- Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials
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Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.
- Dodean, Rozalia A.,Kancharla, Papireddy,Li, Yuexin,Melendez, Victor,Read, Lisa,Bane, Charles E.,Vesely, Brian,Kreishman-Deitrick, Mara,Black, Chad,Li, Qigui,Sciotti, Richard J.,Olmeda, Raul,Luong, Thu-Lan,Gaona, Heather,Potter, Brittney,Sousa, Jason,Marcsisin, Sean,Caridha, Diana,Xie, Lisa,Vuong, Chau,Zeng, Qiang,Zhang, Jing,Zhang, Ping,Lin, Hsiuling,Butler, Kirk,Roncal, Norma,Gaynor-Ohnstad, Lacy,Leed, Susan E.,Nolan, Christina,Huezo, Stephanie J.,Rasmussen, Stephanie A.,Stephens, Melissa T.,Tan, John C.,Cooper, Roland A.,Smilkstein, Martin J.,Pou, Sovitj,Winter, Rolf W.,Riscoe, Michael K.,Kelly, Jane X.
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- Multifunctional cholinesterase inhibitors for Alzheimer's disease: Synthesis, biological evaluations, and docking studies of o/p-propoxyphenylsubstituted-1H-benzimidazole derivatives
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This study indicates the synthesis, cholinesterase (ChE) inhibitory activity, and molecular modeling studies of 48 compounds as o- and p-(3-substitutedethoxyphenyl)-1H-benzimidazole derivatives. According to the ChE inhibitor activity results, generally, para series are more active against acetylcholinesterase (AChE) whereas ortho series are more active against butyrylcholinesterase (BuChE). The most active compounds against AChE and BuChE are compounds A12 and B14 with IC50 values of 0.14 and 0.22 μM, respectively. Additionally, the most active 16 compounds against AChE/BuChE were chosen to investigate the neuroprotective effects, and the results indicated that most of the compounds have free radical scavenging properties and show their effects by reducing free radical production; moreover, some of the compounds significantly increased the viability of SH-SY5Y cells exposed to H2O2. Overall, compounds A12 and B14 with potential AChE and BuChE inhibitory activities, high neuroprotection against H2O2-induced toxicity, free radical scavenging properties, and metal chelating abilities may be considered as lead molecules for the development of multi-target-directed ligands against Alzheimer's disease.
- Sar?kaya, G?rkem,?oban, Güne?,Parlar, Sülünay,Tarikogullari, Ayse H.,Armagan, Güliz,Erdo?an, Mümin A.,Alptüzün, Vildan,Alpan, Ay?e S.
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- Design, synthesis and biological evaluation of novel podophyllotoxin derivatives bearing 4β-disulfide/trisulfide bond as cytotoxic agents
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A novel series of C-4β-disulfide/trisulfide-containing podophyllotoxin derivatives were designed, synthesized, and biologically evaluated for their cytotoxic activities against human cancer cell lines, including KB (Mouth Epidermal Carcinoma Cells) and KB/VCR (Vincristine-resistant Mouth Epidermal Carcinoma Cells). Most of these compounds exhibited promising moderate to good cytotoxic activities. In particular, some of them displayed even superior activities to that of etoposide, especially for KB/VCR cell lines, indicating that introduction of the disulfide/trisulfide moiety would be beneficial for overcoming the multi-drug resistant limitation of etoposide. Moreover, the metabolic evaluation of the most promising compound was further performed to reveal that disulfide bond can be stable in human plasma over 8 hours, indicating good potential of these compounds for in vivo anti-cancer activities.
- Zhu, Shi-Jun,Ying, Hua-Zhou,Wu, Yan,Qiu, Ni,Liu, Tao,Yang, Bo,Dong, Xiao-Wu,Hu, Yong-Zhou
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p. 103172 - 103183
(2015/12/23)
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- CRYSTALLINE FORMS OF [3-(4- -PHENOXY)-PROPYL]-DIETHYL-AMINE
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The present invention relates to crystalline forms of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine (“COMPOUND I”) useful in the treatment of RAGE mediated diseases.
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Page/Page column 6
(2008/12/04)
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- 3- Or 4-monosubstituted phenol derivatives useful as H3 ligands
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The invention relates to 3- or 4-monosubstituted phenol derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. Said 3- or 4-monosubstituted phenol derivatives are H3 ligands and are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.
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Page/Page column 36
(2010/02/14)
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- Azulene derivatives
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The invention provides novel azulene derivatives of general formula I wherein R1 to R6 have the significance given in the description, as well as their tautomers, enantiomers, diastereomers, racemates and physiologically compatible salts or esters and substances which are hydrolyzed or metabolized in vivo to compounds of formula I. The invention is also concerned with a process and intermediates for the manufacture of the above compounds, pharmaceutical compositions which contain such compounds as well as the use of these compounds in the treatment of inflammatory conditions.
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- Facile and General Synthesis of 2-, 3-, or 4-pyridines and -piperidines
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Reaction of (dialkylamino)alkyl chloride with picolyllithiums provides the corresponding pyridine derivatives from which the piperidines are obtained by catalytic hydrogenation.Key Words: Pyridines / Piperidines
- Cohen, Victor I.,Jin, Biyun,Reba, Richard C.
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p. 809 - 810
(2007/10/02)
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