Shibīn al Kawm, Egypt
Shibīn al Kawm, Egypt

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Lu W.-J.,Okayama University | Wicht K.J.,University of Cape Town | Wang L.,Okayama University | Imai K.,Okayama University | And 7 more authors.
European Journal of Medicinal Chemistry | Year: 2013

This report describes the synthesis, and in vitro and in vivo antimalarial evaluations of certain ester-modified neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) derivatives. The modifications were carried out by introducing ester groups at the C2 and/or C9 position on the neocryptolepine core and the terminal amino group of the 3-aminopropylamine substituents at the C11 position with a urea/thiourea unit. The antiplasmodial activities of our derivative agents against two different strains (CQS: NF54, and CQR: K1) and the cytotoxic activity against normal L6 cells were evaluated. The test results showed that the ester modified neocryptolepine derivatives have higher antiplasmodial activities against both strains and a low cytotoxic activity against normal cells. The best results were achieved by compounds 9c and 12b against the NF54 strain with the IC50/SI value as 2.27 nM/361 and 1.81 nM/321, respectively. While against K1 strain, all the tested compounds showed higher activity than the well-known antimalarial drug chloroquine. Furthermore, the compounds were tested for β-haematin inhibition and 12 were found to be more active than chloroquine (IC50 = 18 μM). Structure activity relationship studies exposed an interesting linear correlation between polar surface area of the molecule and β-haematin inhibition for this series. In vivo testing of compounds 7 and 8a against NF54 strain on Plasmodium berghei female mice showed that the introduction of the ester group increased the antiplasmodial activity of the neocryptolepine core substantially. © 2013 Elsevier Inc. All rights reserved.


Wang N.,Okayama University | Wicht K.J.,University of Cape Town | Wang L.,Okayama University | Lu W.-J.,Okayama University | And 8 more authors.
Chemical and Pharmaceutical Bulletin | Year: 2013

This report describes the synthesis and in vitro anti-malarial evaluations of certain C2 or C8 and C11-disubstituted 6-methyl-5H-indolo[2,3-b]quinoline (neocryptolepine congener) derivatives. To attain higher activities, the structure-activity relationship (SAR) studies were conducted by varying the kind of alkylamino or ω-aminoalkylamino stubstituents at C11 and with Cl at the C2 position, or CO2Me at the C9 position. The anti-malarial activities of the tested compounds were significantly increased compared to the 11-non(alkylamino) derivatives. The 3-aminopropylamino group at C11 was further modified to urea and thiourea, which improved the cytotoxicity against normal cells. The best results were achieved with compounds 8 and 9d against the NF54 strain with the IC50/SI values as of 86 nM/20 and 317 nM/370, respectively. Furthermore, the compounds were tested for β-haematin inhibition. Twelve were found to have IC50 values below 100 μM and a linear correlation between the β-haematin inhibition and cell growth inhibition in the NF54 strain was found for those derivatives with basic amino side chains. A second correlation was identified between the NF54 activity and physico-chemical factors related to solvation and polarity. © 2013 The Pharmaceutical Society of Japan.


Wang N.,Okayama University | Wicht K.J.,University of Cape Town | Shaban E.,Okayama University | Ngoc T.A.,Okayama University | And 10 more authors.
MedChemComm | Year: 2014

Hybrids of artesunate-indolo[2,3-b]quinoline, -indolo[3,2-c]quinoline, and -indolo[3,2-b]quinoline were synthesized and screened for their antiplasmodial activity against two different malaria strains (CQS and CQR) and their cytotoxic activities against normal cells were evaluated. All the synthesized hybrids showed a decreased cytotoxicity and increased antimalarial activity relative to the individual, non-hybridized compounds. Furthermore, these hybrids were stronger β-haematin inhibitors than the corresponding molecules from which they were derived. The most effective antimalarial hybrid showed an IC 50 value of 0.45 nM against the CQS strain. At the same time this hybrid also showed effective activity against the CQR strain, with an IC 50 value of 0.42 nM and an RI value of 0.93. With the dosing of the artesunate-indolo[2,3-b]quinoline set at 10 mg kg-1 once a day for four consecutive days, parasitemia was significantly reduced on day 4, with an antiparasitic activity of 89.6%, and a mean mouse survival time of 7.7 days. © 2014 the Partner Organisations.


