Synthesis and Evaluation of Bifunctional Aminothiazoles as Antiretrovirals Targeting the HIV-1 Nucleocapsid Protein.

abstract：:Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound...

journal_title：ACS medicinal chemistry letters

authors： Maurya R,Soni A,Anand D,Ravi M,Raju KS,Taneja I,Naikade NK,Puri SK,Wahajuddin,Kanojiya S,Yadav PP

更新日期：2012-12-11 00:00:00

abstract：:A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racem...

journal_title：ACS medicinal chemistry letters

authors： Bianco G,Meleddu R,Distinto S,Cottiglia F,Gaspari M,Melis C,Corona A,Angius R,Angeli A,Taverna D,Alcaro S,Leitans J,Kazaks A,Tars K,Supuran CT,Maccioni E

更新日期：2017-06-21 00:00:00

abstract：:Two novel benzofuran derivatives coupled with (99m)Tc complexes were tested as probes for imaging cerebral β-amyloid plaques using single photon emission tomography. Although both derivatives bound to Aβ(1-42) aggregates, (99m)Tc-BAT-BF showed higher affinity than (99m)Tc-MAMA-BF. In sections of brain tissue from an a...

journal_title：ACS medicinal chemistry letters

authors： Ono M,Fuchi Y,Fuchigami T,Kobashi N,Kimura H,Haratake M,Saji H,Nakayama M

更新日期：2010-08-02 00:00:00

abstract：:Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysio...

journal_title：ACS medicinal chemistry letters

authors： Liu R,Tzounopoulos T,Wipf P

更新日期：2019-05-08 00:00:00

abstract：:A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interact...

journal_title：ACS medicinal chemistry letters

authors： Millan DS,Kayser-Bricker KJ,Martin MW,Talbot AC,Schiller SER,Herbertz T,Williams GL,Luke GP,Hubbs S,Alvarez Morales MA,Cardillo D,Troccolo P,Mendes RL,McKinnon C

更新日期：2017-07-14 00:00:00

abstract：:Using a multiplexed, reporter gene-based, high-throughput screen, we identified 9-fluoro-7-hydroxy-3-methyl-5-oxo-N-(pyridin-3-ylmethyl)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-6-carboxamide as a TLR2 agonist. Preliminary structure-activity relationship studies on the carboxamide moiety led to the identification o...

journal_title：ACS medicinal chemistry letters

authors： Hu Z,Banothu J,Beesu M,Gustafson CJ,Brush MJH,Trautman KL,Salyer ACD,Pathakumari B,David SA

更新日期：2018-12-20 00:00:00

abstract：:A series of potent and selective β1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; β1/β2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood poo...

journal_title：ACS medicinal chemistry letters

authors： Radeke HS,Purohit A,Harris TD,Hanson K,Jones R,Hu C,Yalamanchili P,Hayes M,Yu M,Guaraldi M,Kagan M,Azure M,Cdebaca M,Robinson S,Casebier D

更新日期：2011-07-22 00:00:00

abstract：:We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in v...

journal_title：ACS medicinal chemistry letters

authors： Chobanian HR,Guo Y,Liu P,Chioda MD,Fung S,Lanza TJ,Chang L,Bakshi RK,Dellureficio JP,Hong Q,McLaughlin M,Belyk KM,Krska SW,Makarewicz AK,Martel EJ,Leone JF,Frey L,Karanam B,Madeira M,Alvaro R,Shuman J,Salituro G

更新日期：2014-04-10 00:00:00

abstract：:SMARTCyp is an in silico method that predicts the sites of cytochrome P450-mediated metabolism of druglike molecules. The method is foremost a reactivity model, and as such, it shows a preference for predicting sites that are metabolized by the cytochrome P450 3A4 isoform. SMARTCyp predicts the site of metabolism dire...

journal_title：ACS medicinal chemistry letters

authors： Rydberg P,Gloriam DE,Zaretzki J,Breneman C,Olsen L

更新日期：2010-03-15 00:00:00

abstract：:A new series of 1,4-naphthoquinones, bearing various cyclic and aliphatic amines on C2, was designed and synthesized to identify antiproliferative agents for triple-negative breast cancer, which represents a clinical challenge without targeted therapies. Among naphthoquinones, 2a and 3a inhibited the proliferation of ...

journal_title：ACS medicinal chemistry letters

authors： Badolato M,Carullo G,Caroleo MC,Cione E,Aiello F,Manetti F

更新日期：2019-02-15 00:00:00

abstract：:The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cel...

journal_title：ACS medicinal chemistry letters

authors： Yu T,Li N,Wu C,Guan A,Li Y,Peng Z,He M,Li J,Gong Z,Huang L,Gao B,Hao D,Sun J,Pan Y,Shen L,Chan C,Lu X,Yuan H,Li Y,Li J,Chen S

