共查询到20条相似文献,搜索用时 0 毫秒
1.
Dong Y Tang Y Chollet J Matile H Wittlin S Charman SA Charman WN Tomas JS Scheurer C Snyder C Scorneaux B Bajpai S Alexander SA Wang X Padmanilayam M Cheruku SR Brun R Vennerstrom JL 《Bioorganic & medicinal chemistry》2006,14(18):6368-6382
Based on the structures of several lipophilic trioxolane antimalarial prototypes, we set out to determine which functional groups were associated with good antimalarial profiles and identify more polar (lower LogP/LogD) lead compounds with good physicochemical properties. More lipophilic trioxolanes tended to have better oral activities than their more polar counterparts. Trioxolanes with a wide range of neutral and basic, but not acidic, functional groups had good antimalarial profiles. 相似文献
2.
Yuanqing Tang Sergio Wittlin Susan A. Charman Jacques Chollet Francis C.K. Chiu Julia Morizzi Lisa M. Johnson Josefina Santo Tomas Christian Scheurer Chistopher Snyder Lin Zhou Yuxiang Dong William N. Charman Hugues Matile Heinrich Urwyler Arnulf Dorn Jonathan L. Vennerstrom 《Bioorganic & medicinal chemistry letters》2010,20(2):563-566
Thirty-three N-acyl 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. For these ozonides, weak base functional groups were not required for high antimalarial potency against Plasmodium falciparum in vitro, but were necessary for high antimalarial efficacy in Plasmodium berghei-infected mice. A wide range of Log P/DpH 7.4 values were tolerated, although more lipophilic ozonides tended to be less metabolically stable. 相似文献
3.
Geraniol, an abundantly available naturally occurring allylic alcohol, has been used as a starting material to prepare a series of 6-[alpha-(3'-aryl-3'-hydroxypropyl)vinyl]-1,2,4-trioxanes. Some of these novel trioxanes have shown very promising antimalarial activity against multi-drug resistant Plasmodium yoelii in mice by both intramuscular (im) and oral routes. 相似文献
4.
Sabbani S Stocks PA Ellis GL Davies J Hedenstrom E Ward SA O'Neill PM 《Bioorganic & medicinal chemistry letters》2008,18(21):5804-5808
Dispiro N-Boc-protected 1,2,4-trioxane 2 was synthesised via Mo(acac)(2) catalysed perhydrolysis of N-Boc spirooxirane followed by condensation of the resulting beta-hydroperoxy alcohol 10 with 2-adamantanone. N-Boc 1,2,4-trioxane 2 was converted to the amine 1,2,4-trioxane hydrochloride salt 3 which was subsequently used to prepare derivatives (4-7). Several of these novel 1,2,4-trioxanes had nanomolar antimalarial activity versus the 3D7 strain of Plasmodium falciparum. Amine intermediate 3 represents a versatile derivative for the preparation of achiral arrays of trioxane analogues with antimalarial activity. 相似文献
5.
Kung Ban Sandra Duffy Yelena Khakham Vicky M. Avery Andrew Hughes Oliver Montagnat Kasiram Katneni Eileen Ryan Jonathan B. Baell 《Bioorganic & medicinal chemistry letters》2010,20(20):6024-6029
We report on the discovery of 3-alkylthio-1,2,4-triazine dimers that are potently toxic to Plasmodium falciparum, with single digit nanomolar activity, and up to several thousand-fold lower toxicity to mammalian cells. They are equipotent against chloroquine-resistant strains of P. falciparum. 相似文献
6.
Dong Y McCullough KJ Wittlin S Chollet J Vennerstrom JL 《Bioorganic & medicinal chemistry letters》2010,20(22):6359-6361
An unsaturated dispiro 1,2,4,5-tetraoxane formed by peroxidation of (+)-dihydrocarvone was converted into four structurally diverse derivatives. X-ray crystallographic analysis shows that the structures possess central tetraoxane rings with spiro-2,5-disubstituted cyclohexylidene substituents and 6-membered rings in classical chair conformations. As polarity in the tetraoxane series increased, in vitro potency against Plasmodium falciparum decreased. 相似文献
7.
Using readily available trioxanes 6a-b, a new series of amino functionalized 1,2,4-trioxanes 8a-e and 9a-e have been prepared and evaluated for antimalarial activity against multi-drug resistant Plasmodium yoelii in Swiss mice model. Several of these novel trioxanes are orally more active than the parent trioxanes 6a-b. Antimalarial activity of amino functionalized trioxane 9a, the most potent compound in the series, is very close to that of beta-arteether. 相似文献
8.
Casagrande M Basilico N Parapini S Romeo S Taramelli D Sparatore A 《Bioorganic & medicinal chemistry》2008,16(14):6813-6823
To develop new classes of antimalarial agents, the possibility of replacing the phenolic ring of amodiaquine, tebuquine, and isoquine with other aromatic nuclei was investigated. Within a first set of pyrrole analogues, several compounds displayed high activity against both D10 (CQ-S) and W-2 (CQ-R) strains of Plasmodium falciparum. The isoquine structure was also modified by replacing the diethylamino group with more metabolically stable bicyclic moieties and by replacing the aromatic hydroxyl function with a chlorine atom. Among these compounds, two quinolizidinylmethylamino derivatives (6f and 7f) displayed high activity against both CQ-S and CQ-R strains. 相似文献
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10.