Mei Z.-W.,Okayama University | Wang L.,Okayama University | Lu W.-J.,Okayama University | Pang C.-Q.,Okayama University | And 7 more authors.
Journal of Medicinal Chemistry | Year: 2013

To obtain a high antimalarial activity with neocryptolepine derivatives, modifying and changing the side chains at the C11 position with varying the substituents of an electron-withdrawing or electron-donating nature at the C2 position for a SAR study were executed. Installation of alkylamino and ω-aminoalkylamino groups at the C11 position of the neocryptolepine core was successful. For further variation, the aminoalkylamino substituents were transformed into the corresponding acyclic or cyclic carbamides or thiocarbamides. These side chain modified neocryptolepine derivatives were tested for antimalarial activity against CQR (K1) and CQS (NF54) of Plasmodium falciparum in vitro and for cytotoxicity toward mammalian L6 cells. Among the tested compounds, the compound 17f showed an IC50 of 2.2 nM for CQS (NF54) and a selectivity index of 1400, and 17i showed an IC50 of 2.2 nM for CQR (K1), a selectivity index of 1243, and a resistance index of 0.5. © 2013 American Chemical Society.


Shaban E.,Okayama University | Wicht K.J.,University of Cape Town | Wang N.,Okayama University | Mei Z.-W.,Okayama University | And 7 more authors.
Heterocycles | Year: 2014

The synthesis and in vitro antimalarial activity of several neocryptolepine analogues carrying either a linear or branched dibasic side chain at C11 are described. Many of these neocryptolepine analogues have low nanomolar antimalarial activity against the chloroquine-sensitive P. falciparum strain (NF54). The data also demonstrated that a branched structural motif is not superior for antimalarial activity over a linear side chain, but their thioureido derivatives showed lower cytotoxicity than the linear one. Ureido and thioureido derivatives also showed stronger ß-haematin inhibition than the corresponding free amines. © 2014 The Japan Institute of Heterocyclic Chemistry.


Lu W.-J.,Okayama University | Switalska M.,Polish Academy of Sciences | Wang L.,Okayama University | Yonezawa M.,Okayama University | And 4 more authors.
Medicinal Chemistry Research | Year: 2013

The research article describes the effect of an ester group on the in vitro antiproliferative activity in SAR studies of 5-methyl-5H-indolo[2,3-b]quinoline (neocryptolepine) derivatives. The C-2 and/or C-9 ester-substituted neocryptolepines were synthesized starting from indole-3-carboxylates and N-methylanilines, which were bearing an ester group. To these ester-substituted neocryptolepines, various aminoalkylamino substituents were further attached at the C-11, and an in vitro antiproliferative assay was performed by varying the substituents at the C-11 and the position of the ester group in the A and/or D ring of neocryptolepines. Results indicated that the antiproliferative activities of the agents could be improved by introducing an ester substituent at the C-9 position. Among them, the methyl 11-(3-aminopropylamino)-5-methyl-5H- indolo[2,3-b]quinoline-9-carboxylate (8b) was the most potent agent with an IC50 value of 0.044 μM against the human leukemia MV4-11 cell line. The selective cytotoxicity of the agents between the cancer cell lines and normal cell lines were also described. The antiproliferative potency of dimethyl 11-(3-aminopropylamino)-5-methyl-5H-indolo[2,3-b]quinoline-2,9- dicarboxylate (9a) against the human colon cancer cell line HCT116 is 28 times higher than against the normal mice fibroblast cell line BALB/3T3. Graphical Abstract: [Figure not available: see fulltext.] © 2013 Springer Science+Business Media New York.


