16800-67-2Relevant academic research and scientific papers
Orally Effective Aminoalkyl 10H-Indolo[3,2-b]quinoline-11-carboxamide Kills the Malaria Parasite by Inhibiting Host Hemoglobin Uptake
Mudududdla, Ramesh,Mohanakrishnan, Dinesh,Bharate, Sonali S.,Vishwakarma, Ram A.,Sahal, Dinkar,Bharate, Sandip B.
, p. 2581 - 2598 (2018)
A series of indolo[3,2-b]quinoline-C11-carboxamides were synthesized by incorporation of aminoalkyl side chains into the core of indolo[3,2-b]quinoline-C11-carboxylic acid. Their in vitro antiplasmodial evaluation against Plasmodium falciparum led to the identification of a 2-(piperidin-1-yl)ethanamine-linked analogue {2-bromo-N-[2-(piperidin-1-yl)ethyl]-10H-indolo[3,2-b]quinoline-11-carboxamide (3 g)} (IC50=1.3 μm) as the most promising compound exhibiting good selectivity indices against mammalian cell lines. The kill kinetics on erythrocytic-stage parasites revealed that 3 g caused complete killing of only the trophozoite-stage parasites. Mechanistic studies showed that 3 g targets the food vacuole of the parasite and inhibits hemoglobin uptake, β-hematin formation, and the basic endocytic processes of the parasite. Analogue 3 g was found to be orally bioavailable, and its curative antimalarial studies at 50 mg per kg p.o. against a Plasmodium berghei (ANKA)-infected mouse model revealed that mice treated with 3 g showed 27–35 % suppression of parasitemia with an increase in life span relative to untreated, control mice. Thus, the present work demonstrated a proof of concept for the oral efficacy of indolo[3,2-b]quinoline-C11-carboxamides.
Pharmacological evaluation of novel PKR inhibitor indirubin-3-hydrazone in-vitro in cardiac myocytes and in-vivo in wistar rats
Udumula, Mary Priyanka,Bhat, Audesh,Mangali, Sureshbabu,Kalra, Jaspreet,Dhar, Indu,Sriram, Dharamrajan,Dhar, Arti
, p. 85 - 96 (2018)
Aims: Double stranded protein kinase R cellular response is associated with various stress signals such as nutrients, endoplasmic stress, cytokines and mechanical stress. Increased PKR activity has been observed under diabetic and cardiovascular disease conditions. Most of the currently available PKR inhibitors are non-specific and have other effects as well. Thus, the aim of the present study was to examine the effect of novel PKR inhibitor indirubin-3-hydrazone (IHZ) in cultured rat H9C2 cardiomyocytes and wistar rats. Materials and methods: PKR expression was determined by Q-PCR, immunofluorescence and immunoblotting. The expression of different gene markers for apoptosis was measured by RT-PCR. Apoptosis and oxidative stress were determined by flow cytometry. KEY FINDINGS: High glucose (HG) treated H9C2 cardiomyocytes and high fructose (HF) treated wistar rats developed a significant increase in PKR expression. A significant increase in apoptosis and generation of reactive oxygen species was also observed in HG treated H9C2 cells and HF treated rats. Reduced vacuole formation and prominent nuclei were also observed in high glucose treated cells. Cardiac hypertrophy and increased fibrosis were observed in HF treated rats. All these effects of HG and HF were attenuated by novel PKR inhibitor, indirubin-3-hydrazone. Significance: Our results indicate IHZ as an effective inhibitor of PKR in vitro and in-vivo, thus it may prove very useful in blocking the multiple harmful effects of PKR.
A concise synthesis of the DNA-intercalating and antimalarial alkaloid cryptolepine and its fluorescence behaviour in solvents of different polarities
Lai, Tapan Kumar,Chatterjee, Asima,Banerji, Julie,Sarkar, Deboleena,Chattopadhyay, Nitin
, p. 1975 - 1983 (2008)
A microwave-induced rapid and facile synthesis of the DNA-intercalating and antimalarial drug cryptolepine is described. The key step in this synthesis involves the aqueous-phase base-catalyzed condensation of isatin and 1-acetyl-1H-indol-3-yl acetate which has been simplified and expedited by dielectric heating, employing an ordinary domestic microwave oven. The method transforms the synthesis of an important drug molecule from a prohibitively lengthy process to a matter of a few minutes with a much improved yield. Dual absorption and fluorescence is observed from the molecular system in solvents of different polarity thus providing valuable insight into its binding modes toward protein or DNA.
Synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine and its bromo-derivative as dual cholinesterase inhibitors
Nuthakki, Vijay K.,Mudududdla, Ramesh,Sharma, Ankita,Kumar, Ajay,Bharate, Sandip B.
, (2019)
Alkaloids have always been a great source of cholinesterase inhibitors. Numerous studies have shown that inhibiting acetylcholinesterase as well as butyrylcholinetserase is advantageous, and have better chances of success in preclinical/ clinical settings. With the objective to discover dual cholinesterase inhibitors, herein we report synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine (1) and its bromo-derivative 2. Our study has shown that cryptolepine (1) and its 2-bromo-derivative 2 are dual inhibitors of acetylcholinesterase and butyrylcholinesterase, the enzymes which are involved in blocking the process of neurotransmission. Cryptolepine inhibits Electrophorus electricus acetylcholinesterase, recombinant human acetylcholinesterase and equine serum butyrylcholinesterase with IC50 values of 267, 485 and 699 nM, respectively. The 2-bromo-derivative of cryptolepine also showed inhibition of these enzymes, with IC50 values of 415, 868 and 770 nM, respectively. The kinetic studies revealed that cryptolepine inhibits human acetylcholinesterase in a non-competitive manner, with ki value of 0.88 μM. Additionally, these alkaloids were also tested against two other important pathological events of Alzheimer's disease viz. stopping the formation of toxic amyloid-β oligomers (via inhibition of BACE-1), and increasing the amyloid-β clearance (via P-gp induction). Cryptolepine displayed potent P-gp induction activity at 100 nM, in P-gp overexpressing adenocarcinoma LS-180 cells and excellent toxicity window in LS-180 as well as in human neuroblastoma SH-SY5Y cell line. The molecular modeling studies with AChE and BChE have shown that both alkaloids were tightly packed inside the active site gorge (site 1) via multiple π-π and cation-π interactions. Both inhibitors have shown interaction with the allosteric “peripheral anionic site” via hydrophobic interactions. The ADME properties including the BBB permeability were computed for these alkaloids, and were found within the acceptable range.