更新日期：2018-02-27 00:00:00

abstract：:To search for effective cancer vaccines based on sTn, a sialylated tumor-associated carbohydrate antigen (sialo-TACA) expressed by a number of tumors, four unnatural N-acyl sTn derivatives, including 5'-N-p-methylphenylacetyl sTn (sTnNMePhAc), 5'-N-p-methoxylphenylacetyl sTn (sTnNMeOPhAc), 5'-N-p-acetylphenylacetyl sT...

journal_title：ACS medicinal chemistry letters

authors： Wang Q,Guo Z

更新日期：2011-05-12 00:00:00

abstract：:The design, synthesis, biological evaluation, and X-ray structural studies are reported for a series of highly potent HIV-1 protease inhibitors. The inhibitors incorporated stereochemically defined amide-based bicyclic and tricyclic ether derivatives as the P2 ligands with (R)-hydroxyethylaminesulfonamide transition-s...

journal_title：ACS medicinal chemistry letters

authors： Ghosh AK,Grillo A,Raghavaiah J,Kovela S,Johnson ME,Kneller DW,Wang YF,Hattori SI,Higashi-Kuwata N,Weber IT,Mitsuya H

更新日期：2020-03-03 00:00:00

abstract：:Reactive oxygen species, contributing to oxidant-antioxidant imbalance, initiate damage to the airways cells, inflammatory processes, and further pathophysiological effects. Enhancing antioxidant properties is the main prophylactic and therapeutic challenge. In this work, a newly synthesized and biocompatible structur...

journal_title：ACS medicinal chemistry letters

authors： Wiśniewski M,Bieniek A,Roszek K,Czarnecka J,Bolibok P,Ferrer P,da Silva I,Terzyk AP

更新日期：2018-11-19 00:00:00

abstract：:The effects of opioids in the central nervous system (CNS) provide significant benefit in the treatment of pain but can also lead to physical dependence and addiction, which has contributed to a growing opioid epidemic in the United States. Gastrointestinal dysfunction is an additional serious consequence of opioid us...

journal_title：ACS medicinal chemistry letters

authors： Long DD,Armstrong SR,Beattie DT,Campbell CB,Church TJ,Colson PJ,Dalziel SM,Jacobsen JR,Jiang L,Obedencio GP,Rapta M,Saito D,Stergiades I,Tsuruda PR,Van Dyke PM,Vickery RG

更新日期：2019-11-26 00:00:00

abstract：:Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic act...

journal_title：ACS medicinal chemistry letters

authors： Prosser GA,de Carvalho LP

更新日期：2013-12-12 00:00:00

abstract：:Cellular proteins that fail to fold properly result in inactive or disfunctional proteins that can have toxic functions. The unfolded protein response (UPR) is a two-tiered cellular mechanism initiated by eukaryotic cells that have accumulated misfolded proteins within the endoplasmic reticulum (ER). An adaptive pathw...

journal_title：ACS medicinal chemistry letters

authors： Flaherty DP,Miller JR,Garshott DM,Hedrick M,Gosalia P,Li Y,Milewski M,Sugarman E,Vasile S,Salaniwal S,Su Y,Smith LH,Chung TD,Pinkerton AB,Aubé J,Callaghan MU,Golden JE,Fribley AM,Kaufman RJ

更新日期：2014-10-29 00:00:00

abstract：:Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lea...

journal_title：ACS medicinal chemistry letters

authors： Zou B,Nagle A,Chatterjee AK,Leong SY,Tan LJ,Sim WL,Mishra P,Guntapalli P,Tully DC,Lakshminarayana SB,Lim CS,Tan YC,Abas SN,Bodenreider C,Kuhen KL,Gagaring K,Borboa R,Chang J,Li C,Hollenbeck T,Tuntland T,Zeeman A

更新日期：2014-07-06 00:00:00

abstract：:Two known cleistriosides and six known cleistetrosides were synthesized and evaluated for anticancer and antibacterial activity. This study, for the first time, reports anticancer activity and comprehensively the antibacterial activity for these oligosaccharide natural products. In addition, two new unnatural cleistet...

journal_title：ACS medicinal chemistry letters

authors： Shi P,Silva MC,Wang HY,Wu B,Akhmedov NG,Li M,Beuning PJ,O'Doherty GA

更新日期：2012-12-13 00:00:00

abstract：:Insulin-regulated aminopeptidase (IRAP) is a transmembrane zinc metallopeptidase with many important biological functions and an emerging pharmacological target. Although previous structural studies have given insight on how IRAP recognizes linear peptides, how it recognizes its physiological cyclic ligands remains el...

journal_title：ACS medicinal chemistry letters

authors： Mpakali A,Saridakis E,Giastas P,Maben Z,Stern LJ,Larhed M,Hallberg M,Stratikos E

更新日期：2020-06-02 00:00:00

abstract：:A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitr...