Wang L.,Okayama University | Switalska M.,Polish Academy of Sciences | Mei Z.-W.,Okayama University | Lu W.-J.,Okayama University | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2012

The present report describes the synthesis and antiproliferative evaluation of certain 11-aminoalkylamino-substituted 5H- and 6H-indolo[2,3-b]quinolines and their methylated derivatives. These 5-Me- and 6-Me-indolo[2,3-b]quinoline derivatives 10-14, 20 were prepared by amination at the C-11 position of the 11-chloro-5-methyl-5H- and 11-chloro-6-methyl-6H-indolo[2,3-b]quinolines with different substituents on the quinoline ring. The 11-aminoalkylaminomethylated 23, the homologue of 11, was prepared from the same intermediate for a further SAR study. These intermediates are accessible from 4-substituted anilines or their N-methylated analogues and methyl indole-3-carboxylate as a counterpart. The in vitro antiproliferative assay indicated that the 5-methylated derivatives 10-14 are more cytotoxic than their respective 6-methylated 6H-indolo[2,3-b]quinoline derivatives 20. Among them, N-(3-aminopropyl)-2-bromo- 5-methyl-5H-indolo[2,3-b]quinolin-11-amine 12f was the most cytotoxic with a mean IC50 value of 0.12 μM against human leukemia MV4-11 cell line, and also exhibited selective cytotoxicities against A549 (lung cancer), HCT116 (colon cancer) cell lines and normal fibroblast BALB/3T3 with IC 50 values of 0.543, 0.274 and 0.869 μM, respectively. The binding constant of products 12f and 20f to salmon fish sperm DNA were also evaluated using UV-vis absorption spectroscopy, indicating intercalation binding with a constant of 2.93 × 105 and 3.28 × 105 L mol-1, respectively. © 2012 Elsevier Ltd. All rights reserved.


Peng W.,Okayama University | Switalska M.,Polish Academy of Sciences | Wang L.,Okayama University | Mei Z.-W.,Okayama University | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2012

To search for new biological activities of the chromeno[2,3-b]indoles, the 5-oxa analog of the indolo[2,3-b]quinolines that are known to have a potent antitumor activity, a series of 11-amino derivatives with various substituents at the C-2 position were prepared. The synthesis of the chromeno[2,3-b]indole structure involves the cyclization of 2-phenoxy-3-indolecarboxylates 3, accessible from the indole-3-carboxylate 1 and phenols 2, producing the chromeno[2,3-b]indol-11(6H)-ones 4, which is followed by dehydroxychlorination with phosphorus oxychloride to afford the 11-chlorochromeno[2,3-b]indoles 5. The treatment of 5 with various amines produced the corresponding 11-aminated chromeno[2,3-b]indoles 6, while some of the 11-ω-aminoalkylamino derivatives 6 were transformed into the 11-ω-sulfonylaminoalkylamino derivatives 8. The antiproliferative activity of these 11-aminochromeno[2,3-b] indoles 6 and 8 in vitro were tested using MV4-11 (human leukemia), A549 (lung cancer), HCT116 (colon cancer), and the normal mice fibroblast (BALB/3T3) and their potencies were described. © 2012 Elsevier Masson SAS. All rights reserved.


El Gokha A.A.,El Menoufeia University | Ali O.M.,El Menoufeia University | Zeid I.F.,El Menoufeia University | Kudoh T.,Okayama University | El-Sayed I.,El Menoufeia University
Phosphorus, Sulfur and Silicon and the Related Elements | Year: 2014

The stereoselective synthesis of a variety of Z-sulfines by the oxidation of organic trithiocarbonates with m-chloroperbenzoic acid (m-CPBA) is described. Transient E-sulfines that are formed upon heating of Z-sulfines during cycloaddition reactions were trapped with 2,3-dimethyl-1,3-butadiene to yield only one of the possible diastereomers of the functionalized cyclic allylic sulfoxides. An X-ray analysis and ab initio calculations were performed to provide insight into the steric course of the oxidation and cycloaddition reactions. [Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional tables and figures.] © 2014 Copyright Taylor and Francis Group, LLC.


El-Sayed I.,El Menoufeia University | Ali O.M.,El Menoufeia University | Hawata M.A.,El Menoufeia University | Hegazey S.A.,El Menoufeia University
Phosphorus, Sulfur and Silicon and the Related Elements | Year: 2010

1,3-Dipolar cycloadditions of the C-sulfonylated- and sulfanylated- dithioformates with mesitonitrile oxide occurred smoothly in organic and aqueous media to afford 1,4,2-oxathiazoles in good yields. The structures of these cycloadducts have been established via the analysis of NMR data and elemental analyses. Copyright © 2010 Taylor & Francis Group, LLC.

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