5979-85-1Relevant academic research and scientific papers
Design, Synthesis, and Antifungal Evaluation of Cryptolepine Derivatives against Phytopathogenic Fungi
Chen, Yong-Jia,Liu, Hua,Zhang, Shao-Yong,Li, Hu,Ma, Kun-Yuan,Liu, Ying-Qian,Yin, Xiao-Dan,Zhou, Rui,Yan, Yin-Fang,Wang, Ren-Xuan,He, Ying-Hui,Chu, Qing-Ru,Tang, Chen
, p. 1259 - 1271 (2021)
Inspired by the widely antiphytopathogenic application of diversified derivatives from natural sources, cryptolepine and its derivatives were subsequently designed, synthesized, and evaluated for their antifungal activities against four agriculturally important fungi Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, and Sclerotinia sclerotiorum. The results obtained from in vitro assay indicated that compounds a1-a24 showed great fungicidal property against B. cinerea (EC50 4 μg/mL); especially, a3 presented significantly prominent inhibitory activity with an EC50 of 0.027 μg/mL. In the pursuit of further expanding the antifungal spectrum of cryptolepine, ring-opened compound f1 produced better activity with an EC50 of 3.632 μg/mL against R. solani and an EC50 of 5.599 μg/mL against F. graminearum. Furthermore, a3 was selected to be a candidate to investigate its preliminary antifungal mechanism to B. cinerea, revealing that not only spore germination was effectively inhibited and the normal physiological structure of mycelium was severely undermined but also detrimental reactive oxygen was obviously accumulated and the normal function of the nucleus was fairly disordered. Besides, in vivo curative experiment against B. cinerea found that the therapeutic action of a3 was comparable to that of the positive control azoxystrobin. These results suggested that compound a3 could be regarded as a novel and promising agent against B. cinerea for its valuable potency.
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.
, (2019/06/20)
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.
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 (2018/11/23)
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.
Bis-alkylamine indolo[3,2- B ]quinolines as hemozoin ligands: Implications for antimalarial cytostatic and cytocidal activities
Paulo, Alexandra,Figueiras, Marta,MacHado, Marta,Charneira, Catarina,Lavrado, Jo?o,Santos, Sofia A.,Lopes, Dinora,Gut, Jiri,Rosenthal, Philip J.,Nogueira, Fátima,Moreira, Rui
, p. 3295 - 3313 (2014/05/20)
To get insight into the relevance of targeting hemozoin (Hz) crystals, two isomeric series, N5,N10-bis-alkylamine (2a-k) and N10,O11-bis-alkylamine (3a-k) indolo[3,2-b]quinolines, were evaluated for their in vitro activity against chloroquine (CQ)-resista
Synthesis, G-quadruplex stabilisation, docking studies, and effect on cancer cells of indolo[3,2-b]quinolines with one, two, or three basic side chains
Lavrado, Joao,Borralho, Pedro M.,Ohnmacht, Stephan A.,Castro, Rui E.,Rodrigues, Cecilia M. P.,Moreira, Rui,Dos Santos, Daniel J.V.A.,Neidle, Stephen,Paulo, Alexandra
, p. 1648 - 1661 (2013/10/21)
G-quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal
Incorporation of basic side chains into cryptolepine scaffold: Structure-antimalarial activity relationships and mechanistic studies
Lavrado, Jo?o,Cabal, Ghislain G.,Prudêncio, Miguel,Mota, Maria M.,Gut, Jiri,Rosenthal, Philip J.,Díaz, Cecília,Guedes, Rita C.,Dos Santos, Daniel J. V. A.,Bichenkov?, Elena,Dougla?, Kenneth T.,Moreira, Rui,Paulo, Alexandra
experimental part, p. 734 - 750 (2011/04/15)
The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity when compared with the parent compound. Localization studies inside parasite blood stages by fluorescence microscopy showed that these derivatives accumulate inside the nucleus, indicating that the incorporation of a basic side chain is not sufficient enough to promote selective accumulation in the acidic digestive vacuole of the parasite. Most of the compounds within this series showed the ability to bind to a double-stranded DNA duplex as well to monomeric hematin, suggesting that these are possible targets associated with the observed antimalarial activity. Overall, these novel cryptolepine analogues with substantially improved antiplasmodial activity and selectivity index provide a promising starting point for development of potent and highly selective agents against drug-resistant malaria parasites.
Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds: Synthesis and evaluation against opportunistic fungal pathogens
Boateng, Comfort A.,Eyunni, Suresh V.K.,Zhu, Xue Y.,Etukala, Jagan R.,Bricker, Barbara A.,Ashfaq,Jacob, Melissa R.,Khan, Shabana I.,Walker, Larry A.,Ablordeppey, Seth Y.
experimental part, p. 458 - 470 (2011/02/27)
Substitution around 5-methyl benzothieno[3,2-b]quinolinium (2) ring system was explored in order to identify positions of substitution that could improve its antifungal profile. The 3-methoxy (10b) was active against C. albicans, C. neoformans, and A. fum
Bis-alkylamine quindolone derivatives as new antimalarial leads
Lavrado, Jo?o,Gani, Kaamil,Nobre, Pedro A.,Santos, Sofia A.,Figueiredo, Paula,Lopes, Dinora,Rosário, Virgílio Do,Gut, Jiri,Rosenthal, Philip J.,Moreira, Rui,Paulo, Alexandra
scheme or table, p. 5634 - 5637 (2010/11/17)
Quindolone derivatives, designed to target the malaria parasite digestive vacuole and heme detoxification pathway, have been synthesized by reaction with 2-chloro-N,N-diethylethanamine. This reaction gave N,O-, N,N- and O-alkylated products containing one
Cryptolepine analogues containing basic aminoalkyl side-chains at C-11: Synthesis, antiplasmodial activity, and cytotoxicity
Lavrado, Joao,Paulo, Alexandra,Gut, Jiri,Rosenthal, Philip J.,Moreira, Rui
, p. 1378 - 1381 (2008/12/21)
A series of cryptolepine derivatives has been synthesized through the incorporation of short basic side-chains in the C-11 position of the 10H-indolo[3,2-b]quinoline scaffold. Their antiplasmodial activity was evaluated in vitro against the chloroquine resistant Plasmodium falciparum W2 strain, showing IC50 values between 22 and 184 nM, while their cytotoxicity was assessed using HUVEC cells, revealing three compounds with a selectivity ratio higher than 10. The most selective of these derivatives, 4d, with a selectivity ratio of 46, was also the least cytotoxic of the series.
Antifungal and antiparasitic indoloquinoline derivates
-
Page/Page column 10, (2008/06/13)
A compound having the formula: wherein: R is an electron withdrawing or electron donating moiety; R5 and R10 may be the same or different and are a straight or branched 1-5 carbon or heteroatom chain substituted terminally by a cycloalkyl or aromatic ring, or other structural isomer or complex thereof; n is the position of substitution of R; Z is N—R10, O, S, S═O, CH2 or C═O; y is 1-5 and Q is Z or NH, with the proviso that, where Z is NH, N—CH3, S or O and Rn is H, R5 may not be CH3; as well as quaternary ammonium salts thereof and their use as pharmacological compositions and for methods of treatment.