Construction of Oxepino[3,2-b]indoles via [4+3] Annulation of 2-Ylideneoxindoles with Crotonate-Derived Sulfur Ylides
Fei, Xing-Hai,Guan, Xiang,He, Bin,Li, Zong-Qin,Wang, Da-Peng,Yang, Fen-Fen,Yang, Yuan-Yong,Zhao, Yong-Long,Zhou, Meng
supporting information, p. 3018 - 3024 (2021/06/26)
A [4+3] annulation of 2-ylideneoxindoles with crotonate-derived sulfur ylides has been developed. A series of oxepino[3,2-b]indoles were prepared in moderate to excellent yields (62-93%) under mild conditions. Moreover, the synthetic oxepino[3,2-b] indoles can be further transformed into more complex cyclopropa[5,6]oxepino[3,2-b]indoles via a [2+1] cyclopropanation. In addition, the synthetic compounds show certain antiproliferative activity against K562 and MCF-7 cells, and its IC50 values for these two kinds of tumor cells up to 5.40±0.88 μM and 18.41±0.50 μM, respectively. (Figure presented.).
Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer
An, Jianxiong,Cao, Zhuoxian,Gu, Zhicheng,He, Bin,Li, Yan,Li, Yongjun,Lin, Hening,Lin, Shuxian,Liu, Ting,Wang, Jie,Wang, Pan,Yang, Fenfen,Zhao, Yonglong
, p. 15280 - 15296 (2021/10/25)
To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound 8b can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound 8b showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound 8b as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.
Phenylimino Indolinone: A Green-Light-Responsive T-Type Photoswitch Exhibiting Negative Photochromism
Buma, Wybren Jan,Crespi, Stefano,Di Donato, Mariangela,Doria, Sandra,Feringa, Ben L.,Hilbers, Michiel F.,Kiss, Ferdinand L.,Simeth, Nadja A.,Stindt, Charlotte N.,Szymański, Wiktor,Toyoda, Ryojun,Wesseling, Sammo
supporting information, p. 25290 - 25295 (2021/10/25)
Imines are photoaddressable motifs useful in the development of new generations of molecular switches, but their operation with low-energy photons and control over isomer stability remain challenging. Based on a computational design, we developed phenylimino indolinone (PIO), a green-light-addressable T-type photoswitch showing negative photochromism. The isomerization behavior of this photoactuator of the iminothioindoxyl (ITI) class was studied using time-resolved spectroscopies on time scales from femtoseconds to the steady state and by quantum-chemical analyses. The understanding of the isomerization properties and substituent effects governing these photoswitches opens new avenues for the development of novel T-type visible-light-addressable photoactuators based on C=N bonds.
Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold
Schwertz, Geoffrey,Witschel, Matthias C.,Rottmann, Matthias,Leartsakulpanich, Ubolsree,Chitnumsub, Penchit,Jaruwat, Aritsara,Amornwatcharapong, Watcharee,Ittarat, Wanwipa,Sch?fer, Anja,Aponte, Raphael A.,Trapp, Nils,Chaiyen, Pimchai,Diederich, Fran?ois
supporting information, p. 931 - 943 (2018/04/20)
With the discovery that serine hydroxymethyltransferase (SHMT) is a druggable target for antimalarials, the aim of this study was to design novel inhibitors of this key enzyme in the folate biosynthesis cycle. Herein, 19 novel spirocyclic ligands based on
The "gatekeeper" Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains
Unzue, Andrea,Zhao, Hongtao,Lolli, Graziano,Dong, Jing,Zhu, Jian,Zechner, Melanie,Dolbois, Aymeric,Caflisch, Amedeo,Nevado, Cristina
, p. 3087 - 3097 (2016/05/19)
Small-molecule hits for the bromodomains of CREBBP and BAZ2B have been identified by scaffold hopping followed by docking of a set of ～200 compounds containing the acetyl indole scaffold. Chemical synthesis of nearly 30 derivatives has resulted in ligands of representatives of three subfamilies of human bromodomains with favorable ligand efficiency. The X-ray crystal structures of three different bromodomains (CREBBP, BAZ2B, and BRPF1b) in complex with acetyl indole derivatives reveal the influence of the gatekeeper residue on the orientation of small-molecule ligands in the acetyl lysine binding site.
CYCLIC AMIDE DERIVATIVES AS INHIBITORS OF 11 - BETA - HYDROXYSTEROID DEHYDROGENASE AND USES THEREOF
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Paragraph 0355, (2015/06/17)
The present invention relates to certain amide derivatives that have the ability to inhibit 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and which are therefore useful in the treatment of certain disorders that can be prevented or treated by inhibition of this enzyme. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of conditions such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, impaired fasting glucose, impaired glucose tolerance, lipid disorders such as dyslipidemia, hypertension and as well as other diseases and conditions.