journal_title：ACS medicinal chemistry letters

authors： Tukulula M,Njoroge M,Abay ET,Mugumbate GC,Wiesner L,Taylor D,Gibhard L,Norman J,Swart KJ,Gut J,Rosenthal PJ,Barteau S,Streckfuss J,Kameni-Tcheudji J,Chibale K

更新日期：2013-10-01 00:00:00

abstract：:CREB (cAMP response element binding protein) has been shown to play an important role in tumor initiation, progression, and metastasis. We discovered that naphthol AS-E, a cell-permeable CREB inhibitor, presented antiproliferative activity in a broad panel of cancer cell lines in vitro. However, it has limited aqueous...

journal_title：ACS medicinal chemistry letters

authors： Li BX,Xie F,Fan Q,Barnhart KM,Moore CE,Rheingold AL,Xiao X

更新日期：2014-08-22 00:00:00

abstract：:Acetaminophen (ApAP) is an electron donor capable of reducing radicals generated by redox cycling of hemeproteins. It acts on the prostaglandin H synthases (cyclooxygenases; COXs) to reduce the protoporphyrin radical cation in the peroxidase site of the enzyme, thus preventing the intra-molecular electron transfer tha...

journal_title：ACS medicinal chemistry letters

authors： Shchepin RV,Liu W,Yin H,Zagol-Ikapitte I,Amin T,Jeong BS,Roberts LJ 2nd,Oates JA,Porter NA,Boutaud O

更新日期：2013-08-08 00:00:00

abstract：:A novel series of tricyclic tetrahydroquinolines were identified as potent and selective CRTh2 receptor antagonists. The agonism and antagonism switch was achieved through structure-based drug design (SBDD) using a CRTh2 receptor homologue model. The challenge of very low exposures in pharmacokinetic studies was overc...

journal_title：ACS medicinal chemistry letters

authors： Huang X,Brubaker J,Zhou W,Biju PJ,Xiao L,Shao N,Huang Y,Dong L,Liu Z,Bitar R,Buevich A,Jung J,Peterson SL,Butcher JW,Close J,Martinez M,MacCoss RN,Zhang H,Crawford S,McCormick KD,Aslanian R,Nargund R,Correll C

更新日期：2018-06-23 00:00:00

abstract：:A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed signific...

journal_title：ACS medicinal chemistry letters

authors： Pryde DC,Marron BE,West CW,Reister S,Amato G,Yoger K,Antonio B,Padilla K,Cox PJ,Turner J,Warmus JS,Swain NA,Omoto K,Mahoney JH,Gerlach AC

更新日期：2017-05-18 00:00:00

abstract：:Abdominal pain and abnormal bowel habits represent major symptoms for irritable bowel syndrome (IBS) patients that are not adequately managed. Although the etiology of IBS is not completely understood, many of the functions of the gastrointestinal (GI) tract are regulated by the enteric nervous system (ENS). Inflammat...

journal_title：ACS medicinal chemistry letters

authors： Schenck Eidam H,Russell J,Raha K,DeMartino M,Qin D,Guan HA,Zhang Z,Zhen G,Yu H,Wu C,Pan Y,Joberty G,Zinn N,Laquerre S,Robinson S,White A,Giddings A,Mohammadi E,Greenwood-Van Meerveld B,Oliff A,Kumar S,Cheung M

更新日期：2018-05-24 00:00:00

abstract：:Pyxinol, the main metabolite of 20S-protopanaxadiol in human liver, was chosen as a novel skeleton for the development of anti-inflammatory agents. Pyxinol derivatives modified at C-3, C-12, or C-25 and selected stereoisomers were designed, prepared, and investigated for in vitro anti-inflammatory activities. Structur...

journal_title：ACS medicinal chemistry letters

authors： Sun Y,Fang X,Gao M,Wang C,Gao H,Bi W,Tang H,Cui Y,Zhang L,Fan H,Yu H,Yang G

更新日期：2020-02-12 00:00:00

abstract：:Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Comp...

journal_title：ACS medicinal chemistry letters

authors： Yu M,Wang Y,Zhu J,Bartberger MD,Canon J,Chen A,Chow D,Eksterowicz J,Fox B,Fu J,Gribble M,Huang X,Li Z,Liu JJ,Lo MC,McMinn D,Oliner JD,Osgood T,Rew Y,Saiki AY,Shaffer P,Yan X,Ye Q,Yu D,Zhao X,Zhou J,Ols

更新日期：2014-06-30 00:00:00

abstract：:An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible rein...

journal_title：ACS medicinal chemistry letters

authors： Liégeois JF,Lespagnard M,Meneses Salas E,Mangin F,Scuvée-Moreau J,Dilly S

更新日期：2014-01-29 00:00:00

abstract：:Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2β1 with IC50s in the low nanomolar r...

journal_title：ACS medicinal chemistry letters

authors： Halland N,Blum H,Buning C,Kohlmann M,Lindenschmidt A

更新日期：2014-01-10 00:00:00