Walsh JJ Coughlan D Heneghan N Gaynor C Bell A 《Bioorganic & medicinal chemistry letters》2007,17(13):3599-3602
Artemisinin was reduced to dihydroartemisinin and coupled to a carboxylic acid derivative of quinine via an ester linkage. This novel hybrid molecule had potent activity against the 3D7 and (drug-resistant) FcB1 strains of Plasmodium falciparum in culture. The activity was superior to that of artemisinin alone, quinine alone, or a 1:1 mixture of artemisinin and quinine. 相似文献
11.
Mithun Rudrapal Dipak Chetia Vineeta Singh 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):1159-1173
Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC50 values of 1.24 µM and 1.24 µM and 1.06 µM and 1.17 µM, against sensitive and resistant strains, respectively. Further, trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, 1,2,4-trioxane derivative(s) reported herein may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria. 相似文献
12.
Tonmunphean S Wijitkosoom A Tantirungrotechai Y 《Bioorganic & medicinal chemistry》2004,12(9):2005-2012
Based on the fact that different isomers may exhibit substantial distinct activities, quantum chemical calculations and automated molecular docking simulations were carried out for 13 dispiro-1,2,4,5-tetraoxane compounds, which experimentally exist as a mixture of several isomers, to elucidate the most probable isomer(s) responsible for their antimalarial activity. The results indicate significant effects of stereoisomer on the binding mode and the activity. Moreover, the antimalarial potency of each compound can be described by the docking results. Compounds 1, 2, 4, 5, 7, and 9 have the most probable isomers coordinate suitably with heme iron and hence they have high activities while the most probable isomer in compounds 3 and 8 could not bind appropriately to heme yielding only moderate activities. On the other hand, the steric hindrance in compounds 11-13 prevents an approach of heme iron to peroxide bonds resulting in a devoid of antimalarial activity. However, compounds 6 and 10 with isopropyl substituents exhibit a different docking character, which is possibly caused by a limitation in molecular flexibility of the available docking technique. Our results can be used as a guideline for stereochemical control in synthesis process to improve drug's potency. 相似文献
13.
A new series of functionalized 1,2,4-trioxanes 10-21 have been prepared and assessed for antimalarial activity in mice. Several of these trioxanes show significant activity. Trioxane 16, the most active compound of the series, has shown activity by oral route which is comparable with that of the clinically used drug, beta-arteether. 相似文献
14.
6-Cycloalkylvinyl substituted 1,2,4-trioxanes 6-15 have been prepared and tested against multi-drug resistant Plasmodium yoelii in mice. The most active trioxane 11 provides 80% protection to the treated mice. Further derivatization of 11 leads to decrease in antimalarial activity. 相似文献
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16.
Ohkanda J Lockman JW Yokoyama K Gelb MH Croft SL Kendrick H Harrell MI Feagin JE Blaskovich MA Sebti SM Hamilton AD 《Bioorganic & medicinal chemistry letters》2001,11(6):761-764
Malaria continues to represent a very serious health problem in the tropics. The current methods of clinical treatment are showing deficiencies due to the increased incidence of resistance in the parasite. In the present paper we report the design, synthesis, and evaluation of potential antimalarial agents against a novel target, protein farnesyltransferase. We show that the most potent compounds are active against Plasmodium falciparum in vitro at submicromolar concentrations. 相似文献
17.
Griesbeck AG El-Idreesy TT Höinck LO Lex J Brun R 《Bioorganic & medicinal chemistry letters》2005,15(3):595-597
A remarkable increase in antimalarial in vitro activity was achieved by integration of spiroadamantane motifs in 6-alkylidene 1,2,4-trioxanes 3a-h via diastereoselective photooxygenation of allylic alcohols and subsequent BF(3)-catalyzed peroxyacetalization with adamantanone to give the active compounds 3e-h. 相似文献
18.
Li Y Yang ZS Zhang H Cao BJ Wang FD Zhang Y Shi YL Yang JD Wu BA 《Bioorganic & medicinal chemistry》2003,11(20):4363-4368
Novel artemisinin derivatives bearing Mannich base group were prepared and tested for their antimalarial activity. These water-soluble artemisinin derivatives were more stable than sodium artesunate and few compounds were found to be more active against Plasmodium berghei in mice than artesunic acid by oral administration. Two most potent derivatives 17b and 17d were examined for their antimalarial activity against Plasmodium knowlesi in rhesus monkeys. 相似文献
19.
Leban J Pegoraro S Dormeyer M Lanzer M Aschenbrenner A Kramer B 《Bioorganic & medicinal chemistry letters》2004,14(8):1979-1982
The high throughput in silico screening of a virtual library into the structure of the P. falciparum lactate dehydrogenase (LDH) with the 4SCan technology yielded a series of biphenyl urea compounds. These were chemically optimized to a new structural class of potent antimalarial agents. The compounds did not inhibit plasmodium LDH enough to fully explain their potency. Therefore we conclude that an unknown mode of action may be the cause of the antimalarial activity. 相似文献
20.
A series of 3-mercapto-1,2,4-triazoles mono or disubstituted at 2-, 3- or 4-positions were synthesized and evaluated as antifungal agents. Many of these derivatives exhibit high activity against Candida albicans and Candida tropicalis. 相似文献