)phenoxy)-5-iodophenylamine (4) and 2-(2-(dimethylaminometh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049917p
更新日期：2004-10-07 00:00:00
abstract：:The chemical synthesis of 2-[(2,6-dichloro-4-iodophenyl)imino]imidazolidine (PIC) and its radioiodinated analogue [125I]PIC is described. PIC was synthesized from 2,6-dichloroaniline in five synthetic steps. This agent displayed a high affinity for the alpha 2-adrenergic receptor (IC50 = 1.5 nM) in competitive binding...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00390a021
更新日期：1987-07-01 00:00:00
abstract：:Collective experience in structure-based lead progression has found electrostatic interactions to be more difficult to optimize than shape-based ones. A major reason for this is that the net electrostatic contribution observed includes a significant nonintuitive desolvation component in addition to the more intuitive ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm051105l
更新日期：2006-04-20 00:00:00
abstract：:Three phosphapeptides designed to mimic two distinct tetrahedral intermediates formed during either the synthesis or hydrolysis of glutathionylspermidine (Gsp) were synthesized and evaluated as inhibitors of the bifunctional enzyme Gsp synthetase/amidase. While the polyamine-containing phosphapeptides were determined ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm970414b
更新日期：1997-11-07 00:00:00
abstract：:In pursuit of truncated glucagon analogues that can interact with the glucagon receptor with substantial binding affinity, 23 truncated glucagon analogues have been designed and synthesized. These truncated analogues consist of several fragments of glucagon with 11 or 12 amino acid residues (1-4), conformationally con...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000453e
更新日期：2001-04-26 00:00:00
abstract：:Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9706933
更新日期：1998-03-26 00:00:00
abstract：:N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations w...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm058261c
更新日期：2005-12-29 00:00:00
abstract：:We previously reported a novel class of stabilized immune-modulatory RNA (SIMRA) compounds that activates TLR8 or both TLR7 and TLR8 depending on the nucleotide composition and chemical modifications incorporated. In the present study, to identify TLR7-selective agonists, we designed and synthesized novel SIMRA compou...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901145s
更新日期：2009-11-12 00:00:00
abstract：:A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade of capsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of the structure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elements required...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070190p
更新日期：2007-07-26 00:00:00
abstract：:PABA/NO is a diazeniumdiolate of structure Me(2)NN(O)=NOAr (where Ar is a 5-substituted-2,4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in wate...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050700k
更新日期：2006-02-09 00:00:00
abstract：:The discovery of a new zinc binding chemotype from screening a nonbiased fragment library is reported. Using the orthogonal fragment screening methods of native state mass spectrometry and surface plasmon resonance a 3-unsubstituted 2,4-oxazolidinedione fragment was found to have low micromolar binding affinity to the...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00606
更新日期：2017-09-14 00:00:00
abstract：:The synthesis and biological activity of a novel cyclic beta-sheet-type antimicrobial dehydropeptide based on gramicidin S (GS) is described. The GS analogue, containing two (Z)-(beta-3-pyridyl)-alpha,beta-dehydroalanine (DeltaZ3Pal) residues at the 4 and 4' positions (2), was synthesized by solution-phase methodologi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm061051v
更新日期：2006-12-28 00:00:00
abstract：:Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially use...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5014055
更新日期：2015-01-08 00:00:00
abstract：:A number of analogues of thapsigargin have been synthesized by alkylating or acylating O-11 and O-12 in the lactol obtained by reducing thapsigargicin. Introduction of alpha-disposed substituents decreased the Ca(2+)-ATPase inhibitory potency of the analogue, whereas the enzyme was more tolerant toward beta-disposed s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00002a009
更新日期：1995-01-20 00:00:00
